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Introduction and aimsDietary polyphenols have long been associated with health benefits, including the prevention of obesity and related chronic diseases. Overfeeding was shown to rapidly induce weight gain and fat mass, associated with mild insulin resistance in humans, and thus represents a suitable model of the metabolic complications resulting from obesity. We studied the effects of a polyphenol-rich grape extract supplementation on the plasma metabolome during an overfeeding intervention in adults, in two randomized parallel controlled clinical trials.MethodsBlood plasma samples from 40 normal weight to overweight male adults, submitted to a 31-day overfeeding (additional 50% of energy requirement by a high calorie-high fructose diet), given either 2 g/day grape polyphenol extract or a placebo at 0, 15, 21, and 31 days were analyzed (Lyon study). Samples from a similarly designed trial on females (20 subjects) were collected in parallel (Lausanne study). Nuclear magnetic resonance (NMR)-based metabolomics was conducted to characterize metabolome changes induced by overfeeding and associated effects from polyphenol supplementation. The clinical trials are registered under the numbers NCT02145780 and NCT02225457 at ClinicalTrials.gov.ResultsChanges in plasma levels of many metabolic markers, including branched chain amino acids (BCAA), ketone bodies and glucose in both placebo as well as upon polyphenol intervention were identified in the Lyon study. Polyphenol supplementation counterbalanced levels of BCAA found to be induced by overfeeding. These results were further corroborated in the Lausanne female study.ConclusionAdministration of grape polyphenol-rich extract over 1 month period was associated with a protective metabolic effect against overfeeding in adults.

El bebé nace con un sistema nervioso por hacer; pero con un dispositivo básico cuya finalidad es vincularse al adulto encargado de cuidarlo, y aprovechar la interacción con él para ir integrando su funcionamiento, de modo que todos sus componentes participen cuando conviene, según las demandas del entorno, regulando el ánimo, la conducta y la actividad de los sistemas corporales de un modo que garantice una buena adaptación y un estado saludable. La proliferación de las prolongaciones neuronales que construirá las redes que hacen funcionar el cerebro se produce de un modo automático, gracias a un programa genético; pero la poda de esas conexiones, destinada a incrementar su eficiencia, no es algo tan espontáneo; depende mucho más de las experiencias ambientales, entre las que tienen una importancia capital las relaciones interpersonales. Cuando las interacciones con los demás proporcionan experiencias de seguridad y unos estados emocionales regulados, las redes neurales van adquiriendo un funcionamiento integrado, en el que cada área y núcleo cerebral contribuye al mantenimiento de un estado físico y psíquico saludable. Por el contrario, cuando los niños y niñas viven experiencias de abandono o negligencia, o bien sufren interacciones marcadas por el abuso emocional, físico o sexual, se producen alteraciones del neurodesarrollo que reducirán las posibilidades de que el sistema nervioso logre un funcionamiento integrado. Todas las formas de maltrato hacen que algunas áreas del cerebro no logren completar su desarrollo, o pierdan capacidad para conectarse con el resto; mientras que otras aumentan tanto su protagonismo y sus conexiones, que tienden a dominar la actividad neural haciendo que gobiernen el funcionamiento mental. El maltrato y la negligencia producen de este modo problemas para mantener un funcionamiento integrado del sistema nervioso; y esta falta de integración acabará perjudicando de por vida la salud mental y física de quien los ha sufrido.

Background and aim Extracellular matrix (ECM) components released during excessive fat mass expansion are considered potential endogenous danger/alarm signals contributing to innate immune system activation. The aim of the current study was to specifically measure plasma levels of low molecular weight (LMW) hyaluronan (HA) and to evaluate its role as pro-inflammatory damage-associated molecular pattern (DAMP) on leukocyte response in the context of human obesity. Subjects and methods Participants were selected according to their body mass index (BMI, kg/m2) as non-obese (BMI n = 18) and obese (BMI > 29.9, n = 33). Plasma samples were size-dependent fractionated using ion-exchange chromatography to specifically obtain LMW HA fractions that were subsequently quantified by ELISA. Cell incubation experiments with synthetic HA molecules were performed on freshly Ficoll-isolated neutrophils (PMN) and peripheral blood monocytes (PBMC). Leukocyte and adipose tissue gene expression was assessed by real-time PCR and NF-κB activation by western blot. Plasma cytokine levels were measured by fluorescent bead-based (Luminex) immunoassay. Results We observed a statistically significant increase in the circulating levels of HA fragments of LMW in individuals with obesity which were consistent with significant up-regulated expression of the LMW HA synthesizing enzyme hyaluronan synthase-1 (HAS-1) in obese adipose tissue. Gene expression assessment of HA receptors revealed up-regulated levels for TLR2 in both obese PMN and PBMC. Synthetic HA molecules of different sizes were tested on leukocytes from healthy donors. LMW HA fragments (15–40 kDa) and not those from intermediate molecular sizes (75–350 kDa) induced a significant up-regulation of the expression of major pro-inflammatory cytokines such as IL-1β, MCP-1 and IL-8 in PBMC. Importantly, LMW HA was able to induce the phosphorylation of IKK α/β complex supporting its pro-inflammatory role through NF-κB activation. Conclusion Circulating LMW HA molecules are elevated in obesity and may play an important role in triggering low-grade inflammation and the development of metabolic complications.

Treballs Finals de Grau de Nutrició Humana i Dietètica, Facultat de Farmàcia i Ciències de l'Alimentació, Campus de l'Alimentació de Torribera, Universitat de Barcelona. Curs: 2022-2023. Tutor: Carme Caelles Franch, [eng] Obesity-associated insulin resistance and hyperinsulinemia are two interrelated health conditions that have become increasingly prevalent in recent years. For many years, it has been thought that hyperinsulinemia comes after insulin resistance. The truth is that recent data suggests that insulin resistance can follow hyperinsulinemia and vice versa. Obesity is commonly associated with insulin resistance and hyperinsulinemia, but although some molecular mechanisms have been proposed, there is no clear evidence as to which condition occur before in humans. Despite much controversy over the timing of the onset of hyperinsulinemia in obesity, it is well established that the presence of insulin is necessary for obesity to occur and that chronically elevated insulin levels enhance diet-induced obesity. Therefore, the aim of this review is to provide a comprehensive up-to-date on the molecular mechanisms underlying hyperinsulinemia and the relationship between hyperinsulinemia and insulin resistance in obesity. In addition, we will examine the role hyperinsulinemia plays in cellular senescence, cancer and in dysregulating the insulin/IGF-1/GH axis. Finally, we will discuss possible current therapeutic strategies targeting hyperinsulinemia that are being used to treat obesity-associated insulin resistance, including current pharmacological therapies, the effects of multiple dietary interventions, physical exercise, and surgery. We conclude that hyperinsulinemia is a prevalent condition in obesity, but its time of occurrence and relationship with obesity are still under investigation. Dietary interventions, particularly low glycemic load diets and low carbohydrate diets, as well as regular exercise have shown promise in reducing hyperinsulinemia, while the long-term efficacy and potential side effects of pharmacological interventions require further study., [cat] L'obesitat associada a la resistència a la insulina i la hiperinsulinemia són dues condicions de salut interrelacionades que han esdevingut cada vegada més prevalents en els últims anys. Durant molts anys, s'ha pensat que la hiperinsulinèmia ve després de la resistència a la insulina. La veritat és que les dades recents suggereixen que la resistència a la insulina pot seguir la hiperinsulinèmia i viceversa. L'obesitat s'associa comunament amb la resistència a la insulina i la hiperinsulinèmia, però tot i que s'han proposat alguns mecanismes moleculars, no hi ha evidència clara de quina condició ocorre abans en els éssers humans. Malgrat molta controvèrsia sobre el moment de l'aparició de la hiperinsulinèmia en l'obesitat, està ben establert que la presència d'insulina és necessària perquè es produeixi l'obesitat i que els nivells d'insulina crònicament elevats promouen l'obesitat induïda per la dieta. Per tant, l'objectiu d'aquesta revisió és proporcionar una actualització completa dels mecanismes moleculars subjacents a la hiperinsulinèmia i la relació entre la hiperinsulinèmia i la resistència a la insulina en l’obesitat. A més a més, examinarem el paper de la hiperinsulinèmia en la senescència cel·lular, el càncer i en la desregulació de l'eix insulina/IGF-1/GH. Finalment, es discutiran possibles estratègies terapèutiques actuals dirigides a la hiperinsulinemia que s'estan utilitzant per tractar l'obesitat associada a la resistència a la insulina, incloent les teràpies farmacològiques actuals, els efectes de múltiples intervencions dietètiques, l'exercici físic i la cirurgia. Concloem que la hiperinsulinèmia és una condició prevalent en l'obesitat, però el seu inici i relació amb l'obesitat encara estan en investigació. Les intervencions dietètiques, en particular les dietes de baixa càrrega glucèmica i dietes baixes en carbohidrats, a més de l'exercici regular, han demostrat ser prometedores per reduir la hiperinsulinèmia, mentre que l'eficàcia a llarg termini i els possibles efectes secundaris de les intervencions farmacològiques requereixen un estudi addicional.

Obesity and its associated metabolic comorbidities are a rising global health and social issue, with novel therapeutic approaches urgently needed. Adipose tissue plays a key role in the regulation of energy balance and adipose tissue-derived mesenchymal stem cells (AT-MSCs) have gained great interest in cell therapy. Carnitine palmitoyltransferase 1A (CPT1A) is the gatekeeper enzyme for mitochondrial fatty acid oxidation. Here, we aimed to generate adipocytes expressing a constitutively active CPT1A form (CPT1AM) that can improve the obese phenotype in mice after their implantation. AT-MSCs were differentiated into mature adipocytes, subjected to lentivirus-mediated expression of CPT1AM or the GFP control, and subcutaneously implanted into mice fed a high-fat diet (HFD). CPT1AM-implanted mice showed lower body weight, hepatic steatosis and serum insulin and cholesterol levels alongside improved glucose tolerance. HFD-induced increases in adipose tissue hypertrophy, fibrosis, inflammation, endoplasmic reticulum stress and apoptosis were reduced in CPT1AM-implanted mice. In addition, the expression of mitochondrial respiratory chain complexes was enhanced in the adipose tissue of CPT1AM-implanted mice. Our results demonstrate that implantation of CPT1AM-expressing AT-MSC-derived adipocytes into HFD-fed mice improves the obese metabolic phenotype, supporting the future clinical use of this ex vivo gene therapy approach. info:eu-repo/semantics/publishedVersion

[cat] Els receptors acoblats a proteïna G o GPCR conformen la major superfamília de proteïnes de membrana cel·lular en organismes eucariotes. De fet, en humans s'han descrit més de 800 tipus de GPCR diferents que suposen al voltant d'un 5% del total del genoma humà. En l'actualitat, ostenten una gran rellevància terapèutica, ja que més del 30% dels fàrmacs aprovats per la FDA (Food and Drug Administration) tenen com a diana terapèutica un d'aquests receptors. Per aquest motiu, els GPCR presenten un gran potencial per a la recerca biomèdica. A més, aquests receptors són capaços d'interaccionar específicament entre ells, originant noves unitats funcionals amb propietats diferents a les que presenten els receptors individualment. En aquest sentit, el procés d'heteromerització entre GPCR és una estratègia puntera pel descobriment de noves dianes terapèutiques per tal de fer front a diverses patologies altament esteses en la nostra societat tals com les malalties neurodegeneratives o l'obesitat. L'objectiu principal d'aquesta Tesi Doctoral ha estat estudiar la possible interacció molecular entre diversos receptors acoblats a proteïna G. En primer lloc, s'ha estudiat la interacció dels receptors cannabinoides CB1 i CB2 amb el receptor de grelina GHS-R1a, per tal d'explicar un dels mecanismes d'acció a través del qual els cannabinoides són capaços de modular processos fisiològics com la sensació de gana i el control del pes corporal. També s'ha valorat l'expressió dels heteròmers CB1R-GHS-R1a i CB2R-GHS-R1a en ratolins alimentats amb una dieta hipercalòrica com a model animal d'obesitat. Els resultats d'aquesta Tesi Doctoral ens demostren que els receptors cannabinoides CB1 i CB2 són capaços d'interaccionar amb el receptor de grelina GHS-R1a i, en ambdós contextos heteromèrics, trobem un bloqueig de la senyalització Gi cannabinoide. A més, s'ha demostrat una sobreexpressió dels heteròmers CB1R-GHS-R1a i CB2R-GHS-R1a en episodis d'obesitat. A més, s'ha caracteritzat l'agonisme esbiaixat de diverses formes àcides i varíniques dels fitocannabinoides CBD, CBG i Δ9-THC al interaccionar amb els receptors CB1, CB2 i amb l'heteròmer CB1R-CB2R. El segon gran objectiu d'aquesta Tesi Doctoral ha consistit en valorar la possible interacció entre els receptors d'adenosina A2A i A3 i determinar la seva implicació en malalties neurodegeneratives, emprant ratolins APPSw,Ind com a model animal d'Alzheimer i ratolins tractats amb cuprizona com a model animal d'Esclerosi Múltiple. La funcionalitat característica dels nous heteròmers descrits en aquest estudi s'ha determinat mitjançant l'anàlisi de diverses vies de senyalització com són l'acumulació d'AMPc intracel·lular, la mobilització del Ca2+, la fosforilació de les MAPK, el reclutament de ß-arrestines i la redistribució dinàmica de masses. El segon gran bloc de resultats d'aquesta Tesi Doctoral demostra que els receptors d'adenosina A2A i A3 són capaços d'interaccionar formant una nova unitat funcional que resulta en un bloqueig de la senyalització Gi del receptor A3. Paral·lelament, s'ha determinat una sobreexpressió dels heteròmers A2AR-A3R en malalties neurodegeneratives tals com l'Alzheimer i l'Esclerosi Múltiple. Per tant, els heteròmers A2AR-A3R es postulen com a grans dianes terapèutiques per combatre aquest tipus de patologies fent ús, per exemple, d'antagonistes del receptor A2A que bloquegin el caràcter pro-inflamatori d'aquest receptor mentre potencien el caràcter anti-inflamatori del receptor A3., [eng] G protein coupled receptors or GPCRs are the largest superfamily of cell membrane proteins in eukaryotic organisms. In fact, more than 800 different types of GPCRs have been described in humans, accounting for about 5% of the total human genome. Currently, they are considered of great therapeutic relevance because more than 30% of FDA-approved drugs have one of these receptors as a therapeutic target. For this reason, GPCRs have great potential in biomedical research. Moreover, these receptors can specifically interact with each other, giving rise to new functional units with different properties from those of the individual receptors. Therefore, the process of heteromerization between GPCRs is a novel strategy for the discovery of new therapeutic targets to combat different pathologies that are highly prevalent in our society, such as neurodegenerative diseases and obesity. The main objective of this PhD Thesis has been to study the possible molecular interactions between different types of G protein coupled receptors. Firstly, the possible interaction of the cannabinoid receptors CB1 and CB2 with the ghrelin receptor GHS-R1a has been analyzed in order to explain one of the mechanisms of action through which cannabinoids are able to modulate physiological processes such as the food intake and the control of body weight. In addition, the expression of CB1R-GHS-R1a and CB2R-GHS- R1a heteromers has been assessed in mice fed with a high-fat diet as an animal model of obesity. The results of this PhD Thesis demonstrate that the cannabinoid receptors CB1 and CB2 are able to interact with the ghrelin receptor GHS-R1a and, in both heteromeric contexts, the interaction results in a blockade of Gi cannabinoid signaling. Furthermore, overexpression of CB1R-GHS-R1a and CB2R-GHS-R1a heteromers has been demonstrated in episodes of obesity. Moreover, the biased agonism of different acidic and varinic forms of the phytocannabinoids CBD, CBG and Δ9-THC has been characterized when interacting with CB1R, CB2R and the CB1R-CB2R heteromer. Next, the second major objective of this PhD Thesis has been to assess the possible interaction between adenosine A2A and A3 receptors and to determine their physiological role in neurodegenerative diseases, using APPSw,Ind mice as an animal model of Alzheimer's disease and cuprizone treated mice as an animal model of Multiple Sclerosis. The characteristic functionality of the new heteromers described in this study has been determined by analyzing several signaling pathways such as intracellular cAMP accumulation, Ca2+ mobilization, ERK1/2 phosphorylation, ß-arrestin recruitment and dynamic mass redistribution. Finally, the second major block of results of this PhD Thesis demonstrates that the A2A and A3 adenosine receptors are able to interact forming a new functional unit that results in a blockade of the Gi signaling of the A3 receptor. In parallel, overexpression of A2AR-A3R heteromers has been found in animal models of neurodegenerative diseases such as Alzheimer's disease and Multiple Sclerosis. Therefore, A2AR-A3R heteromers are postulated as novel therapeutic targets to combat this type of pathologies, using A2A receptor antagonists in order to block the pro- inflammatory character of this receptor while potentiating the anti-inflammatory character of the A3 receptor.

Obesity is a preventable risk factor for cerebrovascular disorders and it is associated with cerebral grey and white matter changes. Specifically, individuals with obesity show diminished grey matter volume and thickness, which seems to be more prominent among fronto-temporal regions in the brain. At the same time, obesity is associated with lower microstructural white matter integrity, and it has been found to precede increases in white matter hyperintensity load. To date, however, it is unclear whether these findings can be attributed solely to obesity or whether they are a consequence of cardiometabolic complications that often co-exist with obesity, such as low-grade systemic inflammation, hypertension, insulin resistance, or dyslipidemia. In this narrative review we aim to provide a comprehensive overview of the potential impact of obesity and a number of its cardiometabolic consequences on brain integrity, both separately and in synergy with each other. We also identify current gaps in knowledge and outline recommendations for future research.

ObjectiveTo compare administration of the glucagon-like peptide-1 (GLP-1) analogue, exenatide, versus dietary supplementation with the omega-3 fatty acid-rich Calanus oil on obesity-induced alterations in mitochondrial respiration.MethodsSix-week-old female C57BL/6JOlaHSD mice were given high fat diet (HFD, 45% energy from fat) for 12 weeks to induce obesity. Thereafter, they were divided in three groups where one received exenatide (10 μg/kg/day) via subcutaneously implanted mini-osmotic pumps, a second group received 2% Calanus oil as dietary supplement, while the third group received HFD without any treatment. Animals were sacrificed after 8 weeks of treatment and tissues (skeletal muscle, liver, and white adipose tissue) were collected for measurement of mitochondrial respiratory activity by high-resolution respirometry, using an Oroboros Oxygraph-2k (Oroboros instruments, Innsbruck, Austria).ResultsIt was found that high-fat feeding led to a marked reduction of mitochondrial respiration in adipose tissue during all three states investigated – LEAK, OXPHOS and ETS. This response was to some extent attenuated by exenatide treatment, but not with Calanus oil treatment. High-fat feeding had no major effect on hepatic mitochondrial respiration, but exenatide treatment resulted in a significant increase in the various respiratory states in liver. Mitochondrial respiration in skeletal muscle was not significantly influenced by high-fat diet or any of the treatments. The precise evaluation of mitochondrial respiration considering absolute oxygen flux and ratios to assess flux control efficiency avoided misinterpretation of the results.ConclusionsExenatide increased hepatic mitochondrial respiration in high-fat fed mice, but no clear beneficial effect was observed in skeletal muscle or fat tissue. Calanus oil did not negatively affect respiratory activity in these tissues, which maintains its potential as a dietary supplement, due to its previously reported benefits on cardiac function

[spa] INTRODUCCIÓN: La obesidad durante el embarazo es un problema de salud pública en nuestra sociedad. Las gestantes con obesidad y ganancia excesiva de peso gestacional tienen mayor riesgo de presentar complicaciones maternas y perinatales. El uso de Apps móviles y pulsera durante el embarazo puede contribuir a promover estilos de vida saludables y, por tanto, mejorar la salud materna y neonatal. OBJETIVOS: Evaluar la efectividad de una intervención digital compleja, en gestantes con obesidad, con el uso de una pulsera de actividad física y la provisión de consejos de salud y soporte virtual de una matrona a través de una APP, respecto a la ganancia ponderal gestacional, la actividad física, los hábitos alimentarios; así como analizar su impacto en los resultados maternos y perinatales. Además, se estudió la frecuencia de uso, la usabilidad y la satisfacción con las Apps móviles utilizadas por las mujeres del grupo de intervención. MÉTODOS: Se realizó un ensayo clínico paralelo aleatorizado con dos brazos 1:1 con grupo intervención (GI) y grupo control (GC). Se incluyeron 150 gestantes con obesidad preconcepcional. El grupo de intervención recibió una intervención digital compleja “Pas & Pes” que consistía en el uso de una pulsera de actividad (Mi band 2© y Mi Fit©) y la recepción de consejos de salud mediante una App, y el soporte virtual de una matrona (Hangouts©), además del control prenatal habitual. El grupo control recibió solo el control prenatal habitual. Se utilizaron las versiones validadas en español del “International Physical Activity Questionnaire Short Form”, la “System Usability Scale” y el “Cuestionario de hábitos alimentarios para pacientes con sobrepeso y obesidad”. La satisfacción se midió en una escala tipo Likert de 1 a 5 puntos. Las pruebas estadísticas fueron bilaterales y se evaluaron a un nivel α de 0,05. Los análisis se realizaron con SPSS v. 25 y SAS v. 9,4. RESULTADOS: Se analizaron un total de 137 gestantes (91,3% del total). La ganancia ponderal gestacional mediana en el grupo de intervención fue de 7,0 kg (Q1=3,8-Q3=11) frente a 9,5 kg (Q1=6-Q3=14) en el grupo control, (p=0,014). La ganancia ponderal gestacional media ajustada por semana fue de 0,5 kg/semana [intervalo de confianza (IC) del 95 %=-0,2 a -0,05] en el grupo de control y de 0,3 kg/semana (IC 95 %=0,2 a 0,4) en el grupo intervención (p=0,002). En el tiempo 1 (35-37 semanas de gestación), las mujeres del grupo de intervención tuvieron una mediana más alta de actividad física que las mujeres del grupo de control, 1.950 frente a 1.386 múltiplo de la tasa de gasto metabólico-min/semana (MET-min/sem) (p=0,007), respectivamente. En el grupo intervención la puntuación media de los hábitos alimentarios fue mayor que en el grupo control [(3,51 ± 0,37) versus (3,33 ± 0,40) puntos; (p=0,009)]. No se observaron diferencias entre los grupos de estudio en la incidencia de resultados maternos y perinatales. Respecto a la intervención digital, el 61% (36) de las gestantes utilizó la pulsera de actividad a diario y la usabilidad de la App Mi Fit© fue valorada como excelente por el 74,6% (44). Todas las mujeres del grupo de intervención utilizaban la aplicación Hangouts© al menos una vez a la semana. La media de la escala de satisfacción con la App de consejos de salud y el apoyo de la matrona virtual fue de 4,8 ± 0,6 sobre 5 puntos. CONCLUSIONES: El uso de una intervención digital compleja mostró ser efectiva en una menor ganancia ponderal gestacional, en un aumento de la actividad física y en la mejora de los hábitos alimentarios. No se hallaron diferencias en las complicaciones perinatales maternas entre ambos grupos. La satisfacción con la intervención y la usabilidad de la App fue muy elevada., [eng] BACKGROUND: Obesity during pregnancy is a public health problem in our society. Pregnant women with obesity and excessive gestational weight gain (GWG) present a higher risk of maternal and perinatal complications. The use of mobile Apps and a wristband during pregnancy may contribute to promoting healthy lifestyles and, thus, improving maternal and neonatal health. OBJECTIVE: To evaluate the effectiveness of a complex digital intervention, using a smartband and an App for health advice with virtual midwife’ counselling, on gestational weight gain, physical activity and eating habits. The secondary objectives are to assess the impact of these interventions on maternal and perinatal outcomes and identify the frequency of use, usability and satisfaction with the mobile Apps used by the women in the intervention group. METHODS: A randomized parallel clinical trial with two arms in a 1:1 ratio with intervention group (IG) and control group (CG) was conducted. 150 pregnant women with pre-pregnancy obesity were included. The intervention group received a complex digital intervention called Pas & Pes. The intervention was delivered with a smartband (Mi band 2© and Mi Fit©) linked to an App with the virtual midwife to provide personal health information (Hangouts©), and also the standard prenatal care. The control group only received standard control prenatal care. The validated Spanish versions of the International Physical Activity Questionnaire Short Form, the System Usability Scale and the Questionnaire of eating habits for patients with overweight and obesity were used. Satisfaction was measured on a 1-5 points Likert scale. Statistical tests were two-sided and evaluated at an α level of 0.05. Analyzes were performed using SPSS v. 25 and SAS v. 9.4. RESULTS: 137 (91.3% of the total) women were analyzed. The mean gestational weight gain in the intervention group was 7.0 kg (Q1=3.8-Q3=11) versus 9.5 kg (Q1=6-Q3=14) in the control group, p=0.014. The adjusted mean gestational weight gain per week was 0.5 kg/week (95% confidence interval [CI]=-0.2 to -0.05) in the control group and 0.3 kg/week (95% CI=0.2 to 0.4) in the intervention group (p= 0.002). In time 1 (35-37 gestational weeks), women in the intervention group had a higher mean physical activity than women in the control group (1,950 metabolic equivalent of tasks [METs]-min/week vs. 1,386 METs/min-week (p=0.007), respectively. The mean score for eating habits was higher in the IG than in the CG [(3.51 ± 0.37) versus (3.33 ± 0.40) points; p=0.009]. No differences were observed between the study groups in the incidence of maternal and perinatal outcomes. In the intervention group, 61% (36) of the pregnant women used the smartband daily, and 74.6% (44) evaluated the usability of the Mi Fit© App as excellent. All women in the intervention group used the Hangouts© App at least once a week. The mean of the satisfaction scale with the health counselling App and virtual midwife support was 4.8 ± 0.6/5 points. CONCLUSIONS: The use of a complex digital intervention was effective in a lower gestational weight gain, in an increase in physical activity and in the improvement of eating habits. No differences were found in maternal perinatal complications between study groups. Satisfaction with the intervention and the usability of the App was very high.

Peer reviewed: True, Funder: International Agency for Research on Cancer (IARC), Funder: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Funder: NIHR Imperial Biomedical Research Centre (BRC), Funder: Danish Cancer Society (Denmark), Funder: Ligue Contre le Cancer, Funder: Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Funder: Institut National de la Santé et de la Recherche Médicale (INSERM), Funder: German Cancer Aid, Funder: German Cancer Research Center (DKFZ), Funder: German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Funder: Federal Ministry of Education and Research (BMBF), Funder: Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Funder: Compagnia di San Paolo, Funder: National Research Council, Funder: Dutch Ministry of Public Health, Welfare and Sports (VWS), Funder: Netherlands Cancer Registry (NKR), Funder: LK Research Funds, Funder: Dutch Prevention Funds, Funder: Dutch ZON (Zorg Onderzoek Nederland), Funder: World Cancer Research Fund (WCRF), Funder: Statistics Netherlands, Funder: Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Funder: Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, Funder: Catalan Institute of Oncology—ICO, Funder: Swedish Cancer Society, Funder: Swedish Research Council, Funder: County Councils of Skåne and Västerbotten, Polyphenols are bioactive compounds from plants with antioxidant properties that may have a protective role against body weight gain, with adipose tissue and systemic oxidative stress as potential targets. We aimed to investigate the dietary intake of individual polyphenols and their association with 5-year body weight change in a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 349,165 adult participants from nine European countries. Polyphenol intake was estimated through country-specific validated dietary questionnaires and the Phenol-Explorer database. Body weight was obtained at recruitment and after a mean follow-up time of 5 years. Associations were estimated using multilevel mixed linear regression models. From 91 polyphenols included, the majority (n = 67) were inversely associated with 5-year body weight change after FDR-correction (q < 0.05). The greatest inverse associations were observed for quercetin 3-O-rhamnoside (change in weight for doubling in intake: -0.071 (95% CI: -0.085; -0.056) kg/5 years). Only 13 polyphenols showed positive associations with body weight gain, mainly from the subclass hydroxycinnamic acids (HCAs) with coffee as the main dietary source, such as 4-caffeoylquinic acid (0.029 (95% CI: 0.021; 0.038) kg/5 years). Individual polyphenols with fruit, tea, cocoa and whole grain cereals as the main dietary sources may contribute to body weight maintenance in adults. Individual HCAs may have different roles in body weight change depending on their dietary source.

Treballs Finals de Grau de Nutrició Humana i Dietètica, Facultat de Farmàcia i Ciències de l'Alimentació, Campus de l'Alimentació de Torribera, Universitat de Barcelona. Curs: 2022-2023. Tutor: Joana Relat Pardo, [eng] Postprandial studies are essential to understand metabolism functioning after food intake and, the metabolic syndrome is a combination of different cardiovascular risk factors which can endanger human health. Thus, this review aims to describe the relationship between the postprandial metabolism of the organism and its possible connection with metabolic syndrome. An electronic search was performed using the databases “Cercabib”, “PubMed”, “Scopus” and “Google Academy” and articles published after the 2000’s were selected. The data indicate that the postprandial response is linked to the ability to suffer from metabolic syndrome. Alterations in the postprandial metabolism of the organism, adherence to Western diets, decrease in physical activity, etc., they are characteristics that are part of the complex definition of the postprandial state, and it will favor the appearance of metabolic syndrome. The conclusion of this work is that more research is needed to prevent the development of metabolic syndrome. Also, there is a great need to promote healthy life in the community and physical activity., [cat] Els estudis postprandial són essencials per comprendre el funcionament del metabolisme després de la ingesta d'aliments i, la síndrome metabòlica és una combinació de diferents factors de risc cardiovascular que poden posar en perill la salut humana. Així, aquesta revisió pretén descriure la relació entre el metabolisme postprandial de l'organisme i la possible connexió amb la síndrome metabòlica. Es va realitzar una cerca electrònica utilitzant les bases de dades "Cercabib", "PubMed", "Scopus" i "Google Academy" i es van seleccionar els articles publicats després dels anys 2000. Les dades indiquen que la resposta postprandial està vinculada a la capacitat de patir de síndrome metabòlica. Alteracions en el metabolisme postprandial de l'organisme, adherència a dietes occidentals, disminució de l'activitat física, etc., són característiques que formen part de la definició complexa de l'estat postprandial, i afavoriran l'aparició de la síndrome metabòlica. La conclusió d'aquest treball és que cal més investigació per prevenir el desenvolupament de la síndrome metabòlica. A més, hi ha una gran necessitat de promoure la vida saludable a la comunitat i l'activitat física.

The present study examined the influence of inulin on fecal microbiota, cardiometabolic risk factors, eicosanoids, and oxidative stress in rats on a high-fat (HF) diet. Thirty-six male Wistar-Kyoto rats were divided into three dietary groups: standard diet, HF diet, and HF diet + Inulin diet. After 10 weeks, the HF + Inulin diet promoted high dominance of a few bacterial genera including Blautia and Olsenella in feces while reducing richness, diversity, and rarity compared to the HF diet. These changes in fecal microbiota were accompanied by an increased amount of propionic acid in feces. The HF + Inulin diet decreased cardiometabolic risk factors, decreased the amount of the eicosanoids 11(12)-EET and 15-HETrE in the liver, and decreased oxidative stress in blood compared to the HF diet. In conclusion, increasing consumption of inulin may be a useful nutritional strategy to protect against the onset of obesity and its associated metabolic abnormalities by means of modulation of gut microbiota., This work was supported by the Spanish Ministry of Economy and Competitiveness (grant number: AGL2017-83599-R). J.P. was supported by the MEIC to the EMBL partnership, Centro de Excelencia Severo Ochoa and CERCA Programme/Generalitat de Catalunya.

[eng] Bioactive compounds have long been proposed as a tool to help facing both obesity and its comorbidities pandemic. Knowledge on their properties, together with the discovery of new therapeutic targets in animals and humans, make then interesting proposals for the prevention and treatment of various metabolic diseases. One of the main parts of this thesis proposal was to evaluate the ability of a pure, isolated polyphenol supplementation to counteract the pernicious metabolic effects of a high-fat diet on a murine model. Contrary to expectations, the polyphenolic supplementation worsened the action of the high-fat diet and pointedly produced an aggression to the kidneys. The other main part of this thesis proposal had been to assess a natural source of bioactive compounds with a broad and diverse profile not only in phenolic species, on a diet-obesity model. Based on the experience of our research group and the positive results demonstrated in different studies on chronic diseases, the Rosa canina fruit was chosen. In this case it was demonstrated how the supplementation with Rosa canina flesh was able to slow down the pernicious effect of the high fat diet, and particularly how exhibited a strong anti-steatotic effect on liver by downregulating several key genes, and thus improving significantly the non-alcoholic fatty liver disease course on obese mice. Furthermore, through the flesh fractionation, bioactive compound characterization and in vitro analysis, it was possible to identify that the most lipophilic phases of the Rosa canina show an antagonistic role on the peroxisome proliferator activated receptor gamma and therefore were partly responsible for the observed anti-steatotic effect., [cat] Els compostos bioactius han estat proposats com a eina dietètica per a fer front a la pandèmica de l’obesitat i de les seves comorbiditats. El coneixement de les seves propietats, junt amb la cerca de noves dianes terapèutiques en animals i humans, els converteixen en una proposta interessant per a la prevenció i el tractament de diverses malalties metabòliques. Una de les principals parts d'aquesta proposta de tesi doctoral ha sigut avaluar la capacitat d'una suplementació de polifenols aïllats purs vers els efectes perniciosos d'una dieta d'alt contingut en greix en el metabolisme sobre un model murí. En contra a les expectatives, la suplementació amb la mescla de polifenols va empitjorar notòriament l’acció de la dieta alta en greix i va produir una clara agressió als ronyons. L’altra part principal d’aquesta proposta de tesi doctoral ha sigut avaluar una font natural de compostos bioactius però amb un ampli i divers perfil d’espècies. Basant-nos en l’experiència del nostre grup de recerca i en resultats previs positius demostrats en diversos estudis sobre malalties cròniques, es va triar el fruit de la Rosa canina. En aquest cas, es va demostrar com la suplementació amb la polpa de Rosa canina va ser capaç de frenar l'efecte perniciós de la dieta d'alt greix, i en particular com va exhibir un fort efecte antiestatotic sobre el fetge mitjançant la regulació de diversos gens clau, i així millorant significativament el quadre de l’esteatosi hepàtica no alcohòlica. Paral·lelament, mitjançant el fraccionament de la polpa, la caracterització dels compostos bioactius i l'anàlisi in vitro, va ser possible identificar que les fases més lipòfiles de la Rosa canina exercien un paper antagonista del receptor PPAR-gamma i que per tant, eren en part responsables de l'efecte antiestatotic observat.

Purpose: Obesity has become a growing public health issue worldwide. Studies have shown that eating rate is one of the most important factors to consider in the strategies to prevent and/or treat obesity. Eating rate can be reduced through different strategies, such as an increase in oro-sensory exposure, the modification of food texture, and an increase in the number of chewing cycles. The aim of this systematic review was to analyze the available evidence regarding the effect of chewing behavior modification on the parameters that contribute to obesity. Methods: A systematic search was done on the electronic databases Pubmed, Cochrane Central Register of Controlled Trials, and Scopus, using the terms mastication, chewing, chewing speed, prolonged chewing, number of chews, masticatory cycles satiety satiety response appetite, appetite regulation, nutritional status and obesity. Results: A total of 23 intervention studies were selected that intervened in the participants' chewing behavior, either by reducing the eating rate, increasing oro-sensory exposure, food hardness or the number of chewing cycles. In most studies these interventions were effective at reducing food intake, subjective appetite and improving the plasma levels of satiety-related hormones and metabolites; moreover, they reduced body mass index in the long term. Conclusion: The currently available evidence seems to indicate that modifications to chewing behavior can bring with it a myriad of benefits for the treatment of obesity.

While income gradients and gender inequalities in excess weight have been noted elsewhere, data from Latin American cities is lacking. We analyzed gender-specific associations between city-level women’s empowerment and income inequality with individual-level overweight/obesity, assessing how these associations vary by individual education or living conditions within cities in Latin America. Data came from national surveys and censuses, and was compiled by the SALURBAL project (Urban Health in Latin America). The sample included 79,422 individuals (58.0% women), living in 538 sub-cities, 187 cities, and 8 countries. We used gender-stratified Poisson multilevel models to estimate the Prevalence Rate Ratios (PRR) for overweight/obesity (body mass index ≥ 25 kg/m2) per a unit change in city-level women’s empowerment (proxied by a score that measures gender inequalities in employment and education) and income inequality (proxied by income-based Gini coefficient). We also tested whether individual education or sub-city living conditions modified such associations. Higher city labor women’s empowerment (in women) and higher city Gini coefficient (in men) were associated with a lower prevalence of overweight/obesity (PRR = 0.97 (95%CI 0.94, 0.99) and PRR = 0.94 (95%CI 0.90, 0.97), respectively). The associations varied by individual education and sub-city living conditions. For labor women’s empowerment, we observed weakened associations towards the null effect in women with lower education and in residents of sub-cities with worse living conditions (men and women). For the Gini coefficient, the association was stronger among men with primary education, and a negative association was observed in women with primary education. Our findings highlight the need for promoting equity-based policies and interventions to tackle the high prevalence of excess weight in Latin American cities. This work received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement Nº 89102 (Dr. Tumas was supported by this grant). Joan Benach gratefully acknowledges the financial support by ICREA under the ICREA Academia programme.

[eng] Obesity and its associated metabolic diseases are currently a priority research topic. The increase in global prevalence at different ages is having a huge economic and health impact. Genetic and environmental factors play a crucial role in the development of obesity, and diet is one of the main factors that directly contributes to the genic obese phenotype. Scientific evidence has shown that increased fat intake is associated with increased body weight that triggers obesity. Rodent animal models have been extremely useful in the study of obesity, as weight gain can be easily induced by a high-fat diet. On the other hand, thermogenesis is a process that our body uses to produce heat. Studies show that the body uses a variety of mechanisms to produce this effect, demonstrating that brown adipose tissue (BAT) is one of the main effector organs. In general, adipose tissue is the organ where energy is stored in the form of fat (triacylglycerols), while BAT, in particular, owes its name to the color that characterizes the presence of a large number of mitochondria, which have a high concentration of uncoupling proteins (UCP}, in addition to a good number of a and beta-adrenergic receptors and high vascularization. BAT is located in specific areas of the body such as the cervical area of the neck, armpits, associated with the ribs, around the heart and kidneys, showing a greater distribution in fetuses and newborns compared to adults. Understanding the activity of adipose tissue is important because of the involvement of this organ in the pathophysiology of obesity. Mitochondria burn fuels such as fatty acids and glucose into useful energy, consuming oxygen in the process. In addition, BAT has a high concentration of the protein UCP1 (uncoupling protein 1). This protein bypasses the respiratory chain, so instead of generating useful energy, it dissipates energy as heat. This function, known as non-shivering thermogenesis, is crucial in infants to maintain body temperature. BAT has emerged as an important regulator of energy expenditure in obesity by controlling thermogenesis. Carnitine palmitoyltransferase 1A (CPT1A), a key enzyme in fatty acid oxidation (FAO), has been implicated in the control of energy homeostasis. However, the specific role of CPT1A in modulating BAT metabolism to control food intake and obesity is still highly unknown. The aim of this research work was to find new approaches to reduce obesity by activating CPT1A, and thus FAO, in BAT. For peripheral activation of FAO in BAT, the mutated and permanently active form (CPT1AM) was expressed. This was done in mice in vivo using adeno-associated (AAV) vectors. As a result, activation of CPT1A in BAT activated thermogenesis and reduced weight gain, identifying new strategy for potential therapy against obesity and its associated metabolic diseases, such as diabetes. In addition, our results showed that expression of CPT1AM in BAT increased lipolysis FAO and thermogenesis in BAT. The increase FAO in BAT prevented the increase in the content of triglycerides, cholesterol and insulin in the blood, and the expression of markers of obesity and inflammation in the tissues, caused by HFD. Our results show that FAO is critical in supplying fuel for BAT-generated thermogenesis, which may be a good strategy to increase energy expenditure through thermogenesis and thus avoid obesity and its associated diseases resulting from HFD., [spa] La obesidad y sus enfermedades metabólicas asociadas son actualmente un tema prioritario de investigación. Los factores genéticos y ambientales juegan un papel crucial en el desarrollo de la obesidad, y la dieta es uno de los principales factores que contribuye directamente al fenotipo obeso génico. Por otra parte, el tejido adiposo marrón (TAM) se ha convertido en un importante regulador del gasto de energía en la obesidad al controlar la termogénesis. La carnitina palmitoiltransferasa 1A (CPT1A), una enzima clave en la oxidación de ácidos grasos (OAG), se ha implicado en el control de la homeostasis energética. Sin embargo, el papel específico de CPT1A en la modulación del metabolismo de TAM para controlar la ingesta de alimentos y la obesidad aún es muy desconocido. El objetivo de este trabajo de investigación fue encontrar nuevos enfoques para reducir la obesidad activando CPT1A, y por lo tanto OAG, en TAM. Para la activación periférica de OAG en TAM, se expresó la forma mutada y permanentemente activa (CPT1AM). Esto se hizo en ratones in vivo utilizando vectores virales adenoasociados (AAVs). Como resultado, la activación de CPT1A en TAM activó la termogénesis y redujo el aumento de peso, identificando una nueva estrategia para la terapia potencial contra la obesidad y sus enfermedades metabólicas asociadas, como la diabetes. Además, nuestros resultados mostraron que la expresión de CPT1AM en TAM aumentó la lipólisis OAG y la termogénesis en TAM. El aumento de la OAG en TAM evitó el aumento del contenido de triglicéridos, colesterol e insulina en sangre, y la expresión de marcadores de obesidad e inflamación en los tejidos, provocados por la dieta alta en grasa. Nuestros resultados muestran que la OAG es fundamental en el suministro de combustible para la termogénesis generada por TAM, lo que puede ser una buena estrategia para aumentar el gasto energético a través de la termogénesis y así evitar la obesidad y sus enfermedades asociadas resultantes de la dieta alta en grasa.

Objective: To investigate the potential role of EGFR, ErbBs receptors and neuregulins in human adipose tissue physiology in obesity. Methods: Gene expression analysis in human subcutaneous (SAT) and visceral (VAT) adipose tissue in three independent cohorts [two cross-sectional (N = 150, N = 87) and one longitudinal (n = 25)], and in vitro gene knockdown and overexpression experiments were performed. Results: While both SAT and VAT ERBB2 and ERBB4 mRNA increased in obesity, SAT EGFR mRNA was negatively correlated with insulin resistance, but did not change in obesity. Of note, both SAT and VAT EGFR mRNA were significantly associated with adipogenesis and increased during human adipocyte differentiation. In vitro experiments revealed that EGFR, but not ERBB2 and ERBB4, gene knockdown in preadipocytes and in fully differentiated human adipocytes resulted in decreased expression of adipogenic-related genes. ERBB2 gene knockdown also reduced gene expression of fatty acid synthase in fully differentiated adipocytes. In addition, neuregulin 2 (NRG2) mRNA was associated with expression of adipogenic genes in human adipose tissue and adipocytes, and its overexpression increased expression of EGFR and relevant adipogenic genes. Conclusions: This study demonstrates the association between adipose tissue ERBB2 and obesity, confirms the relevance of EGFR on human adipogenesis, and suggests a possible adipogenic role of NRG2.

The diagnosis of obesity comprises subjects with totally different phenotypes and metabolic profiles. Systemic inflammation and oxidative stress derived from the white adipose tissue are suggested as the link between this disease and the development of insulin resistance and metabolic comorbidities. The presence of unicellular eukaryotic parasites colonizing the human gut ecosystem is a common circumstance, and yet their influence on the inflammatory and redox status of the obese host has not been assessed. Herein, a set of inflammatory and redox biomarkers were assessed together with a parasitological analysis of 97 severely obese subjects. Information was also collected on insulin resistance and on the antioxidant composition of the diet. The global prevalence of intestinal unicellular parasites was 49.5%, with Blastocystis sp. the most prevalent protozoan found (42.3%). Colonized subjects displayed a higher total antioxidant capacity and a trend towards higher extracellular superoxide dismutase activity, regardless of their insulin resistance status, along with lower reduced glutathione/oxidized glutathione (GSH/GSSG) ratios in plasma in the insulin-resistant subgroup. No changes in malondialdehyde levels, or in inflammatory cytokines in plasma, were found in regard to the colonization status. In conclusion, enteric eukaryotic unicellular parasites may play an important role in modulating the antioxidant defenses of an obese host, thus could have beneficial effects with respect to the development of systemic metabolic disorders.

[cat] La predicció del risc de patir un esdeveniment cardiovascular en les persones amb obesitat severa és imprecisa. A més, els mecanismes que interrelacionen l’obesitat amb l’ateroesclerosi no es coneixen amb suficient profunditat. Es creu que els factors que determinen l’aparició de l’ateroesclerosi subclínica (asimptomàtica) en l’obesitat severa s’estenen més enllà dels factors de risc tradicionals. Per això proposem que algunes molècules plasmàtiques podrien relacionar l’obesitat amb la presència de lesió vascular subclínica i, per tant, permetrien detectar amb antelació aquelles persones amb major risc de desenvolupar esdeveniments cardiovasculars. Tenint en compte aquest context, es formulen els següents objectius: 1. Estudiar si hi ha paràmetres antropomètrics, bioquímics, genètics o fisiològics diferencials entre individus amb ateroma i sense, que puguin explicar perquè individus amb perfil d’obesitat severa similar, tenen diferent risc cardiovascular. Per això analitzarem paràmetres relacionats amb la inflamació, l’estrès oxidatiu i la funció endotelial vascular en una cohort d’individus amb obesitat severa agrupats segons la presència o absència de placa. 2. Analitzar l’efecte de la cirurgia bariàtrica sobre l’evolució de l’ateroesclerosi subclínica i el risc cardiovascular. Per això mesurarem els paràmetres relacionats amb el risc cardiovascular abans mencionats un mes abans de la BS i també al cap de 6 i 12 mesos en la mateixa cohort. 3. Establir si entre els paràmetres que resultin rellevants en el desenvolupament del procés ateromatós hi ha candidats per a l’ús com a biomarcadors amb bona capacitat predictiva per a l’ateroesclerosi subclínica i/o indicadors de l’evolució del risc cardiovascular., [eng] The worldwide prevalence of obesity has risen dramatically. Severe obesity (SE) is characterized by an accumulation of fat and increases the predisposition to comorbidities such as type 2 diabetes mellitus (T2DM), dyslipidemia (DLP) and hypertension. Obesity is also a risk factor for several of the world’s leading causes of death, including cardiovascular diseases. Bariatric surgery (BS) is the most effective treatment for SE. Atherosclerosis is a chronic progressive disease with a long asymptomatic phase during which an atheroma forms. Usually, because of its long silent subclinical phase, atherosclerosis it is not diagnosed until an acute event occurs. Therefore, the aims of this study were, firstly, to evaluate the differences between subjects with and without plaques and the mechanisms underlying subclinical atherosclerosis in SE. Secondly to evaluate the effect of BS in subclinical atherosclerosis and cardiovascular risk. And finally, to assess the utility of circulating parameters as a biomarkers of subclinical atherosclerosis in subjects with SE. Plasma samples from 66 subjects with SE were obtained before BS and 6 and 12 months after. This cohort was divided into two groups based on the presence of atheromatous plaques (detected by ultrasound imaging). A plethora of mechanisms, including abnormalities in lipid metabolism, insulin resistance, inflammation, oxidative stress and endothelial dysfunction, have been observed in SE, especially in subjects with plaque. Endothelial dysfunction was characterized by impaired angiogenesis, vascular function and diapedesis. After BS, most of the atherogenicity parameters decreased, including inflammation and oxidative stress, although the prognosis is better for patients without plaque. BS reduces the likelihood of new plaque formation or a change in existing plaque to a risk status. We found 26 parameters which may have a critical role in plaque development and might be useful in assessing early atherosclerosis and its evolution after BS. We developed a multi-marker risk prediction model, incorporating traditional risk factors and multiple biomarkers simultaneously. Between those, DLP, T2D, Hba1c, glucose levels and TM have a 97% prediction capacity for the presence of atheromatous plaque.

Obesity contributes to a chronic proinflammatory state, which is a known risk factor to develop immune-mediated diseases. However, its role in systemic sclerosis (SSc) remains to be elucidated. Therefore, we conducted a two-sample mendelian randomization (2SMR) study to analyze the effect of three body fat distribution parameters in SSc. As instrumental variables, we used the allele effects described for single nucleotide polymorphisms (SNPs) in different genomewide association studies (GWAS) for SSc, body mass index (BMI), waist-to-hip ratio (WHR) and WHR adjusted for BMI (WHRadjBMI). We performed local (pHESS) and genome-wide (LDSC) genetic correlation analyses between each of the traits and SSc and we applied several Mendelian randomization (MR) methods (i.e., random effects inverse-variance weight, MR-Egger regression, MR pleiotropy residual sum and outlier method and a multivariable model). Our results show no genetic correlation or causal relationship between any of these traits and SSc. Nevertheless, we observed a negative causal association between WHRadjBMI and SSc, which might be due to the effect of gastrointestinal complications suffered by the majority of SSc patients. In conclusion, reverse causality might be an especially difficult confounding factor to define the effect of obesity in the onset of SSc., MCIN/AEI RTI2018101332-B-100 IJC2018-038026-I IJC2019-040080-I PRE2019-087586, "ERDF A way of making Europe" - European Union, Red de Investigacion en Inflamacion y Enfermedades Reumaticas (RIER) from Instituto de Salud Carlos III RD16/0012/0013, ESF Investing in your future

Background: Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of liver alterations that can result in severe disease and even death. Consumption of ultra-processed foods (UPF) has been associated with obesity and related comorbidities. However, the link between UPF and NAFLD has not been sufficiently assessed. We aimed to investigate the prospective association between UPF consumption and liver health biomarkers. Methods: We followed for 1 year 5867 older participants with overweight/obesity and metabolic syndrome (MetS) from the PREDIMED-Plus trial. A validated 143-item semi-quantitative food frequency questionnaire was used to evaluate consumption of UPF at baseline, 6, and 12 months. The degree of processing for foods and beverages (g/day) was established according to the NOVA classification system. The non-invasive fatty liver index (FLI) and hepatic steatosis index (HSI) were used to evaluate liver health at three points in time. The associations between changes in UPF consumption (percentage of total daily dietary intake (g)) and liver biomarkers were assessed using mixed-effects linear models with repeated measurements. Results: In this cohort, UPF consumption at baseline was 8.19% (SD 6.95%) of total daily dietary intake in grams. In multivariable models, each 10% daily increment in UPF consumption in 1 year was associated with significantly greater FLI ( 1.60 points, 95% CI 1.24;1.96 points) and HSI (0.43, 0.29; 0.57) scores (all p-values < 0.001). These associations persisted statistically significant after adjusting for potential dietary confounders and NAFLD risk factors. Conclusions: A higher UPF consumption was associated with higher levels of NAFLD-related biomarkers in older adults with overweight/obesity and MetS., European Research Council (ERC) European Commission 340918, Spanish National Health Institute of Health Carlos III (ISCIII), through CIBEROBN, European Commission PI13/00673 PI13/00492 PI13/00272 PI13/01123 PI13/00462 PI13/00233 PI13/02184 PI13/00728 PI13/01090 PI13/01056 PI14/01722 PI14/00636 PI14/00618 PI14/00696 PI14/01206, Especial Action Project entitled: Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus grant, La Caixa Foundation 2013ACUP00194, Junta de Andalucia PI0458/2013 PS0358/2016 PI0137/2018 RH-0024-2021, Center for Forestry Research & Experimentation (CIEF), European Commission PROMETEO/2017/017, SEMERGEN grant, Spanish Government IJC2019-042420-I, European Social Fund (ESF), Spanish National Health Institute of Health Carlos III (ISCIII) CPII20/00014 ICREA, The European Regional Development Fund PI17/00855 PI17/01347 PI17/00525 PI17/01827 PI17/00532 PI17/00215 PI17/01441 PI17/00508 PI17/01732 PI17/00926 PI19/00957 PI19/00386 PI19/00309 PI19/01032 PI19/00576 European Commission PI19/00017 PI19/01226 PI19/00781 PI19/01560 PI19/01332 PI20/01802 PI20/00138 PI20/01532 PI20/00456 PI20/00339 PI20/00557 PI20/00886 PI20/01158 PI21/00465, "Fondo de Investigacion para la Salud" (FIS), European Commission PI14/01919 PI14/00853 PI14/01374 PI14/00972 PI14/00728 PI14/01471 PI16/00473 PI16/00662 PI16/01873 PI16/01094 PI16/00501 PI16/00533 PI16/00381 PI16/00366 PI16/01522 PI16/01120 PI17/00764 PI17/01183

Obesity is an epidemic disease worldwide, characterized by excessive fat accumulation associated with several metabolic perturbations, such as metabolic syndrome, insulin resistance, hypertension, and dyslipidemia. To improve this situation, a specific combination of metabolic cofactors (MC) (betaine, N-acetylcysteine, L-carnitine, and nicotinamide riboside) was assessed as a promising treatment in a high-fat diet (HFD) mouse model. Obese animals were distributed into two groups, orally treated with the vehicle (obese + vehicle) or with the combination of metabolic cofactors (obese + MC) for 4 weeks. Body and adipose depots weights; insulin and glucose tolerance tests; indirect calorimetry; and thermography assays were performed at the end of the intervention. Histological analysis of epidydimal white adipose tissue (EWAT) and brown adipose tissue (BAT) was carried out, and the expression of key genes involved in both fat depots was characterized by qPCR. We demonstrated that MC supplementation conferred a moderate reduction of obesity and adiposity, an improvement in serum glucose and lipid metabolic parameters, an important improvement in lipid oxidation, and a decrease in adipocyte hypertrophy. Moreover, MC-treated animals presented increased adipose gene expression in EWAT related to lipolysis and fatty acid oxidation. Furthermore, MC supplementation reduced glucose intolerance and insulin resistance, with an increased expression of the glucose transporter Glut4; and decreased fat accumulation in BAT, raising non-shivering thermogenesis. This treatment based on a specific combination of metabolic cofactors mitigates important pathophysiological characteristics of obesity, representing a promising clinical approach to this metabolic disease. Keywords: obesity; adipose tissue; insulin resistance; thermogenesis; metabolic cofactors

Background: Genetic risk scores (GRSs) have partially improved the understanding of the etiology of moderate hypertriglyceridemia (HTG), which until recently was mainly assessed by secondary predisposing causes. The main objective of this study was to assess whether this variability is due to the interaction between clinical variables and GRS. Methods: We analyzed 276 patients with suspected polygenic HTG. An unweighted GRS was developed with the following variants: c.724C > G (ZPR1 gene), c.56C > G (APOA5 gene), c.1337T > C (GCKR gene), g.19986711A > G (LPL gene), c.107 + 1647T > C (BAZ1B gene) and g.125478730A > T (TRIB gene). Interactions between the GRS and clinical variables (body mass index (BMI), diabetes mellitus, diet, physical activity, alcohol consumption, age and gender) were evaluated. Results: The GRS was associated with triglyceride (TG) concentrations. There was a significant interaction between BMI and GRS, with the intensity of the relationship between the number of alleles and the TG concentration being greater in individuals with a higher BMI. Conclusions: GRS is associated with plasma TG concentrations and is markedly influenced by BMI. This finding could improve the stratification of patients with a high genetic risk for HTG who could benefit from more intensive healthcare interventions.

Circulating lipopolysaccharide-binding protein (LBP) is increased in individuals with liver steatosis. We aimed to evaluate the possible impact of liver LBP downregulation using lipid nanoparticle-containing chemically modified LBP small interfering RNA (siRNA) (LNP-Lbp UNA-siRNA) on the development of fatty liver. Weekly LNP-Lbp UNA-siRNA was administered to mice fed a standard chow diet, a high-fat and high-sucrose diet, and a methionine- and choline-deficient diet (MCD). In mice fed a high-fat and high-sucrose diet, which displayed induced liver lipogenesis, LBP downregulation led to reduced liver lipid accumulation, lipogenesis (mainly stearoyl-coenzyme A desaturase 1 [Scd1]) and lipid peroxidation-associated oxidative stress markers. LNP-Lbp UNA-siRNA also resulted in significantly decreased blood glucose levels during an insulin tolerance test. In mice fed a standard chow diet or an MCD, in which liver lipogenesis was not induced or was inhibited (especially Scd1 mRNA), liver LBP downregulation did not impact on liver steatosis. The link between hepatocyte LBP and lipogenesis was further confirmed in palmitate-treated Hepa1-6 cells, in primary human hepatocytes, and in subjects with morbid obesity. Altogether, these data indicate that siRNA against liver Lbp mRNA constitutes a potential target therapy for obesity-associated fatty liver through the modulation of hepatic Scd1.

Background & aims: The circadian clock is involved in the control of daily rhythms and is related to the individual's chronotype, i.e., the morningness-eveneningness preference. Knowledge is limited on the relationship between circadian genes, chronotype, sleeping patterns, chronutrition and obesity. The aim was to explore these associations within the EPIC-Spain cohort study. Methods: There were 3183 subjects with information on twelve genetic variants of six genes (PER1, PER2, PER3, CRY1, NR1D1, CLOCK). Their association was evaluated with: chronotype and sleeping duration/ quality (assessed by questionnaires), chrononutrition (number of meals and timing of intake assessed by a diet history), and also anthropometric measures of obesity at early and late adulthood (in two points in time), such as weight and waist circumference (assessed by physical measurements). Multivariable logistic and linear regression as well as additive genetic models were applied. Odds ratios (ORs), b coefficients, and p-values corrected for multiple comparisons were estimated. Genetic risk scores (GRS) were built to test gene-outcome associations further. Results: At nominal significance level, the variant rs2735611 (PER1 gene) was associated with a 11.6% decrease in long-term weight gain (per-allele b beta - -0.12), whereas three CLOCK gene variants (rs12649507, rs3749474 and rs4864548), were associated with a similar to 20% decrease in waist circumference gain (per-allele beta similar to -0.19). These and other associations with body measures did not hold after multiple testing correction, except waist-to-hip ratio and rs1801260, rs2070062 and rs4580704 (CLOCK gene). Associations with chrononutrition variables, chronotype and sleep duration/quality failed to reach statistical significance. Conversely, a weighted GRS was associated with the evening/late chronotype and with all other outcomes (p < 0.05). The chronotype-GRS was associated with an increased overweight/ obesity risk (vs normal weight) in both early and late adulthood (OR = 2.2; p = 0.004, and OR = 2.1; p = 0.02, respectively). Conclusion: Genetic variants of some circadian clock genes could explain the link between genetic susceptibility to the individual's chronotype and obesity risk., Instituto de Salud Carlos III, Instituto de Salud Carlos III European Commission PI15/00347 PI15/01752 PI15/00579 PI15/02181 PI15/01658 Marato TV3 201604-10

Publisher Copyright: © 2022, Lluch et al. The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream of the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumors. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, decreased mTORC1 signaling in fat (but increased in the liver) segregated with defective epithelial-mesenchymal transition and the impaired expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.

[spa] La obesidad es una enfermedad crónica y un problema de salud pública, producido por un desequilibrio entre la ingesta y el gasto de energía. La prevalencia de la obesidad en todo el mundo se ha duplicado desde 1980, llegando a 650 millones de personas obesas en 2016, y las estimaciones futuras siguen una tendencia similar. Las principales causas de esta epidemia son las conductas alimentarias poco saludables, el aumento de los hábitos sedentarios y, lo más importante, la combinación de ambos. Aunque la obesidad está clasificada por la OMS como un factor de riesgo de enfermedades no transmisibles, su patrón de transmisión comparte rasgos comunes con las enfermedades contagiosas. Además, la obesidad sigue un patrón de agregación, que podría atribuirse en parte a la agrupación natural entre personas previamente obesas al compartir afinidades y moverse en un entorno obesogénico La Dieta Mediterránea no es solamente un tipo de dieta, es un patrón alimentario incluido en un estilo de vida donde se recogen costumbres, alimentos y formas de cocinar característicos en la zona del Mediterráneo. Todo este conjunto representa una serie de beneficios para la salud y concretamente para prevenir y combatir la obesidad. Estudios de intervención intensiva con pérdida de peso, apoyados con educación nutricional, actividad física y terapia conductual pueden ayudar a remitir la obesidad que presentan los individuos, y asimismo provocar un efecto “Halo” en su entorno más cercano y en su red social También es necesaria la validación de herramientas que nos ayuden a cuantificar la adherencia a la Dieta Mediterránea con restricción de energía y poder asociar esta adherencia con una mejoría en los parámetros de salud., [eng] Obesity is a chronic disease and a growing public health problem, caused by an imbalance between energy intake and expenditure. The prevalence of obesity worldwide has doubled since 1980, reaching 650 million obese people in 2016, and future estimates follow a similar trend. The main causes of this epidemic are unhealthy eating behaviors, the increase in sedentary habits and, most importantly, the combination of both. Although obesity is classified by the WHO as a risk factor for non-communicable diseases, its transmission pattern shares common features with contagious diseases. Obesity follows an aggregation pattern, which means that if a person suffers from obesity, their immediate environment is more likely to be obesogenic. Such aggregation could be attributed in part to natural grouping among previously obese people who share affinities. The Mediterranean Diet is not just a type of diet, it is an eating pattern included in a lifestyle where customs, foods and ways of cooking characteristic of the Mediterranean area are collected. All this set represents a series of health benefits and specifically serve to prevent and combat obesity. Intensive intervention studies with weight loss, supported by nutritional education, physical activity and behavioral therapy can help reduce the obesity that individuals present, but can also cause a “Halo” effect in their closest environment and ultimately in their social network. It is also necessary to validate tools that help us to quantify adherence to the energy- restricted Mediterranean Diet and to be able to associate this adherence with an improvement in health parameters.

Màster en Lideratge i Gestió d'Infermeria, Universitat de Barcelona. Escola Universitària d'Infermeria. curs: 2021-2022, Tutor: Maria Montserrat Solà Pola, Objectiu: Avaluar el programa d’intervenció familiar amb dispositiu intel·ligent OBES-CAP PED per a infants de 6 a 8 anys amb obesitat i les seves famílies. Ámbit de l’estudi: L’àmbit de l’estudi és l’Equip d’Atenció Primària de Pediatria (EAPP) del CAP Río de Janeiro dels barris de Porta, Prosperitat, Verdum i Turó de la Peira de Nou Barris, Barcelona. Metodologia: Estudi experimental amb aleatorització controlat per llista d’espera que avaluarà els resultats de la intervenció mixta motivacional, multidisciplinària i multifactorial d’hàbits de vida saludable (dieta mediterrània, exercici físic, temps d’ús de pantalles i hores de son) amb el suport d’aplicacions de mòbil i polsera d’activitat. Implicacions per a la pràctica: En el cas que els resultats fossin rellevants, es podria instaurar dins del programa Infància en Salut per reduir l’obesitat infantil.

Background: Non-alcoholic fatty liver disease is a chronic disease caused by the accumulation of fat in the liver related to overweight and obesity, insulin resistance, hyperglycemia, and high levels of triglycerides and leads to an increased cardiovascular risk. It is considered a global pandemic, coinciding with the pandemic in 2020 caused by the 'coronavirus disease 2019' (COVID-19). Due to COVID-19, the population was placed under lockdown. The aim of our study was to evaluate how these unhealthy lifestyle modifications influenced the appearance of metabolic alterations and the increase in non-alcoholic fatty liver disease. Methods: A prospective study was carried out on 6236 workers in a Spanish population between March 2019 and March 2021. Results: Differences in the mean values of anthropometric and clinical parameters before and after lockdown were revealed. There was a statistically significant worsening in non-alcoholic fatty liver disease (NAFLD) and in the insulin resistance scales, with increased body weight, BMI, cholesterol levels with higher LDL levels, and glucose and a reduction in HDL levels. Conclusions: Lockdown caused a worsening of cardiovascular risk factors due to an increase in liver fat estimation scales and an increased risk of presenting with NAFLD and changes in insulin resistance. Keywords: COVID-19; insulin resistance; non-alcoholic fatty liver disease.

Introduction: Body mass index (BMI) provides little information on body composition. For example, two people with the same BMI might have different body compositions. In this sense, the development of a new BMI able to provide body composition information is of clinical and scientific interest. The aim of the study was to suggest a new modified BMI formula. Material and Methods: A total of 108 subject, females 56 and males 52, 0-73 years old, in various physiopathological conditions were evaluated. Data were collected and processed by a program that through anthropometric measurements calculates classic BMI, volume, surface, V/S (that we can defined like a body-thickness “pseudospessore”) and the new BMI-BFMNU. Results: The basic formula (BMI = Body Mass [kg] / Height [m2]) uses the height squared as the value of the body surface, although this is only an approximation of the real surface, whereas using the real surface instead, the new BMI reflects better the ratio between the body volume and its surface. The ratio called “pseudospessore” is already used in literature from the BFMNU (Italian acronym refereed to Biologia e Fisiologia Modellistica della Nutrizione Umana) method and has been shown to be related to the amount of fat. Conclusions: Using the BMI-BFMNU, it is possible to obtain an indication of the body structure related to the amount of fat. The consequence is that the obtained numerical values do not coincide with the traditional BMI's values and will refer to different normal ranges. For instance, a person may be in the range of normal weight for both BMI measurements, but only the BMI-BFMNU detects whether a person has a higher or lower fat content considering the individual's category. This study opens up to new possible future developments on the application of the new BMI that will allow a more accurate assessment and classification of patients.

Malnutrition comprises two groups of conditions: undernutrition and overweight or obesity. It has been associated with a high risk of contracting infectious diseases and with elevated mortality rates. Community-acquired pneumonia (CAP) is one of the most common infectious diseases worldwide and its prognosis is affected by a large number of recognizable risk factors. This narrative review updates the information on the impact of malnutrition, including both undernutrition and obesity, on the risk and prognosis of adults with CAP. Studies of CAP that have evaluated undernutrition have applied a variety of definitions when assessing the nutritional status of patients. Undernutrition has been associated with unfavorable clinical outcomes, such as prolonged hospital stay, need for intensive care unit admission, and mortality; in contrast, most published studies have found that increased body mass index is significantly associated with higher survival in patients with CAP. However, some authors have presented divergent results, mainly in relation to the etiology of CAP (bacterial versus viral). Influenza infection, caused by influenza A (H1N1) pdm09, has been associated with worse prognosis in obese patients. The current data underscore the need for larger studies to examine the physiological mechanisms that explain the differential impact of malnutrition on outcomes. Achieving a better understanding may help to guide the design of new interventions to improve prognosis.

[eng] INTRODUCTION: Metabolic syndrome (MetS) is a clustering of different cardiovascular and cardiometabolic risk factors. In developed countries, MetS prevalence has risen to 20- 25% in the adult population, and its incidence is increasing. Public health strategies for MetS treatment and prevention are mainly focused on lifestyle modification, including dietary and physical activity promotion. Aligned with MetS, obesity is a multifactorial complex disease defined by excess of adipose mass, which occurs through adipocyte hypertrophy and hyperplasia. However, while waist circumference is a better predictor for CVD than BMI or body weight, it is an index of total adiposity, and it cannot differentiate visceral from subcutaneous adiposity. The adipose tissue is an endocrine organ that secretes a wide variety of inflammatory adipocytokines, such as TNF-alpha, IL-6, resistin, leptin, and adiponectin. Visceral adiposity is associated with a higher production of these inflammatory adipocytokines, leading to systemic inflammation, insulin resistance, and several obesity-related metabolic disorders. Phenolic compounds, also known as polyphenols, are characterized by the presence of one or more aromatic rings and phenol structural units in its molecules. The main food sources of polyphenols in Mediterranean countries are coffee, fruits, red wine, and vegetable oils, especially olive oil, whereas in non-Mediterranean countries, coffee, tea, fruits, and wine were the main food sources. Moreover, a continuous and prolonged polyphenol intake is related to BP and adiposity lowering effects, improvements in lipid profile, and anti-inflammatory effects, which all act as CVD protectors. OBJECTIVE: The general objective of this thesis project is to evaluate the effect of a high dietary polyphenol intake included in an intensive weight-loss-oriented lifestyle intervention program on adiposity parameters and other cardiovascular risk factors in patients with MetS, as well as the mechanisms involved in these effects. Additionally, we aimed to estimate the dietary polyphenol intake in Spanish population from PREDIMED (PRevención con DIeta MEDiterránea) Plus and validate an updated version of a semi- quantitative food frequency questionnaire. RESULTS: The intake of polyphenol subclasses has been reported to have an impact on MetS components, especially HDL-cholesterol. Total polyphenol intake was not associated with a better profile concerning MetS components, except for high-density lipoprotein cholesterol (HDL-c), although stilbenes, lignans, and other polyphenols showed an inverse association with blood pressure, fasting plasma glucose, and triglycerides. A direct association with HDL-c was found for all subclasses except lignans and phenolic acids. In the case of type 2 diabetes prevalence, catechins, proanthocyanidins, hydroxybenzoic acids, and lignans were inversely associated with type 2 diabetes. These associations were different depending on sex and BMI, that is, women and overweight participants obtained stronger inverse associations. In this sense, after one year of follow-up, increments in total polyphenol intake and some classes were inversely associated with better glucose levels and HbA1c. In the case of body composition, some classes of polyphenols and body adiposity markers determined by dual-energy X-Ray absorptiometry, mainly visceral adipose tissue, and total fat mass after one year of follow-up. When participants were categorized into tertiles according to changes in VAT after one-year of follow-up, an increase of VAT content, showed significant mean increasement in PAI-1, resistin and leptin levels. When comparing among tertiles of VAT showed significant differences in insulin, PAI-1 and c-peptide. Additionally, a validated food frequency questionnaire showed moderate reliability according to Mediterranean diet adherence and biological markers. CONCLUSIONS: In conclusion, dietary polyphenol intake improves MetS criteria, body composition, and obesity-related inflammatory markers and adipokines levels. Improvements in visceral adipose tissue are associated with improvements in cardiometabolic parameters, compared to body weight. Additionally, visceral adipose tissue reductions improvements in obesity-related inflammatory response., [cat] La síndrome metabòlica (MetS) és un agrupament de diferents factors de risc cardiovasculars i cardiometabòlics. Les estratègies de salut pública pel tractament i la prevenció de la MetS es centren principalment en la modificació de l'estil de vida. Dins del marc de la Dieta Mediterrània, els compostos fenòlics també coneguts com a polifenols, han demostrat que una ingesta contínua i prolongada de polifenols està relacionada amb una reducció del risc cardiovascular, incloent la reducció de la pressió arterial, paràmetres d’adipositat, millores en el perfil lipídic i efectes antiinflamatoris. L'objectiu d'aquesta tesi doctoral va ser avaluar l'efecte d'una ingesta de polifenols elevada, dins d’una intervenció d'estil de vida orientat a la pèrdua de pes, sobre paràmetres d'adipositat i altres factors de risc cardiovascular en pacients amb MetS. Addicionalment, estimar la ingesta dietètica de polifenols en la població de l’estudi PREDIMED (PRevención con DIeta MEDiterránea) Plus i validar una versió actualitzada d'un qüestionari de freqüència d’aliments semi-quantitatiu. Les conclusions d’aquesta tesi doctoral inclouen que la ingesta dietètica de polifenols millora els criteris de la MetS, la prevalença de diabetis tipus 2, i la composició corporal, especialment el teixit adipós visceral. A més, la reducció del teixit adipós visceral millora els nivells de paràmetres inflamatoris i adipoquines. Per últim, la validació d’eines de recollida d’informació nutricional amb marcadors biològics i l’adherència a patrons dietètics saludables, com la Dieta Mediterrània, permet classificar als individus en funció de la seva ingesta dietètica.

Background: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. Methods: The association of metabolically defined body size phenotypes with endometrial cancer risk was investigated in a nested case–control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue nationale contre le cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, Helmholtz Association, German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Consiglio Nazionale delle Ricerche (CNR), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund (WCRF-ERC) 232997, Netherlands Government, Health Research Fund (FIS)-Instituto de Salud Carlos III (ISCIII), Junta de Andalucia, Principality of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Catalan Institute of OncologyICO (Spain), Swedish Cancer Society Swedish Research Council, European Commission, County Council of Skane, County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017 C19335/A21351, UK Research & Innovation (UKRI), Medical Research Council UK (MRC), European Commission 1000143 MR/M012190/1

La prevalença de l'obesitat i l'envelliment s'han incrementat dràsticament en les últimes dècades. L'obesitat s'associa a una pèrdua de la funció de barrera intestinal i a canvis en la microbiota (disbiosis). Això provoca una major absorció d'endotoxines i, amb això, una resposta inflamatòria sistèmica, directament relacionada amb el desenvolupament de la síndrome metabòlica. Les proantocianidinas són composts bioactivos d'origen natural que protegeixen davant d'alteracions intestinals induïdes per dietes hipercalóricas. Les proantocianidinas redueixen la translocació d'endotoxines i actuen com a agent antiinflamatori en models animals joves. S'ha plantejat la hipòtesi que l'envelliment podria derivar en efectes similars sobre la funcionalitat de la barrera intestinal, però se sap poc sobre l'efecte de les proantocianidinas durant l'envelliment. L'objectiu principal d'aquesta tesi és avaluar el paper de les proantocianidinas en la modulació d'alteracions metabòliques i intestinals associades a l'obesitat i a l'envelliment. Trobem que una dosi farmacològica de GSPE (500 mg/kg bw) redueix el guany de pes corporal actuant sobre la ingesta quan s'administra de manera preventiva a rates envellides alimentades amb dieta estàndard. Aquesta dosi de GSPE també redueix l'augment de pes corporal i la esteatosis hepàtica quan s'administra simultàniament a rates envellides que reben una dieta CAF La prevalencia de la obesidad y el envejecimiento se han incrementado drásticamente en las últimas décadas. La obesidad se asocia a una pérdida de la función de barrera intestinal y a cambios en la microbiota (disbiosis). Esto provoca una mayor absorción de endotoxinas y, con ello, una respuesta inflamatoria sistémica, directamente relacionada con el desarrollo del síndrome metabólico. Las proantocianidinas son compuestos bioactivos de origen natural que protegen frente a alteraciones intestinales inducidas por dietas hipercalóricas. Las proantocianidinas reducen la translocación de endotoxinas y actúan como agente antiinflamatorio en modelos animales jóvenes. Se ha planteado la hipótesis de que el envejecimiento podría derivar en efectos similares sobre la funcionalidad de la barrera intestinal, pero se sabe poco sobre el efecto de las proantocianidinas durante el envejecimiento. El objetivo principal de esta tesis es evaluar el papel de las proantocianidinas en la modulación de alteraciones metabólicas e intestinales asociadas a la obesidad y al envejecimiento. Encontramos que una dosis farmacológica de GSPE (500 mg/kg bw) reduce la ganancia de peso corporal actuando sobre la ingesta cuando se administra de forma preventiva a ratas envejecidas alimentadas con dieta estándar. Esta dosis de GSPE también reduce el aumento de peso corporal y la esteatosis hepática cuando se administra simultáneamente a ratas envejecidas que reciben una dieta CAF. Obesity and aging have become issues of global concern in recent decades. Obesity is associated with a loss of intestinal barrier function and changes in the microbiota (dysbiosis). Together, this causes a greater transport of endotoxins into the bloodstream and, with it, a systemic inflammatory response that is directly related to the development of metabolic syndrome. Proanthocyanidins are bioactive compounds of natural origin that have a protective effect against intestinal alterations associated with obesity induced by the consumption of high-fat/high-sugar diets. Specifically, proanthocyanidins reduce the translocation of endotoxins and act as an anti-inflammatory agent at the systemic level in young animal models. Moreover, it has been hypothesized that aging might derive in similar effects on the intestinal barrier functionality, but little is known about proathocyanidin therapeutic effect during aging. In that sense, the main objective of this thesis is to evaluate the role of proanthocyanidins in the modulation of metabolic and intestinal disruptions associated with obesity and aging. We found that a pharmacological dose of GSPE (500 mg/kg bw) is able to reduce the body weight gain by reducing food intake when administered preventively to aged rats fed a standard diet. This dose of GSPE also reduces body weight gain as well as fat accumulation in the liver when administered simultaneously to aged rats receiving CAF diet.

Orexin-A, a hormone secreted by orexin neurons, is involved in caloric-intake regulation. Current understanding is based primarily on animal studies. Studies of orexin in humans are scarce, and to our knowledge there are no prior studies in adolescents. We studied fasting Orexin-A levels related to energy intake at breakfast and a subsequent snack in adolescents (n = 668) from a longitudinal study in Chile. Body-Mass Index (BMI), components of the metabolic syndrome and fasting blood levels of leptin, insulin, ghrelin, and orexin-A were measured. Energy intake was calculated based on food weights before and after the standardized breakfast and subsequent snack. High energy intake was defined as ≥ 75th percentile. We assessed the relationship between orexin-A and high energy intake, adjusting for confounders. Higher orexin levels were associated with high breakfast energy intake (OR: 1.21; 95%CI: 0.98-1.49). Conversely, those with higher orexin levels showed a non-significant trend for lower odds of high energy intake for the snack (OR: 0.87; 95%CI: 0.70-1.07). There was a significant interaction between high breakfast energy intake and orexin levels. Those who ate more calories at breakfast displayed a lower inhibitory effect of orexin on eating at the snack (p < 0.05). There was no significant interaction between weight status and orexin. In conclusion, orexin-A levels were associated with breakfast energy intake and inversely related with subsequent snack energy intake in participants whose caloric intake at breakfast was within the normal range. Based on these findings, it appears that the association of orexin-A with energy intake depends on eating behavior.