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Background/objectives: Different approaches are used to classify obesity severity. Beyond classical anthropometric measurements, the Edmonton Obesity Staging System (EOSS) considers medical, physical and psychological parameters. However, this method has some limitations, principally due to the absence of an objective measure for physical impairment. The aim of our study is thus to overcome this limitation suggesting a new functional parameter obtained by cardiopulmonary exercise testing (CPET), i.e., cardiorespiratory fitness (CRF), expressed as weight-adjusted peak oxygen consumption (VO 2 peak/kg)., Subjects/methods: This observational cross-sectional study conducted on a population of 843 patients affected by obesity finally enrolled 500 subjects. Every patient underwent clinical, anthropometric, biochemical assessment and CPET. First, participants have been classified according to standard EOSS in five stages. Second, patients were reclassified according to the new modified EOSS (EOSS-CRF) based on their age- and gender-appropriate VO 2 peak/kg percentiles as reported in the healthy normal-weight population of the FRIEND registry., Results: VO 2 peak/kg was significantly different between standard EOSS classes 1 and 2 and classes 1 and 3 (ANCOVA p model = 0.004), whereas patients in classes 2 and 3 showed similar CRF. The EOSS-CRF classification varied in number of patients in each class compared to EOSS, particularly with a shift from class 2 to class 3. Moreover, CRF showed that physical impairment is less addressed by EOSS when compared to EOSS-CRF., Conclusions: The integration of EOSS with CRF allowed us to assign to each patient a severity index that considers not only clinical parameters, but also their functional impairment through a quantitative and prognostically important parameter (VO 2 peak/kg). This improvement of the staging system may also provide a better approach to identify individuals at increased risk of mortality leading to targeted therapeutic management and prognostic risk stratification for patients with obesity., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Although obesity represents a risk factor for the development of type 2 diabetes mellitus (T2DM), the link between these pathological conditions is not so clear. The manner in which the different elements of adipose tissue (AT) interplay in order to grow has been suggested to have a role in the genesis of metabolic complications, but this has not yet been fully addressed in humans. Through IHC, transmission electron microscopy, cytometry, and in vitro cultures, we described the morphological and functional changes of subcutaneous and visceral AT (SAT and VAT) in normoglycemic, prediabetic and T2DM patients with obesity compared to lean subjects. In both SAT and VAT we measured a hypertrophic and hyperplastic expansion, causing similar vascular rarefaction in obese patients with different degrees of metabolic complications. Capillaries display dysfunctional basement membrane thickening only in T2DM patients evidencing VAT as a new target of T2DM microangiopathy. The largest increase in adipocyte size and decrease in adipose stem cell number and adipogenic potential occur both in T2DM and in prediabetes. We showed that SAT and VAT remodeling with stemness deficit is associated with early glucose metabolism impairment suggesting the benefit of an AT-target therapy controlling hypertrophy and hyperplasia already in prediabetic obese patients.

Background: Non-alcoholic fatty liver disease (NAFLD) has a high prevalence in obesity and its presence should be screened. Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for obesity, but its effects on NAFLD are still to be firmly established. The diagnosis of non-alcoholic steatohepatitis (NASH) is currently performed by liver biopsy, a costly and invasive procedure. Squamous cell carcinoma antigen-IgM (SCCA-IgM) is a biomarker of viral hepatitis to hepatocellular carcinoma development and its role in NAFLD to NASH progression has not yet been investigated., Objective: The aim of this study was to evaluate SCCA-IgM as a non-invasive biomarker of NAFLD/NASH in patients with different degrees of metabolic-complicated obesity before and after LSG., Method: Fifty-six patients with obesity were studied before and 12 months after LSG; anthropometric, biochemical, clinical, and imaging data were collected., Results: At baseline steatosis was strongly associated with the glycaemic profile (p = 0.016) and was already present in prediabetic patients with obesity (82%). Only 3 patients had an SCCA-IgM level above the normal cut-off. SCCA-IgM titre did not change according to glycaemic profile or steatosis. Metabolic and inflammatory factors and transaminases significantly reduced after LSG-induced weight loss, except for SCCA-IgM. The ALT/AST ratio decreased post-LSG correlated with BMI (r = 0.297, p = 0.031), insulin (r = 0.354, p = 0.014), and triglycerides (r = 0.355, p = 0.009) reduction., Conclusions: Our results confirm the tight link between NAFLD and metabolic complications, suggesting prediabetes as a new risk factor of steatosis. SCCA-IgM does not seem to have a role in the identification and prognosis of NAFLD., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Insulin plays a major role in glucose metabolism and insulin-signaling defects are present in obesity and diabetes. CK2 is a pleiotropic protein kinase implicated in fundamental cellular pathways and abnormally elevated in tumors. Here we report that in human and murine adipocytes CK2-inhibition decreases the insulin-induced glucose-uptake by counteracting Akt-signaling and GLUT4-translocation to the plasma membrane. In mice CK2 acts on insulin-signaling in adipose tissue, liver and skeletal muscle and its acute inhibition impairs glucose tolerance. Notably, CK2 protein-level and activity are greatly up-regulated in white adipose tissue from ob/ob and db/db mice as well as from obese patients, regardless the severity of their insulin-resistance and the presence of pre-diabetes or overt type 2 diabetes. Weight loss obtained by both bariatric surgery or hypocaloric diet reverts CK2 hyper-activation to normal level. Our data suggest a central role of CK2 in insulin-sensitivity, glucose homeostasis and adipose tissue remodeling. CK2 up-regulation is identified as a hallmark of adipose tissue pathological expansion, suggesting a new potential therapeutic target for human obesity.

Background: Although individual occurrence is rare, syndromic obesity with mental retardation has been reported in conjunction with 140 different diseases., Case Presentation: The patient was born at term after a pregnancy complicated by threatened miscarriage. A diagnosis of Bardet-Biedl syndrome (BBS; OMIM #209900) was made in another hospital when she was 8 years old, but other clinical problems emerged subsequently. She came to our attention for the first time when she was 14 years old. The clinical picture, characterized by the presence of ophthalmological, renal, endocrinological, and liver disorders associated with a peculiar weight growth pattern, was more suggestive for Alström syndrome (ALMS; OMIM #203800); consequently, a genetic study was performed. Genetic analysis revealed a novel compound heterozygous frameshift mutation on exon 8 of ALMS1 (c. [3251_3258delCTGACCAG] and c. [6731delA]), which has not previously been described., Conclusion: Early onset of retinal degeneration associated with obesity represents a diagnostic challenge in paediatric and genetic practice, although the absence of skeletal abnormalities and developmental delay could help in addressing the clinical diagnosis. Confirmation of clinical suspicion by genetic analysis has been diriment in this case, since only a single gene is known to cause ALMS.

Background: Alström syndrome (ALMS) is a rare autosomal recessive monogenic disease associated with obesity, hyperinsulinemia, and alterations of glucose metabolism that often lead to the development of type 2 diabetes at a young age., Objective: To study the relationship between weight and metabolism in a group of ALMS patients and matched controls., Research Design and Methods: Fifteen ALMS patients (eight males, seven females; aged 3-51) were compared in a cross-sectional study with an age- and weight-matched control population. Anthropometric parameters, fat mass, glucose and insulin secretion in basal and dynamic oral glucose tolerance test (OGTT) conditions were measured. Furthermore, anthropometric and body composition data were obtained from an international group of 27 ALMS patients (13 males, 14 females, age range: 4-29 yr)., Results: In ALMS we observed an inverse correlation between age and standard deviation scores for height, weight, and body mass index. The OGTT glycemic curves of ALMS subjects were similar to those of age-matched controls, whereas insulin response was clearly greater. In ALMS individuals the insulin response showed a reduction with age. We documented pathologic values of the derived indices homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index, HOMA%β-cell and insulinogenic index in ALMS, but unlike the insulin-resistance indices, the β-cell function indices showed a significant reduction with age., Conclusions: In ALMS the progression from the early onset obesity toward the impaired fasting glucose or impaired glucose tolerance and overt diabetes is mostly because of a progressive failure of β-cell insulin secretion without any further worsening of insulin resistance with age, even in the presence of weight reduction., (© 2011 John Wiley & Sons A/S.)

Background: Alström syndrome (ALMS) is a rare recessively inherited progressive disease (OMIM 203800). Among its diverse spectrum of clinical features are phenotypes associated with deficiencies of the GH/IGF-I axis, including short stature, obesity, insulin resistance, hypertriglyceridaemia and heart failure., Patients and Measurements: To characterize the IGF system in ALMS, we evaluated a subset of 15 young adults with ALMS for hepatic, renal and thyroid function. Glycaemic and hormone measurements such as insulin, GH, FSH, LH, testosterone and 17-beta-oestradiol were clinically assessed. In addition, we measured IGF-I, IGF-II, IGF binding-protein-3 (IGFBP-3) and acid labile subunit (ALS - the subunits that constitute the main somatomedin complex in the circulation), and IGFBP-1 and IGFBP-2 (known to influence the bioavailability of the IGFs)., Results: A significantly lower height was observed in ALMS patients compared to age-matched controls. ALMS patients were clinically obese (by weight and body mass index (BMI) standards) and leptin levels correlated with BMI. Renal and hepatic dysfunction was implicated in some patients by increased values of blood urea nitrogen (BUN) and creatinine, and transaminases, respectively. One-third of the patients presented with fasting hyperglycaemia and 80% were hyperinsulinaemic. TSH was slightly increased in 20% of patients. Baseline FSH and LH in females were within the normal range, while half of the males had abnormally low testosterone values. Male patients with hypogonadism showed significantly lower testosterone, oestrogen and ALS levels. Baseline GH values were not found to be increased. ALS and IGFBP-1 were significantly reduced and IGFBP-2 was markedly increased in ALMS patients compared to age-matched controls. The IGFs and IGFBPs were not significantly different between males and females affected with ALMS. No significant association was observed between IGFs or IGFBPs levels and weight, height, BMI, glycaemia, hyperinsulinaemia and testosterone levels. However, we found a significant association of gamma-glutamyltransferase (GGT) with IGFBP-2. IGF-I levels were significantly associated with LH in female patients., Conclusions: In summary, the reduction of ALS and the increase of IGFBP-2 points to a growth hormone deficiency (GHD) condition in ALMS. However, further tests, including GH dynamics, are needed to determine whether, or to what degree disturbances in the GH/IGF axis contribute to the relatively short stature.

Context: Visfatin was recently identified as a protein highly expressed and secreted in adipose tissue with insulin-mimetic effect and is a candidate hormone to help explain the association among adipose tissue expansion, insulin resistance, and type 2 diabetes., Objective: The objective of the study was to assess expression of visfatin in lean and obese subjects and in sc and visceral adipose tissue and moreover to explore the role of visfatin on insulin resistance in humans., Design: We measured circulating visfatin and its mRNA expression in sc adipose tissue (SAT) in lean and obese subjects. Furthermore, we measured visfatin mRNA in visceral adipose (VAT) and SAT by quantitative RT-PCR. Finally, plasma visfatin and its mRNA in SAT were measured under free fatty acid-induced insulin resistance in healthy subjects., Results: Plasma visfatin and its mRNA in SAT were significantly lower in obese subjects, compared with normal-weight controls. Both circulating visfatin and SAT visfatin mRNA were negatively correlated with body mass index, whereas no correlation was found with homeostasis model assessment. Significantly higher visfatin mRNA was found in VAT of obese subjects, compared with lean controls. Interestingly, visfatin mRNA in VAT was positively correlated with BMI. Elevation of free fatty acid induced a condition of insulin resistance but did not affect either circulating visfatin or its mRNA., Conclusions: Our findings show that, in human obesity, plasma visfatin is reduced, whereas visfatin mRNA is differentially regulated in SAT and VAT. Visfatin is not related to insulin resistance either as assessed by homeostasis model assessment or during lipid infusion.

Context: Determinants of insulin resistance in Prader-Willi syndrome (PWS) are not completely understood. The discovery of several adipokines with relevant effects on insulin resistance and cardiovascular complications of metabolic syndrome offered new tools of investigation of insulin resistance in PWS., Objective: The purpose of this study was to measure serum resistin and mRNA in adipose tissue of patients with PWS, those with simple obesity, and healthy controls and correlate resistin levels with anthropometric and biochemical features., Design: Twenty-eight adult PWS patients, 29 obese patients, and 25 healthy controls were studied. Anthropometric variables were measured and fasting serum and plasma were collected for measurement of resistin, adiponectin, leptin, lipid profile, glucose, and insulin., Results: Serum resistin and resistin mRNA expression in adipose tissue was significantly higher in PWS patients, compared with both healthy lean controls and obese patients. Moreover, on regression analysis resistin was significantly correlated with body mass index, whereas no significant association was found between resistin and homeostasis model assessment index. A weak association between resistin and adiponectin was found in the PWS group only. However, on multivariate analysis only the correlation between resistin and body mass index remained significant., Conclusions: These results support a link between circulating resistin and obesity in humans but do not support a role for resistin in human insulin resistance.

Objective: Obesity-related insulin resistance is closely associated with visceral fat accumulation. Several adipocyte-secreted molecules have been implicated in the development of type 2 diabetes, among them, the recently discovered adiponectin and resistin proteins. Some of these adipocytokines are also present in the immune system, thus suggesting an intriguing functional connection., Research Methods and Procedures: We determined adiponectin and resistin expressions in visceral (VAT) and subcutaneous adipose tissue of lean and obese Zucker (fa/fa) rats using reverse-transcription polymerase chain reaction. Moreover, we analyzed the variations after body-weight reduction in food-restricted obese rats., Results: Resistin and adiponectin expression was significantly lower in VAT of genetically obese in comparison with lean rats; no differences were observed when subcutaneous adipose tissues of the same animals were compared. Weight loss resulted in an increase of adiponectin expression in VAT, whereas a further significant decrease in resistin mRNA level was observed. Resistin is also present and equally expressed in splenocytes of lean and obese rats., Discussion: Adiponectin and resistin are down-regulated in VAT of obese rats. Adiponectin expression is restored to normal levels after body-weight reduction, supporting its link with obesity-related insulin resistance. On the contrary, the further decrease of resistin mRNA after weight loss does not support the hypothesis that resistin may play a causative role in insulin resistance in obese rats. Moreover, we demonstrated the presence of resistin in immunocompetent cells in both humans and rats, thus adding another factor to the list of molecules that adipose tissue shares with the immune system.

Background: Different approaches are used to classify obesity severity. The Edmonton Obesity Staging System (EOSS) considers medical, physical and psychological parameters. A new modified EOSS with a different functional evaluation method, measuring Cardiorespiratory Fitness (CRF), has been recently proposed, EOSS-CRF. Bariatric surgery (BS) is one of the most efficient treatments of obesity and all aspect of related disorders. No studies have yet applied EOSS-CRF after BS. Therefore, the aim of this study was to evaluate modifications in EOSS and EOSS-CRF before and after BS. Methods: This observational study finally enrolled 72 patients affected by obesity. A multi-disciplinary assessment in order to evaluate eligibility to surgical treatment has been performed, including anamnesis, physical evaluation, anthropometric data measurement, biochemical blood exams and cardiopulmonary exercise testing. One year after BS the same protocol was applied. Patients have been classified according to EOSS and EOSS-CRF before and one year after BS. Results: After BS, patients categorized in classes associated to severe obesity (EOSS = 2 or EOSS-CRF = 2) reduced significantly. Using EOSS, patients without functional impairment were 61% before surgery and 69% after BS (p=0.383). Using EOSS-CRF, patients considered without functional impairment were only 9.7% before BS; this percentage significantly raised to 50% after BS (p<0.001). The impact of functional domains before and after BS is different in grading patients in EOSS and EOSS-CRF, respectively. Conclusions: Improvements obtained after BS are adequately summarized by EOSS and EOSS-CRF. The EOSS-CRF grading method for functional impairment seems to better reflect the known amelioration obtained after BS. Objective measurements of CRF may provide additional value to classify severity of obesity, also in the follow-up after BS. [ABSTRACT FROM AUTHOR]

Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause–effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to the immunometabolism and secretome. Moreover, AT and cancer share similar morpho-functional units which regulate tissue expansion: the adiponiche and tumour-niche, respectively. Through direct and indirect interactions involving different cellular types and molecular mechanisms, the obesity-altered adiponiche contributes to cancer development, progression, metastasis and chemoresistance. Moreover, modifications to the gut microbiome and circadian rhythm disruption also play important roles. Clinical studies clearly demonstrate that weight loss is associated with a decreased risk of developing obesity-related cancers, matching the reverse-causality criteria and providing a causality correlation between the two variables. Here, we provide an overview of the methodological, epidemiological and pathophysiological aspects, with a special focus on clinical implications for cancer risk and prognosis and potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

Alström syndrome (AS) is a rare genetic disease caused by ALMS1 mutations, characterized by short stature, and vision and hearing loss. Patients with AS develop the metabolic syndrome, long-term organ complications, and die prematurely. We explored the association between AS and a shortage of hematopoietic stem/progenitor cells (HSPCs), which is linked to metabolic diseases and predicts diabetic complications. We included patients with AS at a national referral center. We measured HSPCs with flow cytometry at baseline and follow-up. We followed patients up to January 2022 for metabolic worsening and end-organ damage. We evaluated HSPC levels and mobilization as well as bone marrow histology in a murine model of AS. In 23 patients with AS, we found significantly lower circulating HSPCs than in healthy blood donors (−40%; P =.002) and age/sex-matched patients (−25%; P =.022). Longitudinally, HSPCs significantly declined by a further 20% in patients with AS over a median of 36 months (interquartile range 30-44). Patients with AS who displayed metabolic deterioration over 5.3 years had lower levels of HSPCs, both at baseline and at last observation, than those who did not deteriorate. Alms1 -mutated mice were obese and insulin resistant and displayed significantly reduced circulating HSPCs, despite no overt hematological abnormality. Contrary to what was observed in diabetic mice, HSPC mobilization and bone marrow structure were unaffected. We found depletion of HSPCs in patients with AS, which was recapitulated in Alms1 -mutated mice. Larger and longer studies will be needed to establish HSPCs shortage as a driver of metabolic deterioration leading to end-organ damage in AS. [ABSTRACT FROM AUTHOR]

Background: Alström syndrome (AS) is an ultrarare multisystemic progressive disease caused by autosomal recessive variations of the ALMS1 gene (2p13). AS is characterized by double sensory impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, early nonalcoholic fatty liver disease, renal dysfunction, respiratory disease, endocrine and urologic disorders. In female AS patients, hyperandrogenism has been described but fertility issues and conception have not been investigated so far. Case: This case report describes the spontaneous conception, pregnancy, and birth in a 27-year-old woman with AS, characterized by a mild phenotype with late onset of visual impairment, residual perception of light, and hypertension. Before pregnancy, menses were regular with increased levels of dihydrotestosterone and androstanediol glucuronide in the follicular phase, and the ovaries and endometrium were normal during vaginal ultrasound. A thorough clinical follow-up of the maternal and fetal conditions was carried out. A weight gain of 10 kg during pregnancy was recorded, and serial blood and urine tests were all within the normal range, except for mild anemia. The course of pregnancy was uneventful up to 34 weeks of gestation when preeclampsia developed with an abnormally high level of blood pressure and edema in the lower limbs. At 35 weeks + 3 days of gestation, an urgent cesarean section was performed, and a healthy male weighing 1,950 g was born. Histological examination of the placenta showed partial signs of flow obstruction, limited abruption areas, congested fetal vessels and villi, and a small single infarcted area. Conclusion: The present case demonstrates for the first time that conceiving is possible for patients with ALMS. Particular attention should be given to the management of AS systemic comorbidities through the course of pregnancy. [ABSTRACT FROM AUTHOR]

Background: Resting energy expenditure (REE) decreases after weight loss more than expected according to body composition changes. Metabolic adaptation (MA) or metabolic slowing represents the difference between measured (m) and predicted (p) REE, and it is not clear whether it persists in the long-term. The aim of this study is to evaluate MA occurring 1 year (V1) and 5 years (V5) after laparoscopic sleeve gastrectomy (LSG) in patients with obesity and normal glucose tolerance, prediabetes (preDM) and type 2 diabetes (T2DM). Methods: We reassessed 37 patients (14 males/23 females) of 44.8 ± 10 years old, since they registered all the biochemical, body composition, and REE assessments at baseline (V0), V1, and V5. Physical activity (PA) was assessed by interview and questionnaire. Results: Patients displayed a percentage of weight loss of 31.5 ± 7.4% at V1 and a weight regain of 8.9 ± 7.5% at V5. Comparing V1 and V5, fat mass showed a slight increase (P = 0.011), while free fat mass remained unchanged (P = 0.304). PA improved at V1 (P < 0.001), remaining stable at V5 (P = 0.9). Measured REE (mREE) displayed a 31.2% reduction with a corresponding decrease of predicted REE (pREE) of 21.4% at V1, compared with V0 (P = 0.005), confirming a significant MA at V1. Conversely, no difference between mREE and pREE was observed at V5 (P = 0.112). Conclusion: Our results suggested that only patients with preDM and T2DM displayed MA at V1, which vanished 5 years after LSG. Patients who practiced more PA prevent MA after surgery-induced wight loss. [ABSTRACT FROM AUTHOR]

We describe adipose stromal/stem cells (ASCs) in the structural/functional context of the adipose tissue (AT) stem niche (adiponiche), including cell–cell interactions and the microenvironment, and emphasize findings obtained in humans and in lineage-tracing models. ASCs have distinctive markers, 'colors', and anatomical 'locations' which influence their functions. Each adiponiche component can become impaired, thereby contributing to the pathological AT alterations seen in obesity and metabolic diseases. We discuss adiposopathy with a focus on adiponiche dysfunction, and underline the mechanisms that control AT expansion and energy balance. Better understanding of adiponiche regulation and ASC features could help to identify therapeutic targets that favor weight loss and counteract weight regain, and also contribute to innovative strategies for regenerative medicine. ASCs have been analyzed in the structural/functional context of the adiponiche. The adiponiche consists of multiple cell types, the microenvironment, and their interactions that control ASC homeostasis. ASCs possess specific markers distinct characteristics that are associated with their anatomical 'location', and probably their 'color'. ASCs localize near to blood vessels and probably consist of many distinct subpopulations. Each adiponiche component can became dysregulated and can play a role in obesity and metabolic disease. [ABSTRACT FROM AUTHOR]

Determinants of resting energy expenditure (REE) in humans are still under investigation, especially the association with insulin resistance. Brown adipose tissue (AT) regulates energy expenditure through the activity of the uncoupling protein 1 (UCP1). White AT browning is the process by which some adipocytes within AT depots acquire properties of brown adipocytes ("brite" adipocytes) and it correlates with metabolic improvement. We analyzed determinants of REE in patients with obesity and assessed UCP1 expression as a "brite" marker in abdominal subcutaneous AT (SAT) and visceral omental AT (VAT). Clinical data, REE, free fat mass (FFM), and fat mass (FM) were determined in 209 patients with obesity. UCP1 , PPARG coactivator 1 alpha (PPARGC1A), transcription factor A, mitochondrial (TFAM), T-box transcription factor 1 (TBX1), and solute carrier family 27 member 1 (SLC27A1) expression was assayed in SAT and VAT samples, obtained during sleeve gastrectomy from 62 patients with obesity. REE and body composition data were also available for a subgroup of 35 of whom. In 209 patients with obesity a multiple regression model was computed with REE as the dependent variable and sex, waist, FFM, FM, homeostasis model assessment-insulin resistance (HOMA), interleukin-6 and High Density Lipoprotein-cholesterol as the independent variables. Only FFM, FM and HOMA were independently correlated with REE (r = 0.787, AdjRsqr = 0.602). In each patient VAT displayed a higher UCP1, PPARGC1A, TFAM, TBX1 , and SLC27A1 expression than SAT and UCP1 expression in VAT (UCP1 -VAT) correlated with Body Mass Index (BMI) (r = 0.287, p < 0.05). Introducing UCP1 -VAT in the multivariate model, we showed that FFM, HOMA, interleukin-6, High Density Lipoprotein-cholesterol, and UCP1 -VAT were independent factors correlated with REE (r = 0.736, AdjRsqr = 0.612). We confirmed that REE correlates with FFM, FM and HOMA in a large cohort of patients. Our results clearly showed that UCP1 -VAT expression was significantly increased in severe human obesity (BMI > 50 kg/m2) and that it behaved as an independent predictor of REE. Lastly, we suggest that an increased REE and browning in metabolically complicated severe obesity could represent an effort to counteract further weight gain. [ABSTRACT FROM AUTHOR]

Intracellular calcium influences an array of pathways and affects cellular processes. With the rapidly progressing research investigating the molecular identity and the physiological roles of the mitochondrial calcium uniporter (MCU) complex, we now have the tools to understand the functions of mitochondrial Ca2 + in the regulation of pathophysiological processes. Herein, we describe the role of key MCU complex components in insulin resistance in mouse and human adipose tissue. Adipose tissue gene expression was analyzed from several models of obese and diabetic rodents and in 72 patients with obesity as well as in vitro insulin-resistant adipocytes. Genetic manipulation of MCU activity in 3T3-L1 adipocytes allowed the investigation of the role of mitochondrial calcium uptake. In insulin-resistant adipocytes, mitochondrial calcium uptake increased and several MCU components were upregulated. Similar results were observed in mouse and human visceral adipose tissue (VAT) during the progression of obesity and diabetes. Intriguingly, subcutaneous adipose tissue (SAT) was spared from overt MCU fluctuations. Furthermore, MCU expression returned to physiological levels in VAT of patients after weight loss by bariatric surgery. Genetic manipulation of mitochondrial calcium uptake in 3T3-L1 adipocytes demonstrated that changes in mitochondrial calcium concentration ([Ca2+]mt) can affect mitochondrial metabolism, including oxidative enzyme activity, mitochondrial respiration, membrane potential, and reactive oxygen species formation. Finally, our data suggest a strong relationship between [Ca2+]mt and the release of IL-6 and TNFa in adipocytes. Altered mitochondrial calcium flux in fat cells may play a role in obesity and diabetes and may be associated with the differential metabolic profiles of VAT and SAT. [ABSTRACT FROM AUTHOR]

Alström syndrome (ALMS) is an ultra-rare monogenic disease characterized by insulin resistance, multi-organ fibrosis, obesity, type 2 diabetes mellitus (T2DM), and hypertriglyceridemia with high and early incidence of non-alcoholic fatty liver disease (NAFLD). We evaluated liver fibrosis quantifying liver stiffness (LS) by shear wave elastography (SWE) and steatosis using ultrasound sonographic (US) liver/kidney ratios (L/K) in 18 patients with ALMS and 25 controls, and analyzed the contribution of metabolic and genetic alterations in NAFLD progression. We also genetically characterized patients. LS and L/K values were significantly higher in patients compared with in controls (p < 0.001 versus p = 0.013). In patients, LS correlated with the Fibrosis-4 Index and age, while L/K was associated with triglyceride levels. LS showed an increasing trend in patients with metabolic comorbidities and displayed a significant correlation with waist circumference, the homeostasis model assessment, and glycated hemoglobin A1c. SWE and US represent promising tools to accurately evaluate early liver fibrosis and steatosis in adults and children with ALMS during follow-up. We described a new pathogenic variant of exon 8 in ALMS1. Patients with ALMS displayed enhanced steatosis, an early increased age-dependent LS that is associated with obesity and T2DM but also linked to genetic alterations, suggesting that ALMS1 could be involved in liver fibrogenesis. [ABSTRACT FROM AUTHOR]