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Background: Maladaptive ER stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell death-promoting transcription factor C/EBP homologous protein (CHOP). We determined whether therapy with locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CHOP ameliorates experimental DKD. Methods: Following an in vivo dose-escalation study, we determined the efficacy of CHOPASO in the early and later stages of experimental DKD (8- or 16-week-old db/db mice, respectively) alone or in combination with an angiotensin-converting enzyme inhibitor (ACEi). Renal functional parameters and morphological analyses were used to determine the effects. Renal gene expression profiling was conducted to determine differentially regulated genes and pathways. Several human CHOP-ASOs were tested in hyperglycemia-exposed human kidney cells. Results: CHOP-ASOs efficiently reduced renal CHOP expression in diabetic mice and reduced markers of DKD at early and late stages. Early combined intervention (CHOP-ASO and ACEi) efficiently prevented interstitial damage. At the later timepoint, the combined treatment reduced indices of both glomerular and tubular damage more efficiently than either intervention alone. A significantly larger number of genes and disease pathways were affected by CHOP-ASO, including reduced Slc5a2 (sodium-glucose transport protein 2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented cell death of human kidney cells in vitro Conclusions: The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi in particular at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD.

Lifestyle intervention (LI) can prevent type 2 diabetes, but response to LI varies depending on risk subphenotypes. We tested whether individuals with prediabetes with low risk (LR) benefit from conventional LI and individuals with high risk (HR) benefit from an intensification of LI in a multicenter randomized controlled intervention over 12 months with 2 years’ follow-up. A total of 1,105 individuals with prediabetes based on American Diabetes Association glucose criteria were stratified into an HR or LR phenotype based on previously described thresholds of insulin secretion, insulin sensitivity, and liver fat content. LR individuals were randomly assigned to conventional LI according to the Diabetes Prevention Program (DPP) protocol or control (1:1) and HR individuals to conventional or intensified LI with doubling of required exercise (1:1). A total of 908 (82%) participants completed the study. In HR individuals, the difference between conventional and intensified LI in postchallenge glucose change was −0.29 mmol/L [95% CI −0.54; −0.04], P = 0.025. Liver fat (−1.34 percentage points [95% CI −2.17; −0.50], P = 0.002) and cardiovascular risk (−1.82 percentage points [95% CI −3.13; −0.50], P = 0.007) underwent larger reductions with intensified than with conventional LI. During a follow-up of 3 years, intensified compared with conventional LI had a higher probability of normalizing glucose tolerance (P = 0.008). In conclusion, it is possible in HR individuals with prediabetes to improve glycemic and cardiometabolic outcomes by intensification of LI. Individualized, risk phenotype–based LI may be beneficial for the prevention of diabetes.

ZusammenfassungDie Versorgungssituation für Menschen mit Adipositas ist in Deutschland defizitär. Dies liegt auch daran, dass es bisher keine gesetzlichen Rahmenbedingungen für eine leitlinien- und bedarfsgerechte Versorgung von Menschen mit Adipositas gab. Mit der Annahme des Gesetzes zur Weiterentwicklung der Gesundheitsversorgung durch den Deutschen Bundestag am 11. Juni 2021 wurden die formalen Voraussetzungen für ein strukturiertes Behandlungsprogramm für Menschen mit Adipositas in Deutschland geschaffen. Ein in diesem Gesetz gefordertes Disease Management Programm Adipositas könnte die Qualität der Versorgung für Betroffene erheblich verbessern.

BACKGROUND AND AIMS In the CENTRAL trial context, we found diverse liver fat dynamics in response to different dietary interventions. Epigenetic mechanisms may contribute to the intraindividual variation. Moreover, genetic factors are involved in developing nonalcoholic fatty-liver disease (NAFLD), a disease reflected by an increase in intrahepatic fat (IHF). In this exploratory analysis, we primarily aimed to examine the effect of lifestyle interventions on DNA-methylation of NAFLD related genes associated with IHF. METHODS For 120 participants from the CENTRAL trial, an 18-month regimen of either low-fat (LF) or Mediterranean-low carbohydrate (MED/LC) diets, with or without physical activity (PA+/PA-), was instructed. Magnetic resonance imaging was used to measure IHF%, which was analysed for association with CpG specific DNA-methylation levels of 41 selected candidate genes. Single-nucleotide polymorphisms known to be associated with NAFLD within the studied genes were genotyped by TaqMan assays. RESULTS At baseline, participants (92% men; body mass index = 30.2 kg/m2 ) had mean IHF of 10.7% (59% NAFLD). Baseline-IHF% was inversely correlated with DNA-methylation at individual CpGs within AC074286.1, CRACR2A, A2MP1, FARP1 (P

Background: Positron emission tomography (PET) has provided evidence that adult humans retain metabolically active brown adipose tissue (BAT) depots. Thyroid hormones (TH) stimulate BAT thermogenes...

Adipositas gehört zu den größten Herausforderungen im Gesundheitssystem, da ihre Prävalenz weltweit kontinuierlich steigt und sie das Risiko für Typ-2-Diabetes, kardiovaskuläre, metabolische, spezielle maligne, muskuloskelettale, neurodegenerative, pulmonale, psychische und andere Erkrankungen deutlich erhöht.Zu den Mechanismen, über die Adipositas zu diesen Folgekrankheiten beiträgt, zählt eine Aktivierung proinflammatorischer Signalwege. Infolge einer dauerhaft positiven Energiebilanz kommt es zur Überlastung der physiologischen Energiespeicher in subkutanen Fettdepots und vermehrter ektoper und viszeraler Fetteinlagerung. Der dadurch initiierte metabolische Stress im Fettgewebe löst eine lokale Entzündung aus, auch als Metaflammation bezeichnet. Eine vermehrte Infiltration des viszeralen Fettgewebes durch Zellen des Immunsystems führt zu veränderten Signalen aus diesem Gewebe (z. B. Zytokine, Adipokine, Metaboliten), die an Zielstrukturen, wie Leber, Muskulatur, Gefäßsystem, Hirn und anderen, zu Organschäden beitragen und eine niedriggradige, systemische Inflammation unterhalten können.Regelmäßige körperliche Aktivität gehört zur Basistherapie der Adipositas und des Typ-2-Diabetes, weil sie zu einer Verbesserung der Insulinsensitivität und zur Reduktion der viszeralen Fettmasse beiträgt. Sport und gezielte Steigerung der Bewegung können die inflammatorische Aktivierung sowie den metabolischen Stress des Fettgewebes reduzieren und wirken sich über diesen Mechanismus auch antientzündlich auf den Organismus auf. Daneben beeinflusst körperliche Aktivität die bei Adipositas und Typ-2-Diabetes häufig aktivierte humorale und zelluläre Immunantwort auch direkt. Die Entstehung von Metaflammation und deren Beeinflussung durch regelmäßigen Sport werden im vorliegenden Beitrag diskutiert.

Background Elucidation of lipid metabolism and accumulation mechanisms is of paramount importance to understanding obesity and unveiling therapeutic targets. In vitro cell models have been extensively used for these purposes, yet, they do not entirely reflect the in vivo setup. Conventional lipomas, characterized by the presence of mature adipocytes and increased adipogenesis, could overcome the drawbacks of cell cultures. Also, they have the unique advantage of easily accessible matched controls in the form of subcutaneous adipose tissue (SAT) from the same individual. We aimed to determine whether lipomas are a good model to understand lipid accumulation. Methods We histologically compared lipomas and control SAT, followed by assessment of the lipidome using high-resolution 1H NMR spectroscopy and ESI-IT mass spectrometry. RNA-sequencing was used to obtain the transcriptome of lipomas and the matched SAT. Results We found a significant increase of small-size (maximal axis 150 µm) adipocytes within lipomas. This suggests both enhanced adipocyte proliferation and increased lipid accumulation. We further show that there is no significant change in the lipid composition compared to matched SAT. To better delineate the pathophysiology of lipid accumulation, we considered two groups with different genetic backgrounds: (1) lipomas with HMGA2 fusions and (2) without gene fusions. To reduce the search space for genes that are relevant for lipid pathophysiology, we focused on the overlapping differentially expressed (DE) genes between the two groups. Gene Ontology analysis revealed that DE genes are enriched in pathways related to lipid accumulation. Conclusions We show that the common shared lipid accumulation mechanism in lipoma is a reduction in lipolysis, with most gene dysregulations leading to a reduced cAMP in the adipocyte. Superficial lipomas could thus be used as a model for lipid accumulation through altered lipolysis as found in obese patients.

ZusammenfassungZiel Analyse des derzeitigen Wissens zur Bedeutung der SARS-CoV-2-Pandemie für Menschen mit Adipositas. Formulierung von Gesundheitsempfehlungen der Deutschen Adipositas-Gesellschaft.Methodik Selektive Literatursuche in PubMed und Internetrecherche.Ergebnisse Derzeit gibt es keine belastbaren Hinweise, dass Menschen mit Adipositas ein erhöhtes SARS-CoV-2-Infektionsrisiko aufweisen. Adipositas ist jedoch ein wichtiger Risikofaktor für einen schweren COVID-19-Verlauf. Eine kausale Beziehung zwischen Adipositas und schwerem Krankheitsverlauf kann derzeit allerdings nicht abgeleitet werden. Jedoch zeigt die COVID-19-Situation, dass PatientInnen mit Adipositas bei Intensiv- und Beatmungspflichtigkeit klinisch in der Regel schwer zu führen sind.Schlussfolgerungen Die DAG rät Menschen mit Adipositas, die empfohlenen Hygieneregeln und Maßnahmen des Infektionsschutzgesetzes sowie der Kontaktbeschränkungen sorgfältig zu befolgen. Darüber hinaus sollten grundlegende Empfehlungen zum Gesundheitsschutz und zu einem gesunden Lebensstil beachtet werden.

Background: Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-neurotensin (Pro-NT) was associated with metabolic diseases and predicted incident CVD and mortality. However, Pro-NT regulation in CKD and its potential role linking CKD and mortality have not been investigated, so far. Methods: In a central lab, circulating Pro-NT was quantified in three independent cohorts comprising 4715 participants (cohort 1: patients with CKD; cohort 2: general population study; and cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. In a 4th independent cohort, serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-specific Nts expression was further investigated in two mouse models of diabetic CKD and compared to non-diabetic control mice. Results: Pro-NT significantly increased with deteriorating renal function (P < 0.001). In meta-analysis of cohorts 1–3, Pro-NT was significantly and independently associated with estimated glomerular filtration rate (P ≤ 0.002). Patients in the middle/high Pro-NT tertiles at baseline had a higher all-cause mortality compared to the low Pro-NT tertile (Hazard ratio: 2.11, P = 0.046). Mice with severe diabetic CKD did not show increased Nts mRNA expression in different tissues compared to control animals. Conclusions: Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4715 subjects and is related to all-cause mortality in patients with end-stage kidney disease. Our human and rodent data are in accordance with the hypotheses that Pro-NT is eliminated by the kidneys and could potentially contribute to increased mortality observed in patients with CKD.

ZusammenfassungIm Fettgewebe üben Omega-3-Fettsäuren multiple Effekte aus, verbunden mit systemischen Wirkungen. Veränderungen der Fettsäure-Zusammensetzung zellulärer Membranen, die sich funktionell auswirken, Interaktionen mit Membran- und intrazellulären Rezeptoren und die Synthese einer Vielzahl bioaktiver Metabolite sind eingeschlossen. Besonders bedeutsam sind die anti-inflammatorischen und entzündungsauflösenden Wirkungen von Omega-3-Fettsäuren. Die Effekte langkettiger Omega-3-Fettsäuren wie Eicosapentaensäure (EPA) und Docosahexaensäure (DHA) sowohl auf metabolische als auch auf Immunzellen des Fettgewebes modulieren inflammatorische Prozesse und wirken Fettgewebe-Dysfunktionen bei Adipositas entgegen. Weil eine chronisch-subklinische Entzündung und Dysfunktionen im Fettgewebe Risikofaktoren für Adipositas-Folgeerkrankungen darstellen, ist eine ausgewogene Ernährung einschließlich optimaler Aufnahme von Omega-3-Fettsäuren mit gesundheitsfördernden Wirkungen unter den Bedingungen der Adipositas verbunden.

Cartilage oligomeric matrix protein (COMP)-Angiopoietin-1 is a potent angiopoietin-1 (Ang-1) variant that possesses therapeutic potential in angiogenesis and vascular endothelial dysfunction. Noteworthy, we have shown that COMP-Ang-1 improves hyperglycemia and neuroregeneration in ob/ob mice. However, the mechanism of the antidiabetic effect of COMP-Ang-1 is completely unknown. Therefore, we elucidated the diabetes protective molecular mechanisms of COMP-Ang-1 in diabetic db/db mouse model. COMP-Ang-1 (0.5 ng/g body weight) or aqueous NaCl solution was injected intraperitoneally per day in 21 consecutive days into 3-month old, male db/db mice (n=10 per group). Blood glucose and HbA1c levels were determined at baseline and 21 days after COMP-Ang-1 or NaCl treatment. The effect of COMP-Ang-1 on glucose uptake was investigated by euglycemic-hyperinsulinemic clamp studies and key genes of glucose metabolism were studied by Western blot analysis. Our findings indicate that COMP-Ang-1 improves glucose metabolism in a tissue specific manner by regulating HIF-1α transcriptional genes of GLUT-1 expression.

Introduction The role of preoperative upper-gastrointestinal (GI) gastroscopy has been discussed with controversy in bariatric surgery. The aim of this study was to evaluate the incidence of upper-GI pathologies detected via endoscopy prior to bariatric surgery along with their clinical significance for patients’ management. Material and Methods In our single center prospectively established database of obese patients, who underwent bariatric surgery from January 2011 to December 2017, we retrospectively analyzed the perioperative endoscopic findings along with their influence on patients’ management. Results In total, 636 obese patients with median BMI (body mass index) of 49 kg/m2 [range 31–92] received an upper-GI endoscopy prior to bariatric surgery. Among the surgical procedures, laparoscopic Roux-Y-gastric bypass (72.6%; n = 462) was the most frequent operation. Endoscopically detected pathological conditions were peptic ulcer 3.5% (22/636), Helicobacter pylori (Hp) gastritis 22.4% (143/636), and gastric or duodenal polyps 6.8% (43/636). Reflux esophagitis could be detected in 139/636 patients (21.9%). Barrett’s esophagus (BE) was histologically diagnosed in 95 cases (15.0%), whereas BE was suspected endoscopically in 75 cases (11.3%) only. Esophageal adenocarcinomas were detected in 3 cases (0.5%). Change of the operative strategy due to endoscopically or histologically detected pathologic findings had to be performed in 10 cases (1.6%). Conclusion Preoperative upper-GI endoscopy identifies a wide range of abnormal endoscopic findings in obese patients, which may have a significant impact on decision-making, particularly regarding the most suitable bariatric procedure and the appropriate follow-up. Therefore, preoperative upper-GI endoscopy should be considered in all obese patients prior to bariatric procedure.

Background In 2017, the prevalence of obesity (BMI ≥ 30 kg/m2) in Germany was approximately 16%. Obesity increases an individual's risk of developing type 2 diabetes (T2DM) and arterial hypertension; it also increases overall mortality. Consequently, effective treatment is a necessity. Approximately 20 000 bariatric operations are performed in Germany each year. Methods This review is based on pertinent publications retrieved by a selective search in the PubMed and Cochrane databases and on current German clinical practice guidelines. Results The types of obesity surgery most commonly performed in Germany, Roux-en-Y gastric bypass and sleeve gastrectomy, lead to an excess weight loss of 27-69% ≥ 10 years after the procedure. In obese patients with T2DM, the diabetes remission rate ≥ 10 years after these procedures ranges from 25% to 62%. Adjusted regression analyses of data from large registries have shown that the incidence of malignancies is 33% lower in persons who have undergone obesity surgery compared to control subjects with obesity (unadjusted incidence 5.6 versus 9.0 cases per 1000 person-years). The operation can cause vitamin deficiency, surgical complications, gastroesophageal reflux, and dumping syndrome. Therefore, lifelong follow-up is necessary. Conclusion In view of an increasing number of patients undergoing bariatric surgery, it will probably not be feasible in the future for lifelong follow-up to be provided exclusively in specialized centers.

ZusammenfassungDas Darmmikrobiom ist ein komplexes Ökosystem, das aus einer Vielzahl von hauptsächlich Bakterien, aber auch Archaeen und Viren besteht. In den letzten Jahren konnte ein starker Zusammenhang zwischen Mikrobiom-Veränderungen und der Entstehung von Erkrankungen, zu denen auch Adipositas und verschiedene Stoffwechselkrankheiten gehören, gefunden werden. Darmbakterien sind an der Synthese essentieller Vitaminen, Extraktionen von Nährstoffen sowie den Abbau von Ballaststoffen beteiligt. Zusätzlich spielt das Mikrobiom eine wichtige Rolle in der Reifung des Immunsystems des Wirts, seiner Darmbarriere, der neuronalen intestinalen Aktivität, und der Produktion und Freisetzung von gastrointestinalen Hormonen. Veränderungen der Zusammensetzung des mikrobiellen Ökosystems im Darm sind mit dem Auftreten von Adipositas, Typ 2 Diabetes, arterieller Hypertonie, nicht alkoholischer Lebererkankung (NAFLD) sowie kardiovaskulären Krankheiten assoziiert.Vor allem tierexperimentelle Untersuchungen weisen auf einen starken Kausalzusammenhang zwischen dem Mikrobiom und diesen Erkrankungen hin. Hierfür können zusätzlich zu wirtspezifischen oder Umweltfaktoren sowohl Zusammensetzung wie auch die Funktion der Darmbakterien eine chronische systemische Inflammation mitverursachen und unterhalten.Ein möglichst diverses Mikrobiom kann die metabolische Gesundheit des Wirts positiv beeinflussen und stellt somit einen potentiellen therapeutischen Ansatz bei kardiometabolischen Erkrankungen dar. Beispielsweise werden Stuhltransplantationen zur Therapie unterschiedlicher Erkrankungen wie Clostridium difficile-Infektionen eingesetzt und verbessern auch bei Personen mit Metabolischem Syndrom die Insulinsensitivität. Bevor eine Modulation des Mikrobioms in der Zukunft zur Prävention und Therapie von Adipositas und begleitenden Erkrankungen eingesetzt werden kann, müssen noch weitere klinische Studien die Effektivität und Sicherheit einer gezielten Manipulation der Darmbakterien belegen.

Visceral adipose tissue shows remarkable plasticity, constantly replacing mature adipocytes from an inherent pool of adipocyte precursors. The number of precursors is set in the juvenile organism and remains constant in adult life. Which signals drive precursor pool expansion in juveniles and why they operate in visceral but not in subcutaneous white adipose tissue (WAT) are unclear. Using mouse models, we identified the insulin-sensitizing receptor SORLA as a molecular factor explaining the distinct proliferative capacity of visceral WAT. High levels of SORLA activity in precursors of juvenile visceral WAT prime these cells for nutritional stimuli provided through insulin, promoting mitotic expansion of the visceral precursor cell pool in overfed juvenile mice. SORLA activity is low in subcutaneous precursors, blunting their response to insulin and preventing diet-induced proliferation of this cell type. Our findings provide a molecular explanation for the unique proliferative properties of juvenile visceral WAT, and for the genetic association of SORLA with visceral obesity in humans. ISSN:0021-9525 ISSN:1540-8140

BackgroundRNA-seq emerges as a valuable method for clinical genetics. The transcriptome is “dynamic” and tissue-specific, but typically the probed tissues to analyze (TA) are different from the tissue of interest (TI) based on pathophysiology.ResultsWe developed Phenotype-Tissue Expression and Exploration (PTEE), a tool to facilitate the decision about the most suitable TA for RNA-seq. We integrated phenotype-annotated genes, used 54 tissues from GTEx to perform correlation analyses and identify expressed genes and transcripts between TAs and TIs. We identified skeletal muscle as the most appropriate TA to inquire for cardiac arrhythmia genes and skin as a good proxy to study neurodevelopmental disorders. We also explored RNA-seq limitations and show that on-off switching of gene expression during ontogenesis or circadian rhythm can cause blind spots for RNA-seq-based analyses.ConclusionsPTEE aids the identification of tissues suitable for RNA-seq for a given pathology to increase the success rate of diagnosis and gene discovery. PTEE is freely available athttps://bioinf.eva.mpg.de/PTEE/

Background A treatment-induced drop in HbA1c has been suggested to be a risk factor for TIND. Methods From 60 included patients with severe diabetes mellitus (HbA1c over 8.5) only 21 patients adhered to the study protocol over 1 year with a battery of autonomic nervous system tests scheduled before and after starting antidiabetic treatment. Results In patients with a drop of HbA1c greater than 2 per cent points only some neurophysiologic tests and lab values tended to deteriorate with a trend to improve at later time points along the study. None of these changes were statistically significant, most likely because the study failed to reach the planned number of patients. Conclusion Poor adherence to diabetes treatment and to following the study protocol were the assumed obstacles in our patient cohort selected for very high HbA1c levels. In future studies a multi-center trial and case numbers of up to 500 patients may be needed to account for drop outs in the range observed here. Moreover, the number of tests in each patient at each visit may have to be reduced and special educational group sessions are warranted to cope with the limited adherence. Trial registration Ethic Committee University of Leipzig 439/15-ek. Registered 22 April 2016

AIMS: Recent evidence points towards a distinct obese phenotype among patients with heart failure with preserved ejection fraction (HFpEF). We aimed to identify differentially expressed circulating biomarkers in obese HFpEF patients and link them to disease severity and outcomes. METHODS AND RESULTS: From the LIFE-Heart study, 999 patients with HFpEF and 999 patients without heart failure (no-HF) were selected and 92 circulating serum biomarkers were measured using a proximity extension assay. Elevation of identified biomarkers was validated in 220 patients from the Aldo-DHF trial with diagnosed HFpEF. HFpEF patients were older and had more comorbidities including coronary artery disease and type 2 diabetes as compared to no-HF patients (p

Introduction The study was designed to assess patient satisfaction, preferences and injection habits for patients using insulin lispro 200 units/ml pen (IL200) compared to their previously used disposable 100 units/ml mealtime insulin pen (“MTI-100 pen”) in Germany. Methods A site-based, cross-sectional study involving a self-reported survey and medical record extraction in patients with diabetes currently using IL200 for between 3 and 12 months and had previously used any disposable MTI-100 pen. Results Of 114 patients included, 83.3% were satisfied with IL200 and 3.5% were dissatisfied; 70.2% preferred IL200 over their previous MTI-100 pen and 4.4% preferred their previous MTI-100 pen. The main reasons for IL200 preference were the amount of insulin the pen carries, longer use before discarding, number of non-empty pens discarded, injection volume and frequency replacing pens. Patients discarded (median) 4 IL200 pens per month with 5.3% discarding more than 10 units in their last pen. When insufficient insulin remained to complete a dose, 74.6% injected the remainder and completed with a new pen, 19.3% discarded the pen with remaining insulin, 7.0% saved it for future use and 1.8% left the dose incomplete. Conclusions Satisfaction and preference for IL200 was high in this sample of patients using IL200 for 3–12 months. Reasons were consistent with IL200 features, explaining the better patient experience and potential resource saving transitioning from a disposable MTI-100 pen. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-021-01150-7.

MicroRNAs (miRNAs) are small non-coding RNAs, and adipose tissue is a major source of circulating miRNAs that may regulate body fat distribution. We investigated whether changes in circulating adipose-derived miRNAs (miR-99a-5p, miR-99b-5p, and miR-100-5p) were related to improvements in visceral and ectopic fat depots in abdominal obese adults who participated in the CENTRAL diet-and-lifestyle intervention trial. We further tested whether changes in these miRNAs were related to improved glucose metabolism and insulin sensitivity after the intervention. Plasma levels of miRNAs were measured both at baseline (n=227) and 18 months (n=157) after the intervention; changes in miRNAs from baseline to 18 months were calculated. Magnetic resonance imaging (MRI) was performed to assess visceral adipose tissue (VAT), intrahepatic fat %, and pancreatic fat %. At baseline, higher levels of miR-99a-5p and miR-100-5p were associated with greater intrahepatic fat (p Disclosure Y. Heianza: None. P. Kovacs: None. I. Shai: None. L. Qi: None. K. K. Krohn: None. M. Wang: None. A. Yaskolka meir: None. Q. Xue: None. S. Ziesche: None. U. Ceglarek: Research Support; Self; Roche Diagnostics Germany. M. Blüher: Consultant; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH, Speaker’s Bureau; Self; Daiichi Sankyo, Novartis AG. M. Keller: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK091718, DK100383, DK115679)

Physical exercise plays an important role in both the prevention and treatment of cardiometabolic diseases. Peptides secreted or released from skeletal muscle, so-called myokines, contribute to the beneficial anti-inflammatory and insulin-sensitizing effects of increased muscle activity and may, therefore, counteract pathomechanisms of obesity and type 2 diabetes (T2D) [1]. However, the impact of myokines including interleukin (IL)-6, IL-8, IL-13, IL-15, angiopoietin-like 4 (ANGPTL4), fibroblast growth factors (FGF)-2, FGF-21, and irisin on altered organ cross-talk in cardiometabolic diseases is still poorly understood [1]. Irisin has been described as a protein released from skeletal muscle after physical activity [2] which may, in rodents and more controversially discussed in humans [1], mediate browning of white adipose tissue. Although the existence of circulating human irisin has even been questioned because human FNDC5 has a noncanonical ATA translation start, irisin has been detected in human plasma using mass spectrometry with appropriate control peptides [3]. IL-15 increases upon both aerobic and resistance exercise and exerts beneficial metabolic effects in patients with obesity and T2D [1]. IL-15 inhibits lipogenesis, induces fat oxidation, enhances energy expenditure, and improves insulin sensitivity and glucose metabolism [4]. To better understand the potential role of these myokines in T2D, we tested the hypotheses that IL-15 and irisin serum concentrations correlate with cardiometabolic risk parameters and are different in subgroups of T2D patients with or without diabetes complications independently of ethnicity.

It is unclear if a reduction in hepatic fat content (HFC) is a major mediator of the cardiometabolic benefit of lifestyle intervention, and whether it has prognostic significance beyond the loss of visceral adipose tissue (VAT). In the present sub-study, we hypothesized that HFC loss in response to dietary interventions induces specific beneficial effects independently of VAT changes.In an 18-month weight-loss trial, 278 participants with abdominal obesity/dyslipidemia were randomized to low-fat (LF) or Mediterranean/low-carbohydrate (MED/LC + 28 g walnuts/day) diets with/without moderate physical activity. HFC and abdominal fat-depots were measured using magnetic resonance imaging at baseline, after 6 (sub-study, n = 158) and 18 months.Of 278 participants (mean HFC 10.2% [range: 0.01%-50.4%]), the retention rate was 86.3%. The %HFC substantially decreased after 6 months (-6.6% absolute units [-41% relatively]) and 18 months (-4.0% absolute units [-29% relatively]; p 0.001 vs. baseline). Reductions of HFC were associated with decreases in VAT beyond weight loss. After controlling for VAT loss, decreased %HFC remained independently associated with reductions in serum gamma glutamyltransferase and alanine aminotransferase, circulating chemerin, and glycated hemoglobin (p 0.05). While the reduction in HFC was similar between physical activity groups, MED/LC induced a greater %HFC decrease (p = 0.036) and greater improvements in cardiometabolic risk parameters (p 0.05) than the LF diet, even after controlling for VAT changes. Yet, the greater improvements in cardiometabolic risk parameters induced by MED/LC were all markedly attenuated when controlling for HFC changes.%HFC is substantially reduced by diet-induced moderate weight loss and is more effectively reduced by the MED/LC diet than the LF diet, independently of VAT changes. The beneficial effects of the MED/LC diet on specific cardiometabolic parameters appear to be mediated more by decreases in %HFC than VAT loss.High hepatic fat content is associated with metabolic syndrome, type 2 diabetes mellitus, and coronary heart disease. In the CENTRAL 18-month intervention trial, a Mediterranean/low-carbohydrate diet induced a greater decrease in hepatic fat content than a low-fat diet, conferring beneficial health effects that were beyond the favorable effects of visceral fat loss. ClinicalTrials.gov Identifier: NCT01530724.

Background In brain, CREB-regulated transcription co-activator 1 (CRTC1) is involved in metabolic dysregulation. In humans a SNP in CRTC1 was associated to body fat percentage and two SNPs affected RNA Pol II binding and chromatin structure, implying epigenetic regulation of CRTC1. We sought to understand the relevance of CRTC1 SNPs, DNA methylation and expression in human eating behaviour and its relationship to clinical variables of obesity in blood and adipose tissue. Methods 13 CRTC1 SNPs were included to analyze eating behaviour. For rs7256986, follow up association analyses were applied on DNA methylation, CRTC1 expression and clinical parameters. Linear regression was used throughout the study adjusted for age, sex and BMI. Besides data extraction from previous work, rs7256986 was de-novo genotyped and DNA methylation was evaluated by using pyrosequencing. Findings We found several SNPs in the CRTC1 locus nominally associated with human eating behaviour or 2hr postprandial insulin levels and observed a correlation with alcohol and coffee intake (all P

Zusammenfassung Einleitung Die Bauchwand bildet eine feste anatomische Einheit und ist essentiell für die für Stabilisierung des Rumpfes. Erhöhter intraabdomineller Druck und Veränderungen der Gravitationskräfte können zu Dysbalancen und hierdurch Entwicklung von Rektusdiastasen und abdominellen Hernien führen. Material/Methode Die Betreuung und operative Behandlung postpartaler adipöser Patienten verlangt ein interdisziplinäres Konzept. In unserer Klinik wurde hierzu ein spezieller Behandlungsalgorithmus für adipöse Patienten mit postpartalen Bauchwandinsuffizienzen unter Berücksichtigung ihres BMI erstellt. Diskussion Der Verschluss von Rektusdiastasen ist eine zusätzliche Technik bei durchgeführter Abdominoplastik. Hierdurch kann eine verbesserte Stabilisierung der vorderen Bauchwand erzielt werden. Des Weiteren kann der Operateur die Kontur der Taille wiederherstellen und das äußere Erscheinungsbild optimieren. Je nach Ausmaß der Fettschürze und Größe der Hernien und Diastasen stehen unterschiedliche chirurgische Behandlungsalternativen zur Verfügung. Zusammenfassung Mit Hilfe der rekonstruktiven plastischen Chirurgie kann bei diesem Patientengut eine funktionelle Rekonstruktion der Bauchwand wiederhergestellt werden. Einen sekundären Therapiegewinn stellt die simultane Mitbehandlung der ästhetischen Problemzonen dar und hilft eine langfristige physische und psychosoziale Rehabilitation der Patientinnen zu ermöglichen.

Peripheral diabetic neuropathy (PDN) is one of the most common complications of diabetes mellitus. Previous studies showed an association between dietary iron load and inflammation in the development of PDN in a rat model of type 1 diabetes (T1D). Here we investigated the role of iron and neural inflammation in development of PDN in a animal model of obesity and type 2 diabetes (T2D). 3-month-old db/db mice were fed with a high, standard or low iron diet for 4 months. High iron chow lead to a significant increase in motor nerve conduction velocities compared to mice on standard and low iron chow. Direct beneficiary effects on lowering blood glucose and HbA1c concentrations were shown in the high iron treated diabetic mice. Numbers of pro-inflammatory M1 macrophages were reduced in nerve sections, and anti-inflammatory M2 macrophages were increased in db/db mice on high iron diet compared to other groups. These results confirm and extend our previous findings in STZ-diabetic rats by showing that dietary non-hem iron supplementation may partly prevent the development of PDN in opposition to iron restriction. The identification of these dietary iron effects on the metabolic and inflammatory mechanisms of PDN supports a role of dietary iron and leads us to suggest testing for iron levels in human diabetic patients.

VASPIN, visceral adipose tissue-derived serpin, is an adipokine ameliorating insulin resistance in obesity. Here, we investigated the role of VASPIN and its genetic variants in lipid metabolism. We measured serum VASPIN concentrations by ELISA in 823 metabolically well-characterized Caucasian subjects (Sorbs from Germany). Furthermore, we genotyped 30 representative single nucleotide polymorphisms (SNP) in two independent cohorts with metabolic phenotyping, the Sorbs (N = 823) and Leipzig (N = 919), and conducted genotype-phenotype association analyses. Circulating VASPIN strongly correlated with triacylglycerol levels (TAG; p = 1.079 × 10-11 ), and moderately with apolipoprotein A1 and low-density lipoprotein cholesterol (p = 0.026). Genetic variants in VASPIN were nominally associated with cholesterol, high-density and low-density lipoprotein (HDL-chol, LDL-chol), lipoprotein A, and apolipoprotein B as well as with TAG and free fatty acids (all p < 0.05 adjusted for age, sex, and body mass index [BMI]). Mendelian randomization analysis using VASPIN SNP as an instrumental variable showed borderline influence of VASPIN on LDL-chol levels (p = 0.05). Associations of VASPIN and its genetic variation with metabolic traits suggest a role of VASPIN in human lipid metabolism.

SUMMARY We found that exposure of adult animals to caloriedense foods rapidly abolished expression of mitofusin 2 (Mfn2), a gene promoting mitochondrial fusion and mitochondrion-endoplasmic reticulum interactions, in white and brown fat. Mfn2 mRN was also robustly lower in obese human subjects compared with lean controls. Adipocyte-specific knockdown of Mfn2 in adult mice led to increased food intake, adiposity, and impaired glucose metabolism on standard chow as well as on a diet with high calorie content. The body weight and adiposity of mature adipocyte-specific Mfn2 knockout mice on a standard diet were similar to those of control mice on a high-fat diet. The transcriptional profile of the adipose tissue in adipocyte-specific Mfn2 knockout mice was consistent with adipocyte proliferation, increased lipogenesis at the tissue level, and decreased glucose utilization at the systemic level. These observations suggest a possible crucial role for mitochondrial dynamics in adipocytes in initiating systemic metabolic dysregulation., Graphical Abstract, In Brief Mancini et al. find that the mitochondrial fusion protein Mfn2 is lower in adipose tissue of mice on a high-fat diet and that of obese humans and that this protein in the fat is important for systemic control of metabolism.

Adipositas erhoht das Risiko fur Stoffwechsel- (z. B. Typ-2-Diabetes, Fettlebererkrankung), kardiovaskulare (z. B. arterielle Hypertonie, Myokardinfarkt, Schlaganfall), muskuloskelettale (z. B. Osteoarthrosen) und neurodegenerative Erkrankungen, Depression sowie einige Krebserkrankungen signifikant. Zudem geht sie bei den Betroffenen haufig mit einer Verminderung der Lebensqualitat, sozialer Benachteiligung und einer deutlichen Verkurzung der Lebenserwartung einher. Die Zunahme des Fettgewebes bei Adipositas kann uber Insulinresistenz und die Aktivierung proinflammatorischer Stoffwechselwege zu obigen Erkrankungen beitragen, obwohl die genauen Mechanismen dafur nicht vollstandig verstanden sind. Fettleibigkeit fuhrt haufig zur vermehrten Infiltration des Fettgewebes mit Immunzellen sowie zu dessen Inflammation, die eine systemische, haufig subklinische und chronische Entzundung aufrechterhalten kann. Die Inflammation des Fettgewebes scheint jedoch auch bei dessen physiologischer Expansion und dessen Anpassung an eine positive Energiebilanz eine wichtige Rolle zu spielen. Insgesamt kann ein besseres Verstandnis der molekularen Mechanismen, uber die Adipositas und Inflammation des Fettgewebes zu Insulinresistenz und chronischer Entzundung fuhren, zur Entwicklung antientzundlicher Therapiestrategien beitragen, die die zukunftige Behandlung von Folgeerkrankungen der Adipositas verbessern konnten. Im Rahmen dieses kurzen Ubersichtsbeitrages sollen aktuelle Erkenntnisse, wie eine Inflammation des Fettgewebes entsteht und zu Endorganschaden bei Adipositas beitragen konnte, diskutiert werden.

ZusammenfassungAdipositas führt zu einer gestörten Funktion des Fettgewebes, die sich in ektoper Fettverteilung, Hypertrophie von Adipozyten, Veränderungen der zellulären Zusammensetzung und der intrazellulären Matrix sowie zu einer gestörten endokrinen Funktion manifestiert. Neben den wichtigen Funktionen als Energiespeicher, mechanischer Schutz und Wärmeisolator produziert das Fettgewebe auch Peptidhormone, sogenannte Adipokine, die zu sekundären Veränderungen an Organen wie der Leber, dem Hirn oder dem Gefäßsystem beitragen. Mit der Vermehrung des Fettgewebes bei Adipositas entwickelt sich häufig ein diabetogenes, pro-inflammatorisches und atherogenes Adipokinmuster. Adipokine tragen zumindest zum Teil zum Adipositas-assoziierten Risiko für Typ-2-Diabetes, Fettlebererkrankung, endotheliale Dysfunktion, Arteriosklerose, Bluthochdruck, Fettstoffwechselstörungen und bestimmte Krebserkrankungen bei. Zukünftig könnten Adipokine deshalb als Risikomarker und als Substrat oder Therapeutikum für pharmakologische Therapiestrategien klinisch relevant werden. Im Rahmen dieses Beitrages sollen aktuelle Erkenntnisse zur potentiellen klinischen Bedeutung von Adipokinen vorgestellt und diskutiert werden.

Background and aims Pro-Neurotensin (NT), a stable surrogate parameter of NT, has recently been introduced as a peptide predicting the development of obesity, diabetes mellitus, cardiovascular diseases, and cardiovascular mortality. However, regulation of Pro-NT in gestational diabetes mellitus (GDM) remains uninvestigated. Methods and results Pro-NT was quantified in 74 women with GDM, 74 healthy, gestational age-matched, pregnant controls, as well as in a second cohort comprising of 74 healthy, non-pregnant control women, using a chemiluminometric sandwich immunoassay. Pro-NT was correlated to measures of obesity, hypertension, glucose and lipid metabolism, renal function, and inflammation. Mean ± standard deviation of circulating Pro-NT levels were not significantly different in women with GDM (100.2 ± 75.7 pmol/l) as compared to healthy, pregnant controls (103.2 ± 37.4 pmol/l) and healthy, non-pregnant female controls (105.9 ± 38.9 pmol/l) (p = 0.661). Homeostasis model assessment of insulin resistance (HOMA-IR) and creatinine positively correlated with serum Pro-NT in multivariate regression analysis. In contrast, free fatty acids (FFA) were inversely correlated with circulating Pro-NT. Results sustained adjustment for pregnancy status. Conclusions Circulating Pro-NT is not independently associated with GDM, but is with HOMA-IR, creatinine, and FFA even after adjustment for pregnancy status.

Background/Aims: Altered expression and circulating levels of glutathione peroxidase 3 (GPX3) have been observed in obesity and type 2 diabetes (T2D) across species. Here, we investigate whether GPX3 serum concentrations and adipose tissue (AT) GPX3 mRNA expression are related to obesity and weight loss. Methods: GPX3 serum concentration was measured in 630 individuals, including a subgroup (n = 293) for which omental and subcutaneous (SC) GPX3 mRNA expression has been analyzed. GPX3 analyses include three interventions: 6 months after bariatric surgery (n = 80) or combined exercise/hypocaloric diet (n = 20) or two-step bariatric surgery (n = 24) studies. Results: Bariatric surgery-induced weight loss (–25.8 ± 8.4%), but not a moderate weight reduction of –8.8 ± 6.5% was associated with significantly reduced GPX3 serum concentrations. GPX3 mRNA is significantly higher expressed in AT from individuals with normal glucose metabolism compared to T2D patients. SC AT GPX3 expression is significantly higher in lean compared to obese as well as in insulin-sensitive compared insulin-resistant individuals with obesity. Weight loss after bariatric surgery causes a significant increase in SC AT GPX3 expression. AT GPX3 expression significantly correlates with age, BMI, fat distribution, insulin sensitivity (only SC AT), but not with circulating GPX3. Conclusion: Our data support the notion that SC AT GPX3 expression is associated with obesity, fat distribution and related to whole body insulin resistance.

The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes., The soluble bioactive form of the transmembrane protein fibronectin type III domain containing 4 (sFNDC4) has anti-inflammatory effects and improves insulin sensitivity. Here the authors show that liver derived sFNDC4 signals through adipose tissue GPCR GPR116 to promote insulin-mediated glucose uptake.

Genome-wide association studies have identified adenylyl cyclase type 5 (ADCY5) as candidate gene for diabetes-related quantitative traits and an increased risk of type 2 diabetes. Mice with a whole-body deletion of Adcy5 (Adcy5–/–) do not develop obesity, glucose intolerance and insulin resistance, have improved cardiac function and increased longevity. Here, we investigated Adcy5 knockout mice (Adcy5–/–) to test the hypothesis that changes in adipose tissue (AT) may contribute to the reported healthier phenotype. In contrast to previous reports, we found that deletion of Adcy5 did not confer any physiological or biochemical benefits. However, this unexpected finding allowed us to investigate the effects of Adcy5 depletion on AT independently of lower body weight and a metabolically healthier phenotype. Adcy5–/– mice exhibited an increased number of smaller adipocytes, lower mean adipocyte size and a distinct AT gene expression pattern with midline 1 (Mid1) as the most significantly downregulated gene compared to control mice. Our Adcy5–/– model challenges previously described beneficial effects of Adcy5 deficiency and suggests that targeting Adcy5 does not improve insulin sensitivity and may therefore limit the relevance of ADCY5 as potential drug target.

BackgroundThe microbiome has emerged as an environmental factor contributing to obesity and type 2 diabetes (T2D). While the majority of studies have focused on associations between the gut microbiome and metabolic disease, increasing evidence suggests links between circulating bacterial components (i.e. bacterial DNA) and cardiometabolic disease as well as blunted response to metabolic interventions such as bariatric surgery. In this aspect, thorough next generation sequencing based and contaminant aware approaches are lacking. To address these points, we tested whether bacterial DNA could be amplified in the blood of subjects with obesity and high metabolic risk under strict experimental and analytical control to minimize bacterial contamination. Moreover we characterized a bacterial signature associated with the individual metabolic risk and explored its dynamics alongside metabolic improvement after bariatric surgery.MethodsSubjects undergoing elective bariatric surgery were recruited into sex and BMI matched subgroups with (n=24) or without T2D (n=24). Bacterial DNA in the blood was quantified and prokaryotic 16S rRNA gene amplicons were sequenced. A contaminant aware approach was applied to derive a compositional microbial signature from bacterial sequences in subjects with and without T2D and within subjects at baseline and at three and twelve months post bariatric surgery. We modelled associations between bacterial load and composition with host metabolic and anthropometric markers. We further tested whether compositional shifts were related to weight loss response and T2D remission after bariatric surgery. Lastly, Catalyzed Reporter Deposition (CARD) - Fluorescence In Situ Hybridization (FISH) was employed to visualize bacteria in blood samples.ResultsContaminant aware classification of bacterial 16S rRNA sequences allowed the derivation of a blood bacterial signature, which was associated with metabolic health. Based on bacterial phyla and genera detected in the blood samples, a metabolic syndrome classification index score was derived and shown to robustly classify subjects along their actual clinical group. T2D was characterized by decreased bacterial richness and a loss of genera associated with improved metabolic health. Moreover, circulating bacterial load was significantly associated with metabolic health and increased after bariatric surgery. Weight loss and metabolic improvement following bariatric surgery were associated with an early and stable increase of these genera in parallel with improvements in key cardiometabolic risk parameters. CARD-FISH allowed the detection of living Bacteria in blood samples in obesity.ConclusionsWe show that the circulating bacterial signature reflects metabolic disease and its improvement after bariatric surgery. Our work provides contaminant aware evidence for the presence of living bacteria in the blood and suggests a putative crosstalk between components of the blood and metabolism in metabolic health regulation.

Purpose Adipokines may play an important role in the complex etiology of human obesity and its metabolic complications. Here, we analyzed the relationship between 15 adipokines, eating behavior and body-mass index (BMI). Methods The study included 557 participants of the Sorbs (62.1% women, 37.9% men) and 3101 participants of the population-based LIFE-Adult cohorts (53.4% women, 46.4% men) who completed the German version of the Three-Factor-Eating Questionnaire to assess the eating behavior types cognitive restraint, disinhibition and hunger. Serum levels of 15 adipokines, including adiponectin, adipocyte fatty acid-binding protein (AFABP), angiopoietin-related growth factor (AGF), chemerin, fibroblast growth factor (FGF)-19, FGF-21, FGF-23, insulin-like growth factor (IGF)-1, interleukin (IL) 10, irisin, progranulin, vaspin, pro-neurotensin (pro-NT), pro-enkephalin (PENK) and leptin were measured. Based on significant correlations between several adipokines with different eating behavior items and BMI, we conducted mediation analyses, considering the eating behavior items as potential mediation variable towards BMI. Results Here, we found that the positive association between chemerin, AFABP or leptin and BMI in Sorbian women was mediated by higher restraint or disinhibited eating, respectively. Additionally, in Sorbian women, the negative relation between IGF-1 and BMI was mediated by higher disinhibition and the positive link between AGF and BMI by lower disinhibition. In Sorbian men, the negative relationship between PENK and BMI was mediated by lower disinhibition and hunger, whereas the negative relation between IGF-1 and BMI was mediated by higher hunger. In the LIFE-Adult women´s cohort, associations between chemerin and BMI were mediated by decreased hunger or disinhibition, respectively, whereas relations between PENK and BMI were fully mediated by decreased disinhibition. Conclusion Our study suggests that adipokines such as PENK, IGF-1, chemerin, AGF, AFABP and leptin might affect the development of obesity by directly modifying individual eating behavior. Given the observational nature of the study, future experimental or mechanistic work is warranted.

The leptin receptor (Lepr) pathway is important for food intake regulation, energy expenditure and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chromosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-LeprL536Hfs∗6-1NKB), which is located at chromosome 4, exon 11 within the CRH2-leptin binding site. Compared to C57BL/6N mice, LeprL536Hfs∗6 develop early onset obesity and their body weight exceeds that of Leprdb/db mice at an age of 30 weeks. Similar to Leprdb/db mice, the LeprL536Hfs∗6 model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared to C57BL/6N mice. Crossing Leprdb/wt with LeprL536Hfs∗6/wt mice results in compound heterozygous LeprL536Hfs∗6/db mice, which develop even higher body weight and fat mass than both homozygous Leprdb/db and LeprL536Hfs∗6 mice. Our study suggests that the phenotype of monogenic Lepr deficient mice depends on the molecular localization of the Lepr mutation. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.

BackgroundLifestyle intervention (LI) can successfully prevent type 2 diabetes, but response to LI strongly varies depending on risk subphenotypes. We tested if individuals with prediabetes and a high-risk phenotype benefit from an intensification of LI.Methods and findingsWe conducted a risk stratified multicenter randomized controlled intervention study over 12 months with additional 2 year follow up. In eight University Hospitals in Germany, 1105 individuals (female 59%, age 58±11 years, BMI 31.1±6.0 kg/m2 (mean±SD)) with impaired fasting glucose and/or impaired glucose tolerance were included between May 2012 and May 2016 in the study. Participants were stratified into 2 groups; a high- and low-risk phenotype, based on insulin secretion, insulin sensitivity and liver fat content. Low-risk individuals were randomly assigned to conventional LI or control (1:1), high-risk individuals to conventional or intensified LI (1:1), each over one year. Intensified LI included doubling of physical exercise and time of counselling. The primary endpoint was change in post-challenge glucose levels, assessed by frequently sampled oral glucose tolerance tests. Secondary endpoints included changes in liver fat content, assessed by magnetic resonance spectroscopy. A total of 908 (82%) participants completed the study after 12 months of LI. In high-risk individuals, the mean difference estimate between conventional and intensified LI in change in post-challenge glucose levels from baseline was −0.290 mmol/l [CI: −0.544;−0.036], p=0.025. Liver fat content was more reduced by intensified LI than by conventional LI (mean difference estimate: −1.34 percentage points [CI: −2.17;−0.50], p=0.002), and cardiovascular risk decreased stronger with intensified LI than with conventional LI (mean difference estimate −1.82 [CI: −3.13−0.50], p=0.007). In low-risk individuals, conventional LI was not superior to control in reducing postprandial glucose, liver fat or cardiovascular risk. During the total observation period of 3 years, high-risk participants with intensified LI had a higher probability to normalize glucose tolerance compared to conventional LI (p=0.003). The limitations of this study include a relative short duration of LI, a non-completer rate of 18% and an underrepresentation of low risk individuals.ConclusionsIn high-risk individuals with prediabetes it is possible to improve glycemic and cardiometabolic outcomes by intensification of the commonly recommended conventional LI. Our results show that individualized, risk-phenotype-based LI can be implemented for the prevention of diabetes.RegistrationNCT01947595Author summaryWhy Was This Study Done?Clinical trials in individuals with prediabetes have shown that the onset of type 2 diabetes can be delayed or prevented with lifestyle intervention.Among individuals with prediabetes, there is a large variability in the response to lifestyle intervention.It is unknown whether an intensification of intervention is able to improve the beneficial response.What Did the Researchers Do and Find?The present multicenter, risk stratified randomized and controlled intervention trial in 1105 German individuals with prediabetes prospectively confirms the existence of a high-risk prediabetes phenotypeThe intensification of lifestyle intervention in high-risk individuals improves the glycemic outcome after 1 year of lifestyle intervention, and additionally results in a higher frequency of regression to normal glucose tolerance after 3 years of follow up..Intensification of lifestyle intervention results in a larger reduction of liver fat content and stronger improves cardiometabolic outcomes in high-risk individuals.What Do These Findings Mean?Strategies for the prevention of type 2 diabetes should include risk stratification and individualised interventions.Our results highlight a dose-effect relationship for lifestyle intervention and suggest that “one size fits NOT all” in the field of diabetes prevention.It remains to be clarified whether low risk individuals benefit from lifestyle intervention, as there was a low number of individuals in this risk group in the current study.

Context Lower fasting ghrelin levels (FGL) are associated with obesity and metabolic syndrome. Objective We aimed to explore the dynamics of FGL during weight loss and its metabolic and adiposity-related manifestations beyond weight loss. Methods This was a secondary analysis of a clinical trial that randomized participants with abdominal obesity/dyslipidemia to 1 of 3 diets: healthy dietary guidelines (HDG), Mediterranean diet (MED), or green-MED diet, all combined with physical activity (PA). Both MED diets were similarly hypocaloric and included 28 g/day walnuts. The green-MED group further consumed green tea (3-4 cups/day) and a Wolffia globosa (Mankai) plant green shake. We measured FGL and quantified body fat depots by magnetic resonance imaging at baseline and after 18 months. Results Among 294 participants (body mass index = 31.3 kg/m2; FGL = 504 ± 208 pg/mL; retention rate = 89.8%), lower FGL was associated with unfavorable cardiometabolic parameters such as higher visceral adipose tissue (VAT), intrahepatic fat, leptin, and blood pressure (P < 0.05 for all; multivariate models). The ∆FGL18-month differed between men (+7.3 ± 26.6%) and women (−9.2% ± 21.3%; P = 0.001). After 18 months of moderate and similar weight loss among the MED groups, FGL increased by 1.3%, 5.4%, and 10.5% in HDG, MED, and green-MED groups, respectively (P = 0.03 for green-MED vs HDG); sex-stratified analysis revealed similar changes in men only. Among men, FGL18-month elevation was associated with favorable changes in insulin resistance profile and VAT regression, after adjusting for relative weight loss (HbA1c: r = −0.216; homeostatic model of insulin resistance: r = −0.154; HDL-c: r = 0.147; VAT: r = −0.221; P < 0.05 for all). Insulin resistance and VAT remained inversely related with FGL elevation beyond that explained by weight loss (residual regression analyses; P < 0.05). Conclusion Diet-induced FGL elevation may reflect insulin sensitivity recovery and VAT regression beyond weight loss, specifically among men. Green-MED diet is associated with greater FGL elevation.

Objective Thyroid hormones (TH) are essential for the homeostatic control of energy metabolism and the regulation of body temperature. The hypothalamic–pituitary–thyroid (HPT) axis is regulated by negative feedback mechanisms, ensuring that TH levels are maintained at a constant level. However, the feedback mechanisms underlying the resetting of the HPT axis regulation in the control of body temperature are still not fully understood. Here, we aimed to determine the thermoregulatory response in hypothyroid mice to different environmental temperatures and the underlying mechanisms. Methods Distinct thermogenic challenges were induced in hypothyroid female C57BL/6N and leptin-deficient ob/ob mice through housing at either room temperature or thermoneutrality. The thermogenic and metabolic effects were analyzed through metabolic chambers, 18F-FDG-PET/MRI, infrared thermography, metabolic profiling, histology, gene expression and Western blot analysis. Results In hypothyroid mice maintained at room temperature, high leptin serum levels induce a pyrexic effect leading to the stabilization of body temperature through brown adipose tissue thermogenesis and white adipose tissue browning. Housing at thermoneutrality leads to the normalization of leptin levels and a reduction of the central temperature set point, resulting in decreased thermogenesis in brown and white adipose tissue and skeletal muscle and a significant decline in body temperature. Furthermore, anapyrexia in hypothyroid leptin-deficient ob/ob mice indicates that besides its pyrexic actions, leptin exerts a stimulatory effect on the HPT axis to stabilize the remaining TH serum levels in hypothyroid mice. Conclusion This study led to the identification of a previously unknown endocrine loop in which leptin acts in concert with the HPT axis to stabilize body temperature in hypothyroid mice., Highlights • Thyroid hormones are essential for the regulation of body temperature. • Thyroid hormone-deficient (hypothyroid) mice show distinct leptin serum concentrations in response to changes in ambient housing temperature. • High leptin serum levels confer a stimulatory effect on the hypothalamic-pituitary-thyroid axis. • High leptin serum level prevents fall in body temperature in hypothyroid mice at room temperature through its pyrexic effects.

Objective Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state. Methods Protein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130Δadipo) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively. Results Inguinal WAT of HFD-fed gp130Δadipo mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = −0.413, p, Graphical abstract Image 1, Highlights • OSM is regulated under obesity and negatively correlates with UCP1 in WAT. • OSM suppresses isoproterenol-induced UCP1 in subcutaneous adipocytes. • OSM signals through the gp130-STAT3 pathway to lower UCP1 expression. • Obese mice lacking gp130 in adipocytes exhibit increased WAT browning.

Increased plasma and adipose tissue protease activity is observed in patients with type 2 diabetes and obesity. It has been proposed that specific proteases contribute to the link between obesity, adipose tissue inflammation and metabolic diseases. We have recently shown that ablation of the serine protease kallikrein-related peptidase 7 (Klk7) specifically in adipose tissue preserves systemic insulin sensitivity and protects mice from obesity-related AT inflammation. Here, we investigated whether whole body Klk7 knockout (Klk7&minus, /&minus, ) mice develop a phenotype distinct from that caused by reduced Klk7 expression in adipose tissue. Compared to littermate controls, Klk7&minus, mice gain less body weight and fat mass both under chow and high fat diet (HFD) feeding, are hyper-responsive to exogenous insulin and exhibit preserved adipose tissue function due to adipocyte hyperplasia and lower inflammation. Klk7&minus, mice exhibit increased adipose tissue thermogenesis, which is not related to altered thyroid function. These data strengthen our recently proposed role of Klk7 in the regulation of body weight, energy metabolism, and obesity-associated adipose tissue dysfunction. The protective effects of Klk7 deficiency in obesity are likely linked to a significant limitation of adipocyte hypertrophy. In conclusion, our data indicate potential application of specific KLK7 inhibitors to regulate KLK7 activity in the development of obesity and counteract obesity-associated inflammation and metabolic diseases.

Background/Objectives People with metabolically healthy obesity (MHO) may still have an increased risk for cardiovascular mortality compared to metabolically healthy lean (MHL) individuals. However, the mechanisms linking obesity to cardiovascular diseases are not entirely understood. We therefore tested the hypothesis that circulating cell adhesion molecules (CAMs) are higher in MHO compared to MHL individuals. Subjects/Methods Serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), E-selectin and P-selectin were measured in age- and sex-matched groups of MHL (n = 32), MHO categorized into BMI-matched insulin sensitive (IS, n = 32) or insulin resistant (IR) obesity (n = 32) and people with metabolically unhealthy obesity (MUO, n = 32). Results Indeed, individuals with MHO have significantly higher sICAM-1, E-selectin, and P-selectin serum concentrations compared to MHL people. However, these CAMs are still significantly lower in IS compared to IR MHO. There was no difference between the groups in sVCAM-1 serum concentrations. Compared to all other groups, circulating adhesion molecules were significantly higher in individuals with MUO. Conclusions These findings suggest that obesity-related increased cardiovascular risk is reflected and may be mediated by significantly higher CAMs. The mechanisms causing elevated adhesion molecules even in the absence of overt cardio-metabolic risk factors and whether circulating CAMs could predict cardiovascular events need to be explored.

During insulin resistance, lipid uptake by the liver is promoted with peroxisome proliferator activated protein (PPAR) γ-upregulation, leading to hepatic steatosis. Insulin, however, does not directly regulate adipogenic gene expression in liver, and the mechanisms for their upregulation in obesity remains unclear. Here, we show that the Irs2locus, a critical regulator of insulin actions, encodes an antisense transcript ASIrs2, whose expression increased in obesity or after refeeding in liver, reciprocally to that of Irs2. ASIrs2 regulates hepatic Pparg-expression, and its suppression ameliorates steatosis in obese mice. The human orthologue AL162497.1 shows similar genomic organization like ASIrs2, whose expression being correlated with hepatic PPARG and severity of NASH. We also identified HARS2 as a potential binding protein for ASIrs2, functioning as a regulator of Pparg. Collectively, our data revealed a functional duality of Irs2 gene locus, where reciprocal changes of Irs2 and ASIrs2 in obesity cause insulin resistance and steatosis.

Background DNA methylation age (mAge), a methylation biomarker for the aging process, might serve as a more accurate predictor of morbidity and aging status than chronological age. We evaluated the role of multiple factors, including fat deposition, cardiometabolic risk factors and lifestyle weight-loss intervention, on the deviation of mAge from chronological age (mAge deviation) or 18-month change in mAge (∆mAge). In this sub-study of the CENTRAL magnetic resonance imaging weight-loss trial, we evaluated mAge by a validated 240-CpG-based prediction formula at baseline and after 18-month intervention of either low fat (LF) or mediterranean/low carbohydrate (MED/LC) diets. Results Among 120 CENTRAL participants with abdominal obesity or dyslipidemia, mAge (mean ± SD: 60.3 ± 7.5 years) was higher than the chronological age (48.6 ± 9.3 years) but strongly correlated (r = 0.93; p = 3.1 × 10–53). Participants in the lowest tertile of mAge deviation from their chronological age had significantly lower waist-circumference, visceral adipose tissue, intrahepatic fat (IHF) content, fasting-glucose and HOMA-IR, as compared with participants in the highest sex-specific residual tertile (p β = 0.23; p = 0.02). After 18-month weight-loss lifestyle intervention, mAge remained significantly correlated with chronological age (r = 0.94, p = 1.5 × 10–55). mAging occurred, with no difference between lifestyle intervention groups (∆ = 0.9 ± 1.9 years in MED/LC vs. ∆ = 1.3 ± 1.9 years in LF; p = 0.2); however, we observed a mAging attenuation in successful weight losers (> 5% weight loss) vs. weight-loss failures ( ∆ = 0.6 years vs. ∆ = 1.1 years; p = 0.04), and in participants who completed the trial with healthy liver fat content (p = 0.003). Overall, 18 months of weight-loss lifestyle intervention attenuated the mAging of the men, mainly the older, by 7.1 months than the expected (p Conclusions Lifestyle weight-loss intervention may attenuate mAging. Deviation of mAge from chronological age might be related to body fat distribution and glycemic control and could indicate biological age, health status and the risk for premature cardiometabolic diseases. Trial registration: ClinicalTrials.gov NCT01530724. Registered 10 February 2012, https://clinicaltrials.gov/ct2/show/study/NCT01530724.

ObjectiveHuman white adipose tissue (AT) is a metabolically active organ with distinct depot-specific functions. Despite their locations close to the gastrointestinal tract, mesenteric AT and epiploic AT (epiAT) have only scarcely been investigated. Here, we aim to characterise these ATs in-depth and estimate their contribution to alterations in whole-body metabolism.DesignMesenteric, epiploic, omental and abdominal subcutaneous ATs were collected from 70 patients with obesity undergoing Roux-en-Y gastric bypass surgery. The metabolically well-characterised cohort included nine subjects with insulin sensitive (IS) obesity, whose AT samples were analysed in a multiomics approach, including methylome, transcriptome and proteome along with samples from subjects with insulin resistance (IR) matched for age, sex and body mass index (n=9). Findings implying differences between AT depots in these subgroups were validated in the entire cohort (n=70) by quantitative real-time PCR.ResultsWhile mesenteric AT exhibited signatures similar to those found in the omental depot, epiAT was distinct from all other studied fat depots. Multiomics allowed clear discrimination between the IS and IR states in all tissues. The highest discriminatory power between IS and IR was seen in epiAT, where profound differences in the regulation of developmental, metabolic and inflammatory pathways were observed. Gene expression levels of key molecules involved in AT function, metabolic homeostasis and inflammation revealed significant depot-specific differences with epiAT showing the highest expression levels.ConclusionMulti-omics epiAT signatures reflect systemic IR and obesity subphenotypes distinct from other fat depots. Our data suggest a previously unrecognised role of human epiploic fat in the context of obesity, impaired insulin sensitivity and related diseases.

Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.