An overview of obesity-related complications: The epidemiological evidence linking body weight and other markers of obesity to adverse health outcomes.

Obesity is a highly prevalent chronic multisystem disease associated with shortened life expectancy due to a number of adverse health outcomes. Epidemiological data link body weight and parameters of central fat distribution to an increasing risk for type 2 diabetes, hypertension, fatty liver diseases, cardiovascular diseases including myocardial infarction, heart failure, atrial fibrillation, stroke, obstructive sleep apnoea, osteoarthritis, mental disorders and some types of cancer. However, the individual risk to develop cardiometabolic and other obesity-related diseases cannot entirely be explained by increased fat mass.

Glucose-dependent insulinotropic polypeptide (GIP).

Background: Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes.

Deep Learning Derived Adipocyte Size Reveals Adipocyte Hypertrophy is under Genetic Control.

Fat distribution and macro structure of white adipose tissue are important factors in predicting obesity-associated diseases, but cellular microstructure of white adipose tissue has been less explored. To investigate the relationship between adipocyte size and obesity-related traits, and their underlying disease-driving genetic associations, we performed the largest study of automatic adipocyte phenotyping linking histological measurements and genetics to date. We introduce deep learning based methods for scalable and accurate semantic segmentation of subcutaneous and visceral adipose tissue histology samples (N=2,667) across 5 independent cohorts, including data from 9,000 whole slide images, with over 27 million adipocytes.

adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue.

We developed the Adipose Tissue Knowledge Portal by centralizing previously dispersed datasets, integrating clinical and experimental results with transcriptomic and proteomic data from >6,000 women and men. The platform includes multiple adipose depots, resident cell types, and adipocyte perturbation studies. By providing streamlined data access, the portal enables integrative analyses and serves as a powerful tool to interrogate various dimensions of adipose biology down to the single-cell level.

Normal-Weight Offspring of Parents With Diet-Induced Obesity Display Altered Gene Expression Profiles.

Objective: A Western diet is associated with obesity, and the link between parental and offsprings' obesity is unclear. Among mice, this study examined how parents' Western diets affect their male offspring's obesity risk. This study further explored whether early exposure to obesogenic diets from either parent influences offsprings' long-term weight gain.

Sex-specific role of epigenetic modification of a leptin upstream enhancer in adipose tissue.

Objective: Maternal hormonal status can have long-term effects on offspring metabolic health and is likely regulated via epigenetic mechanisms. We elucidated the effects of maternal thyroid hormones on the epigenetic regulation of leptin (Lep) transcription in adipose tissue (AT) and subsequently investigated the role of DNA methylation at a Lep upstream enhancer (UE) in adipocyte biology.

Results: Pregnant mice treated with triiodothyronine (T3) produced offspring with reduced body weight, total fat mass, and gonadal white adipose tissue (gWAT) mass at 6 months of age (treatment: N = 8; control: N = 12).

Visceral adipose tissue area and proportion provide distinct reflections of cardiometabolic outcomes in weight loss; pooled analysis of MRI-assessed CENTRAL and DIRECT PLUS dietary randomized controlled trials.

Background: Visceral adipose tissue (VAT) is well established as a pathogenic fat depot, whereas superficial subcutaneous adipose tissue (SAT) is associated with either an improved or neutral cardiovascular state. However, it is unclear to what extent VAT area (VATcm) and its proportion of total abdominal adipose tissue (VAT%) are distinguished in predicting cardiometabolic status and clinical outcomes during weight loss.

Methods: We integrated magnetic resonance imaging (MRI) measurements of VAT, deep-SAT, and superficial-SAT from two 18-month lifestyle weight loss clinical trials, CENTRAL and DIRECT PLUS (n = 572).

Human subcutaneous and visceral adipocyte atlases uncover classical and nonclassical adipocytes and depot-specific patterns.

Human adipose depots are functionally distinct. Yet, recent single-nucleus RNA sequencing (snRNA-seq) analyses largely uncovered overlapping or similar cell-type landscapes. We hypothesized that adipocyte subtypes, differentiation trajectories and/or intercellular communication patterns could illuminate this depot similarity-difference gap.

Circulating Cell-Free DNA in Metabolic Diseases.

Metabolic diseases affect a consistent part of the human population, leading to rising mortality rates. This raises the need for diagnostic tools to monitor the progress of these diseases. Lately, circulating cell-free DNA (cfDNA) has emerged as a promising biomarker for various metabolic diseases, including obesity, type 2 diabetes, and metabolic-associated fatty liver disease.

Definition and diagnostic criteria of clinical obesity.

Current BMI-based measures of obesity can both underestimate and overestimate adiposity and provide inadequate information about health at the individual level, which undermines medically-sound approaches to health care and policy. This Commission sought to define clinical obesity as a condition of illness that, akin to the notion of chronic disease in other medical specialties, directly results from the effect of excess adiposity on the function of organs and tissues. The specific aim of the Commission was to establish objective criteria for disease diagnosis, aiding clinical decision making and prioritisation of therapeutic interventions and public health strategies.

A hypocaloric protein-rich diet before metabolic surgery improves liver function in patients with obesity and diabetes : A secondary analysis of a randomized clinical trial.

Purpose: Obesity and type 2 diabetes (T2DM) are major risk factors for hepatic steatosis. Diet or bariatric surgery can reduce liver volume, fat content, and inflammation. However, little is known about their effects on liver function, as evaluated here using the LiMAx test.

Understanding Adipose Tissue Dysfunction.

Diseases affecting adipose tissue (AT) function include obesity, lipodystrophy, and lipedema, among others. Both a lack of and excess AT are associated with increased risk for developing diseases including type 2 diabetes mellitus, hypertension, obstructive sleep apnea, and some types of cancer. However, individual risk of developing cardiometabolic and other 'obesity-related' diseases is not entirely determined by fat mass.

Sodium butyrate is incorporated into central metabolism in fly head while inducing oxygen consumption increase.

Butyrate has been proposed as a drug therapy by acting as a lysine deacetylase (KDAC) inhibitor and elevating protein acetylation, in particular on histones. Nonetheless, recent studies suggest that tissues such as the gut can utilize butyrate as a metabolite. We have previously shown that the addition of butyrate induces a rapid increase of oxygen consumption in whole Drosophila melanogaster heads.

Unveiling adipose populations linked to metabolic health in obesity.

Precision medicine is still not considered as a standard of care in obesity treatment, despite a large heterogeneity in the metabolic phenotype of individuals with obesity. One of the strongest factors influencing the variability in metabolic disease risk is adipose tissue (AT) dysfunction; however, there is little understanding of the link between distinct cell populations, cell-type-specific transcriptional programs, and disease severity. Here, we generated a comprehensive cellular map of subcutaneous and visceral AT of individuals with metabolically healthy and unhealthy obesity.

FGF21 and its underlying adipose tissue-liver axis inform cardiometabolic burden and improvement in obesity after metabolic surgery.

Background: This research investigates the determinants of circulating FGF21 levels in a cohort reflecting metabolic disease progression, examining the associations of circulating FGF21 with morphology and function of adipose tissue (AT), and with metabolic adjustments following metabolic surgery.

Methods: We measured serum FGF21 in 678 individuals cross-sectionally and in 189 undergoing metabolic surgery longitudinally. Relationships between FGF21 levels, AT histology, transcriptomes and proteomes, cardiometabolic risk factors, and post-surgery metabolic adjustments were assessed using univariate and multivariate analyses, causal mediation analysis, and network integration of AT transcriptomes and proteomes.

Gut microbial metabolism of bile acids modifies the effect of Mediterranean diet interventions on cardiometabolic risk in a randomized controlled trial.

Bile acids (BAs) undergo extensive microbial metabolism in the gut and exert hormone-like functions on physiological processes underlying metabolic risk. However, the extent to which gut BA profiles predict cardiometabolic risk and explain individual responses to dietary interventions in humans is still unclear. In the DIRECT-PLUS Trial, we conducted a multi-omics analysis of 284 participants randomized into three groups: healthy dietary guidelines and two Mediterranean diet (MedDiet) groups.

GCKIII kinases control hepatocellular lipid homeostasis via shared mode of action.

Metabolic dysfunction-associated steatotic liver disease has emerged as a leading global cause of chronic liver disease. Our recent translational investigations have shown that the STE20-type kinases comprising the GCKIII subfamily-MST3, STK25, and MST4-associate with hepatic lipid droplets and regulate ectopic fat storage in the liver; however, the mode of action of these proteins remains to be resolved. By comparing different combinations of the silencing of MST3, STK25, and/or MST4 in immortalized human hepatocytes, we found that their single knockdown results in a similar reduction in hepatocellular lipid content and metabolic stress, without any additive or synergistic effects observed when all three kinases are simultaneously depleted.

Expression of Intelectin-1, also known as Omentin-1, is related to clinical phenotypes such as overweight, obesity, insulin resistance, and changes after bariatric surgery.

Intelectin-1 (ITLN1; also Omentin-1, OMNT1) is secreted by adipose tissue (AT) and plays an important role in glucose metabolism regulation, with links to obesity-associated diseases. ITLN1 activity so far has rarely been investigated using RNA-sequencing and in larger cohorts. We evaluated ITLN1 expression among three clinical cohorts of the Leipzig Obesity BioBank-a cross-sectional cohort comprising of 1480 people, a cohort of people with metabolically healthy or unhealthy obesity (31 insulin-sensitive, 42 insulin-resistant individuals with obesity), and a longitudinal two-step bariatric surgery cohort (n = 65).