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Obesity is considered an important factor for many chronic diseases, including diabetes, cardiovascular disease and cancer. The expansion of adipose tissue in obesity is due to an increase in both adipocyte progenitor differentiation and mature adipocyte cell size. Adipocytes, however, are thought to be unable to divide or enter the cell cycle. We demonstrate that mature human adipocytes unexpectedly display a gene and protein signature indicative of an active cell cycle program. Adipocyte cell cycle progression associates with obesity and hyperinsulinemia, with a concomitant increase in cell size, nuclear size and nuclear DNA content. Chronic hyperinsulinemia in vitro or in humans, however, is associated with subsequent cell cycle exit, leading to a premature senescent transcriptomic and secretory profile in adipocytes. Premature senescence is rapidly becoming recognized as an important mediator of stress-induced tissue dysfunction. By demonstrating that adipocytes can activate a cell cycle program, we define a mechanism whereby mature human adipocytes senesce. We further show that by targeting the adipocyte cell cycle program using metformin, it is possible to influence adipocyte senescence and obesity-associated adipose tissue inflammation. Studies in mature human adipocytes demonstrate that obesity and hyperinsulinemia can induce reentry into the cell cycle and induce senescence.

Aims/hypothesis: The crosstalk between skeletal muscle (SkM) and beta cells plays a role in diabetes aetiology. In this study, we have investigated whether SkM-released exosome-like vesicles (ELVs) can be taken up by pancreatic beta cells and can deliver functional cargoes.Methods: Mice were fed for 16 weeks with standard chow diet (SCD) or with standard diet enriched with 20% palmitate (HPD) and ELVs were purified from quadriceps muscle. Fluorescent ELVs from HPD or SCD quadriceps were injected i.v. or intramuscularly (i.m.) into mice to determine their biodistributions. Micro (mi)RNA quantification in ELVs was determined using quantitative real-time RT-PCR (qRT-PCR)-based TaqMan low-density arrays. Microarray analyses were performed to determine whether standard diet ELVs (SD-ELVs) and high palmitate diet ELVs (HPD-ELVs) induced specific transcriptional signatures in MIN6B1 cells.Results: In vivo, muscle ELVs were taken up by pancreas, 24 h post-injection. In vitro, both SD-ELVs and HPD-ELVs transferred proteins and miRNAs to MIN6B1 cells and modulated gene expressions whereas only HPD-ELVs induced proliferation of MIN6B1 cells and isolated islets. Bioinformatic analyses suggested that transferred HPD-ELV miRNAs may participate in these effects. To validate this, we demonstrated that miR-16, which is overexpressed in HPD-ELVs, was transferred to MIN6B1 cells and regulated Ptch1, involved in pancreas development. In vivo, islets from HPD mice showed increased size and altered expression of genes involved in development, including Ptch1, suggesting that the effect of palm oil on islet size in vivo was reproduced in vitro by treating beta cells with HPD-ELVs.Conclusions/interpretation: Our data suggest that muscle ELVs might have an endocrine effect and could participate in adaptations in beta cell mass during insulin resistance.

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In this phase 2 trial in patients with metabolic dysfunction–associated steatohepatitis and moderate or severe fibrosis, tirzepatide was more effective than placebo with respect to resolution of MASH without worsening of fibrosis.

Purpose of ReviewNonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are strongly associated. Both also associate with an increased risk of cardiovascular disease (CVD).Recent FindingsSeveral studies have provided evidence that NAFLD could be an independent CVD risk factor. Given the strong association between NAFLD and T2DM, assessing the independent CV effect of these two conditions remains challenging. However, patients with T2DM and NAFLD exhibit higher risk of CVD compared with T2DM without NAFLD suggesting a potential synergistic increase of CV risk in patients with both T2DM and NAFLD supported by several shared pathophysiological pathways. Several anti-diabetic therapies have shown beneficial effect on both NAFLD and CVD.SummaryPatients with T2DM and NAFLD should be considered at high risk of CVD and could benefit from more intensive CV prevention. Additional long-term follow-up is needed to demonstrate that the treatment of NAFLD effectively reduces the risk of CVD.

Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied. We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being). A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation. Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.).

Aims/hypothesisCardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium–glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have been reported. The risk/benefit ratio of SGLT2i remains unquantified. We aimed to provide an estimation of their risk/benefit ratio in individuals with type 2 diabetes.MethodsWe conducted a systematic review (MEDLINE, up to 14 September 2021) and meta-analysis. We included randomised CVOTs assessing SGLT2i in individuals with type 2 diabetes with or without other diseases. We used the Cochrane ‘Risk of bias’ assessment tool. The primary outcomes were overall mortality, major adverse cardiovascular events (MACE), hospitalisation for heart failure (HHF), end-stage renal disease (ESRD), amputation, diabetic ketoacidosis (DKA) and reported genital infections. For each outcome, we estimated the incidence rate ratio (IRR) with a 95% CI; we then computed the number of events expected spontaneously and with SGLT2i.ResultsA total of 46,969 participants from five double-blind, placebo-controlled international trials (weighted mean follow-up 3.5 years) were included. The prevalence of previous CVD ranged from 40.6% to 99.2%. The definition of reported genital infections ranged from ‘genital mycotic infection’ to ‘genital infections that led to discontinuation of the trial regimen or were considered to be serious adverse events’. The number of included studies for each outcomes was five. The use of SGLT2i decreased the risk of all-cause death (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HHF (IRR 0.69 [95% CI 0.62, 0.76]) and ESRD (IRR 0.67 [95% CI 0.53, 0.84]), and increased the risk of DKA (IRR 2.59 [95% CI 1.57, 4.27]) and genital infection (IRR 3.50 [95% CI 3.09, 3.95]) but not of amputation (IRR 1.23 [95% CI 1.00, 1.51]). For 1000 individuals treated over 3.5 years, SGLT2i are expected, on average, to decrease the number of deaths from 70 to 61, to prevent nine MACE, 11 HHF and two cases of ESRD, while inducing two DKA occurrences and 36 genital infections; 778 individuals are expected to avoid all the following outcomes: MACE, HHF, ESRD, amputation, DKA and genital infection.Conclusions/interpretationOur study is limited to aggregate data. In a population of individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits of SGLT2i remain substantial despite the risk of DKA and even the hypothetical risk of amputation.Trial registrationOSF Registries: https://doi.org/10.17605/OSF.IO/J3R7YFundingThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Butyrate and R-beta-hydroxybutyrate are two related short chain fatty acids naturally found in mammals. Butyrate, produced by enteric butyric bacteria, is present at millimolar concentrations in the gastrointestinal tract and at lower levels in blood; R-beta-hydroxybutyrate, the main ketone body, produced by the liver during fasting can reach millimolar concentrations in the circulation. Both molecules have been shown to be histone deacetylase (HDAC) inhibitors, and their administration has been associated to an improved metabolic profile and better cellular oxidative status, with butyrate inducing PGC1alpha and fatty acid oxidation and R-beta-hydroxybutyrate upregulating oxidative stress resistance factors FOXO3A and MT2 in mouse kidney. Because of the chemical and functional similarity between the two molecules, we compared here their impact on multiple cell types, evaluating i) histone acetylation and hydroxybutyrylation levels by immunoblotting, ii) transcriptional regulation of metabolic and inflammatory genes by quantitative PCR and iii) cytokine secretion profiles using proteome profiling array analysis. We confirm that butyrate is a strong HDAC inhibitor, a characteristic we could not identify in R-beta-hydroxybutyrate in vivo nor in vitro. Butyrate had an extensive impact on gene transcription in rat myotubes, upregulating PGC1alpha, CPT1b, mitochondrial sirtuins (SIRT3-5), and the mitochondrial anti-oxidative genes SOD2 and catalase. In endothelial cells, butyrate suppressed gene expression and LPS-induced secretion of several pro-inflammatory genes, while R-beta-hydroxybutyrate acted as a slightly pro-inflammatory molecule. Our observations indicate that butyrate induces transcriptional changes to a higher extent than R-beta-hydroxybutyrate in rat myotubes and endothelial cells, in keep with its HDAC inhibitory activity. Also, in contrast with previous reports, R-beta-hydroxybutyrate, while inducing histone beta-hydroxybutyrylation, did not display a readily detectable HDAC inhibitor activity and exerted a slight pro-inflammatory action on endothelial cells.

In most animal species, juvenile growth is marked by an exponential gain in body weight and size. Here we show that the microbiota of infant mice sustains both weight gain and longitudinal growth when mice are fed a standard laboratory mouse diet or a nutritionally depleted diet. We found that the intestinal microbiota interacts with the somatotropic hormone axis to drive systemic growth. Using monocolonized mouse models, we showed that selected lactobacilli promoted juvenile growth in a strain-dependent manner that recapitulated the microbiota's effect on growth and the somatotropic axis. These findings show that the host's microbiota supports juvenile growth. Moreover, we discovered that lactobacilli strains buffered the adverse effects of chronic undernutrition on the postnatal growth of germ-free mice.

Glycine is the proteinogenic amino-acid of lowest molecular weight, harboring a hydrogen atom as a side-chain. In addition to being a building-block for proteins, glycine is also required for multiple metabolic pathways, such as glutathione synthesis and regulation of one-carbon metabolism. Although generally viewed as a non-essential amino-acid, because it can be endogenously synthesized to a certain extent, glycine has also been suggested as a conditionally essential amino acid. In metabolic disorders associated with obesity, type 2 diabetes (T2DM), and non-alcoholic fatty liver disease (NAFLDs), lower circulating glycine levels have been consistently observed, and clinical studies suggest the existence of beneficial effects induced by glycine supplementation. The present review aims at synthesizing the recent advances in glycine metabolism, pinpointing its main metabolic pathways, identifying the causes leading to glycine deficiency—especially in obesity and associated metabolic disorders—and evaluating the potential benefits of increasing glycine availability to curb the progression of obesity and obesity-related metabolic disturbances. This study focuses on the importance of diet, gut microbiota, and liver metabolism in determining glycine availability in obesity and associated metabolic disorders.