Metabolism

Selectively bred diet-induced obesity-prone (DIO-P) rats have defective nutrient sensing prior to obesity onset. We hypothesized that glial inflammation in the arcuate nucleus (ARC) impairs hypothalamic responses to dietary clues, thereby promoting obesity development in genetically susceptible animals. This study established a timeline of inflammatory events in male and female DIO-P and diet-resistant (DR) rats fed either a low fat chow or exposed to a high energy diet (HED; 32% fat, 25% sucrose) for three days or four weeks. On chow diet, DIO-P rats of both sexes displayed elevated astrocyte density and increased expression of pro-inflammatory markers in the ARC, alongside reduced microglial content, compared to DR rats. Three days of HED transiently amplified most MBH pro-inflammatory markers in DIO-P rats. Four weeks of HED decreased GFAP expression in DIO-P rats while Iba1 density remained unchanged, whereas, DR rats showed a reduction in Iba1with no change in GFAP or cytokine expression. To determine whether mediobasal hypothalamus (MBH) astrocyte inflammation contributes to the development and maintenance of an obesity, astrocytic IKK{beta} was depleted before or after HED exposure. Prophylactic MBH astrocyte-specific IKK{beta} knockdown prevented subsequent body weight gain, improved glucose tolerance and decreased leptin levels in DIO-P rats to levels comparable to DR rats, with no effect in the latter. In contrast, MBH IKK{beta} astrocytic depletion in already obese DIO-P rats had no effect on energy homeostasis. Together, these findings validate the DIO-P rat as a polygenic model of obesity predisposition and demonstrate that preventing ARC astrogliosis is sufficient to HED-induced body weight gain and obesity development in genetically susceptible animals, highlighting MBH inflammation as a marker and driver of obesity predisposition. HighlightsO_LIChow-fed DIO-P rats present heightened ARC astrogliosis and cytokine expression preceding HED-induced obesity. C_LIO_LIInhibition of IKK{beta} in MBH astrocytes prevents DIO-P rats from becoming obese. C_LIO_LIOnce obese, inhibition of IKK{beta} in MBH astrocytes is not sufficient to reverse the obese phenotype. C_LI

Systemic inflammation is implicated in various diseases, yet its upstream determinants remain poorly examined. We conducted a large scale two-sample Mendelian randomisation (MR) study to systematically evaluate the potential causal effects of 3,213 molecular (metabolomic, proteomic), physiological and disease traits on circulating interleukin-6 (IL-6) and C-reactive protein (CRP) levels. Genetic instruments were derived from genome wide association studies and analysed using inverse variance weighted (IVW), weighted median, and MR-Egger methods with multiple testing correction. Bidirectional MR was performed to assess reverse causation. After Bonferroni correction, evidence of potential causal effects was observed for 72 traits on CRP and 9 traits on IL-6. CRP was predominantly influenced by metabolomic traits, especially lipid and fatty acid measures. Genetically proxied adiposity (body mass index and obesity), triglyceride rich lipoproteins, glycoprotein acetyls (GlycA), and apolipoprotein E increased CRP levels, whereas HDL-related cholesterols, polyunsaturated fatty acids, and glutamine decreased CRP. Most associations were consistent across MR methods, supporting the robustness of these results. As expected, IL-6 had a large effect on CRP. IL-6 was influenced by primarily adiposity and HDL-related lipid measures, with generally smaller effect sizes and limited support across sensitivity analyses. Bidirectional analyses indicated little evidence that CRP directly drives metabolic traits when restricting to cis-acting instruments, whereas genetically proxied IL-6 signalling showed consistent downstream effects on HDL particle concentration and composition. Adiposity is a shared upstream determinant of both inflammatory biomarkers, with stronger and broader effects on CRP. These findings suggest that CRP acts as an integrated downstream readout of systemic inflammatory burden, whereas IL-6 reflects a more tightly regulated and context-dependent process. Our work clarifies traits that may causally influence systemic inflammation and highlights biological pathways linking inflammation to cardiometabolic and inflammatory diseases. By mapping upstream determinants of IL-6 and CRP, we also provide a resource to prioritise key drivers for mechanistic study and therapeutic targeting.

Background: The gluteus maximus (GM) is a major hip extensor essential for mobility and metabolic health. Most MRI studies rely on global measures, such as muscle volume or fat fraction, which can overlook spatially localised remodelling. Here, we integrate conventional volumetric and fat fraction metrics with 3D mesh-based shape phenotypes to provide a spatially resolved characterisation of GM morphology in relation to anthropometric, lifestyle, and cardiometabolic factors, with a focus on type 2 diabetes (T2D) and sex-specific effects. Methods: We analysed T1 Dixon MRI from UK Biobank participants to quantify GM muscle volume, fat fraction, and regional surface morphology using 3D meshes. Statistical parametric mapping was used to assess regional associations with anthropometric, lifestyle, and clinical variables Bi-directional causal mediation analyses were performed using GM volumetric and principal components (PCs) of shape variation. PCs were also tested for associations with prevalent and incident disease. Longitudinal changes in GM composition were evaluated in participants with repeated imaging evaluations. Results: GM muscle volume and fat fraction were strongly associated with age, adiposity, and physical activity. Shape analysis revealed spatially localised remodelling patterns not captured by global measures, with region-specific surface shrinkage linked to age, BMI, alcohol intake, grip strength, physical activity, frailty, osteoporosis, and cardiometabolic disease. T2D showed marked sex-differences, with regional shrinkage in men and relative expansion in women. PCA reduced high-dimensional shape variation into interpretable components. Mediation analyses indicated that T2D-related differences in GM morphology partly mediated increases in fat fraction, suggesting that disease effects manifest through spatially patterned shape changes rather than overall muscle size. PCs capturing variations in the central-upper posterior and anterior GM, differentiated between T2D cases from controls, and were associated with incident T2D risk (Men: PC6 HR per SD: 0.81 [0.70-0.95], false discovery rate (FDR)-adjusted p = 0.038, in left GM; 0.76 [0.65-0.88], p = 0.002, in right GM; women; PC5 HR = 1.32, [1.08-1.61], p = 0.032, in right GM). Conclusions: Integrated 3D quantification of GM composition and morphology provides spatially resolved biomarkers that go beyond muscle volume and fat fraction. By capturing region-specific GM remodelling, linked to anthropometric, lifestyle and cardiometabolic factors, this approach offers a more nuanced characterisation of muscle-fat phenotypes and enhances mechanistic insight and risk stratification in population-based imaging studies.

Background: The glucagon-like peptide-1 receptor (GLP1R) is a key regulator of glucose metabolism and appetite and a major therapeutic target for type 2 diabetes (T2D) and obesity. Genetic studies have implicated the GLP1R locus in both body mass index (BMI) and T2D, but it remains unclear whether their underlying genetic associations are the same. Methods: We analyzed 431,107 participants of genetically inferred European ancestry from the Million Veteran Program. Within 500 kb of GLP1R, we performed locus-wide linear regression models for BMI and logistic regression models for T2D, adjusted for age, sex, and 10 principal components. We identified primary and secondary BMI sentinel variants using conditional analyses and evaluated their associations with T2D. Bayesian fine-mapping was used to construct credible sets of GLP1R locus for BMI and T2D. Results: Conditioning on the primary sentinel variant rs12213929 (upstream of GLP1R, {beta} = 0.11; 95% CI 0.09-0.14; p = 1.94E-17), we identified a secondary variant (rs13216992, intron of GLP1R) independently associated with BMI ({beta} = 0.10; 95% CI 0.07-0.13; p = 7.88E-14). The two sentinel variants showed low linkage disequilibrium (r2 = 0.03). A two-variant allelic burden score (0-4; sum of the rs12213929 G-allele count and rs13216992 C-allele count) showed that participants with 4 risk alleles had 0.47 kg/m2 higher BMI than those with 0 risk alleles (95% CI 0.39-0.55; p < 2E-16). Both variants were associated with higher T2D risk, but with distinct patterns after BMI adjustment: the rs12213929-T2D association persisted after adjustment for BMI (OR = 1.02; 95% CI 1.01-1.03; p = 0.0004), whereas the rs13216992-T2D association was fully attenuated (OR = 1.00; 95% CI 0.99-1.01; p = 0.68). Fine-mapping identified a compact 95% BMI credible set of 17 variants and a broader 95% T2D credible set of 42 variants, with all BMI credible variants contained within the T2D set. Conclusions: The GLP1R locus harbors at least two independent BMI-associated variants that exhibit heterogeneous relationships with T2D: rs12213929 influences T2D risk partly through BMI-independent pathways, whereas rs13216992 appears to act predominantly via adiposity. These findings refine the genetic architecture at this key therapeutic target gene and provide a foundation for functional and pharmacogenomic studies to determine whether GLP1R variation can inform precision prevention and treatment of obesity and T2D.

{beta}2-Adrenergic receptor (Adr{beta}2) is the most abundant form of adrenergic receptors in skeletal muscle. Our previous studies have shown that the ventromedial hypothalamic nucleus (VMH) regulates metabolic benefits of exercise, potentially by skeletal muscle Adr{beta}2. Although a large body of literature has shown the importance of Adr{beta}2 on skeletal muscle physiology, it remains unexplored whether skeletal muscle Adr{beta}2 contributes to metabolic benefits of exercise, such as prevention of diet-induced obesity (DIO). Here, we generated mice lacking Adr{beta}2 in skeletal muscle cells (SKMAdr{beta}2) and tested whether SKMAdr{beta}2 is required for metabolic benefits of exercise on DIO. Deletion of SKMAdr{beta}2 completely abolished the induction of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1) in skeletal muscle by {beta}2-agonist, which is a potent activator of Pgc-1. Exercise upregulates Pgc-1, which regulates a broad range of skeletal muscle physiology, including hypertrophy and mitochondrial function. Deletion of SKMAdr{beta}2 hampers augmented Pgc-1 in skeletal muscle by a single bout of exercise. Intriguingly, we found that deletion of SKMAdr{beta}2 increased endurance capacity. Further, our data showed that body weight in DIO mice lacking SKMAdr{beta}2 is comparable to that of control DIO mice during exercise training, suggesting that deletion of SKMAdr{beta}2 did not affect the metabolic benefits of exercise in DIO. Collectively, our data indicate that SKMAdr{beta}2 contributes to exercise-induced transcriptional changes and endurance capacity, however, it is not required for exercise benefits on bodyweight in DIO mice.

Obesity affects millions of people worldwide and has serious complications such as cardiovascular disease and diabetes. Current treatments for obesity target proteins such as the receptors for glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and/or glucagon (GCG). These interventions have revolutionized the treatment of obesity and represent first-line pharmacotherapeutic strategies. One major weakness to these strategies is that once drug treatment stops, most patients are unable to maintain the new body weight setpoint, often gaining weight back rapidly. Thus, the identification of new therapies that focus on the ability to maintain homeostatic setpoint are necessary. The glucocorticoid receptor (GR) has been implicated in several pathways including reward-seeking, inflammation, stress and energy balance. Here, we investigated the effects of 30 days treatment with PT150 (40 mg/kg), a novel GR antagonist, alone and in combination with semaglutide (30 nmol/kg) on food intake, glucose homeostasis, body weight and setpoint maintenance using a C57Bl/6 diet-induced obesity (DIO) mouse model. We monitored food intake and body weight throughout treatment and after drug washout for 20 days to evaluate defended body weight maintenance (body weight setpoint). Our results indicate that treatment with PT150 alone does not significantly alter body weight but in combination with semaglutide it shows the most promising effects in body weight reduction and homeostatic setpoint maintenance. Together, these data suggest that PT150, a GR modulator, may be effective as a homeostatic setpoint modulator when combined with semaglutide.

Obesity, a global health crisis affecting 16% of the world population, is characterized by chronic inflammation that contributes to health complications such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Emerging evidence suggests that self-DNA released from dying cells aberrantly activates inflammatory responses during obesity. However, the role of extracellular deoxyribonucleases (DNASEs), which at steady state regulate abundance of extracellular self-DNA, remains poorly understood in this context. Here, we show that individuals with obesity exhibit elevated levels of circulating cell-free DNA (cfDNA) with a distinctive end-motif signature, anti-DNASE1L3 autoantibodies and a reduction in circulating DNASE activity. These cfDNA alterations correlate with the severity of obesity and can be corrected by therapeutic intervention such as bariatric surgery. Similarly, mice fed a high-fat diet (HFD) displayed increased cfDNA levels and decreased DNASE activity. Genetic deficiency of the extracellular nuclease DNASE1L3 in mice worsened HFD-induced metabolic complications, including glucose intolerance, insulin resistance, MASLD, and metabolic tissue inflammation. Conversely, targeted supplementation of DNASE1L3 in the liver using adeno-associated viral vectors protected obese mice from developing MASLD and liver inflammation. These findings uncover a novel role of DNASE1L3 in controlling obesity-associated inflammation and its potential therapeutic use for preventing metabolic disease.

BackgroundElevated postprandial hypertriglyceridemia (PP-HTG) is a significant risk factor for development of cardiovascular diseases, however, the mechanisms underlying its exaggerated rise remains poorly understood. MicroRNAs (miRs) are known to be implicated in the regulation of lipid metabolism, thus identifying them as potential key players. We presently investigated whether miRs may control postprandial triglyceride (PP-TG) response. MethodsPostprandial changes in circulating miR expression as a function of the degree of postprandial TG response were evaluated in non-dyslipidemic healthy subjects (n=32). The impact of miR-100-5p on hepatic gene expression was evaluated in differentiated Caco2 and HepG2 cells by analysis of hepatic transcriptome (RNAseq), western blot and ELISA. In vivo studies were conducted in C57BL/6J mice overexpressing mimic miR-100-5p. ResultsPostprandial variation in circ-miR-100-5p levels inversely correlate with PP-TG response. Cir-miR-100-5p was preferentially associated with TGRL particles of intestinal origin in subjects exhibited a low PP TG response. Differential analysis of transcriptome from HepG2 cells transfected by either mimic miR-100-5p or scrambled mimic miR as control allowed us to identify PCSK9 as a down-regulated gene. Overexpression of miR-100-5p in HepG2 cells significantly decreased PCSK9 mRNA levels by 52% (p<0.0001), cellular protein content by 28 % (p<0.0001) as well as PCSK9 secretion by 39% (p<0.0001). In vivo systemic delivery of mimic miR-100-5p induced a two-fold reduction (p<0.0001) on PP-TG in mice, such effect being abolished by blocking the circulating form of PCSK9 with alirocumab. Finally, we revealed a significant inverse relationship between circulating miR-100-5p expression levels and both PCSK9 levels and the magnitude of postprandial hypertriglyceridemia. ConclusionTaken together, our observations reveal that miR-100-5p regulates postprandial hypertriglyceridemia by targeting PCSK9, thus enhancing hepatic triglyceride-rich lipoproteins (TGRL) uptake. Our findings allow us to propose circ-miR-100-5p as a potential biomarker for early identification of subjects at high cardiovascular risk, prior to appearance of classical clinical features of metabolic disorders. Postprandial clinical study, HDL-PP (NCT03109067) Lay summaryThis study examined whether miRs may control postprandial triglyceride response Key findingsOur data reveal that miR-100-5p regulates postprandial hypertriglyceridemia by targeting PCSK9 Our observations allow us to propose miR-100-5p as a potential biomarker for early identification of subjects at high cardiovascular risk

Aims: Although metabolic dysregulation is implicated in DCM, the involvement of metabolic syndrome (MetS) remains unclear. This study aims to systematically examine MetS in DCM pathogenesis. Materials and methods: By leveraging 378,837 UK Biobank participants, instead of the conventional binary MetS, we calculated a continuous metabolic risk score (MRS) and evaluated its influence on DCM risk within a multi-model evidence framework. Bidirectional weighted quantile sum regression identified key MRS components, a nested case-control study assessed 14-year pre-diagnosis MRS trajectories, mediation analyses evaluated MRS mediating lifestyle-DCM links and inflammation mediating MRS-DCM relationships, and Mendelian randomization (MR) evaluated causality for genetically predicted MetS and components on DCM. Results: During a median follow-up period of 13.4 years (interquartile range 12.7~14.1 years), 820 (0.2%) participants developed DCM. Higher MRS (HR=1.26 [1.18~1.34]) was associated with increased DCM risk, and such an association persisted across all robustness assessments even among non-MetS individuals. Waist circumference (WC, HR=1.36 [1.28~1.45], weight=0.58) and glycated hemoglobin (HR=1.23 [1.16~1.30], weight=0.22) dominated MRS' risk contribution. The trajectories of MRS diverged in cases approximately 10 years pre-diagnosis. MRS mediated 5.1~26.2% of lifestyle-related DCM risk, while inflammation mediated 16.4% of the MRS-DCM association. MR analysis further confirmed causal effects of MetS (OR=1.65 [1.45~1.88]), WC (OR=1.79 [1.58~2.03]) on DCM risk. Conclusions: Metabolic dysfunction, which was dominated by central adiposity and hyperglycemia, plays a key role in the occurrence of DCM. Early intervention targeting metabolic factors may prevent DCM onset.

Metabolic dysfunction-associated steatotic liver disease (MASLD) afflicts more than one-third of adults globally, contributing significantly to an increased cardiovascular disease risk. Further, patients with severe liver disease experience muscle weakness (sarcopenic obesity) and fatigue. Hypoxia-inducible factor 2 (HIF2) accumulates in the livers of MASLD patients and has been implicated in disease progression. Here we sought to understand the role of hepatic HIF2 in mediating hepatic and extra-hepatic features of MASLD. Using a well-validated obese mouse model of MASLD, we investigated the impact of hepatocyte-specific HIF2 deletion (hHIF2-/-) on hepatic, cardiac and skeletal muscle metabolism, and cardiac function. Over 28 weeks, mice were exposed to a high-fat, high-fructose, high-cholesterol (GAN) diet, which induced obesity alongside hepatic steatosis, fibrosis and inflammation. In contrast to observations in lean mouse models of liver disease, hHIF2-/- did not protect against MASLD, despite greater hepatic NADH-supported mitochondrial respiration and higher intracellular sphingomyelin levels. Instead, in the hearts of GAN-fed mice, hHIF2-/- caused diacylglycerol accumulation independent of diet, accumulation of long-chain acyl-carnitines and exacerbation of ceramide accumulation. Langendorff-perfused hearts from hHIF2-/- mice showed systolic and diastolic dysfunction, including 24% lower left ventricular developed pressure and 34% lower maximal rate of relaxation (dP/dtmin). However, isolated hearts from hHIF2-/- mice were protected against MASLD-associated sympathetic dominance, determined using autonomic receptor agonist stimulation. Both GAN-feeding and hHIF2-/- were associated with lower lean mass (14% and 5.4% lower than respective controls), whilst hHIF2-/- enhanced OXPHOS-associated protein levels in gastrocnemius muscle. Overall, hHIF2-/- resulted in detrimental extra-hepatic effects, including myocardial lipid accumulation, impaired cardiac function, and loss of whole-body lean mass, with no apparent protection against MASLD disease progression.

Background: Obesity has become increasingly common among US adults with hypertension. However, national data are limited on weight-loss efforts among adults with hypertension and overweight/obesity, and whether these efforts have translated into clinically meaningful weight loss at the population level. Methods: We analyzed repeated cross-sectional data from the National Health and Nutrition Examination Survey, 1999-2023. Adults aged 20 years with hypertension and body mass index 25 kg/m2 were included. Weight-loss attempt was defined as self-report of trying to lose weight during the prior 12 months. Among those attempting weight loss, successful weight loss was defined as 5% or 10% reduction in body weight over the prior year. Survey-weighted logistic regression was used to assess temporal trends and associations between strategies and successful weight loss. Results: Overall, 57.6% reported a weight-loss attempt, increasing from 55.9% in 1999-2000 to 60.4% in 2021-2023 (P for trend=0.002). The most reported strategies were eating less food (65.3%) and exercise (52.4%). Among those attempting weight loss, 33.4% achieved 5% weight loss and 14.7% achieved 10% weight loss; neither improved over time (P for trend=0.976 and 0.174, respectively). Weight-loss surgery was strongly associated with success but was rarely reported (0.35%). Eating less fat and changing eating habits were also positively associated with successful weight loss, whereas skipped meals and use of diet foods or products were inversely associated. Conclusions: Weight-loss attempts increased, but clinically meaningful weight-loss success did not improve, highlighting a persistent gap between effort and outcome in hypertension care.

Background & AimsMetabolic disorders such as dyslipidemia, metabolic dysfunction-associated steatotic liver disease (MASLD), and diabetes are promoted by chronic pro-inflammatory and pro-oxidative states. Paraoxonase 1 (PON1), a liver-derived HDL-associated enzyme, plays an important antioxidant role by hydrolyzing oxidized lipids and protecting against oxidative stress- induced damage. Genetic variation in PON1, particularly in promoter and coding regions, modulates enzyme expression and activity, thereby influencing susceptibility to metabolic and cardiovascular diseases. This study investigated the genetic determinants of serum paraoxonase (PONase) activity and their relationship with dysmetabolic phenotypes. MethodsA genome-wide association study was conducted in 922 Portuguese individuals from the PREVADIAB2 cohort. Genetic variants and haplotypes related to PONase activity were analyzed, and associations with dysglycemia and liver fibrosis were evaluated in individuals aged over 55 years. ResultsWe identified two key PON1 variants as determinants of PONase activity: rs2057681 (in strong linkage disequilibrium with the non-synonymous Q192R variant) and rs854572 (located in the promoter region). Analysis of rs854572-rs2057681 haplotypes revealed that specific combinations differentially modulate PONase activity and confer risk or protection for dysglycemia and liver fibrosis, depending on the rs2057681 genotype context. Notably, although PONase activity was strongly associated with PON1 variants, it did not directly correlate with dysmetabolic phenotypes, suggesting that genetic context and haplotype structure, rather than enzyme activity alone, shape disease susceptibility. ConclusionsThese findings highlight the complex genetic architecture of PON1 and its role in metabolic disease risk, supporting the use of PON1 genetic information to uncover predisposition to dysmetabolic conditions. Our results provide insights into the interplay between PON1 genetics, enzyme function, and dysmetabolism, with implications for risk stratification in metabolic liver disease. Lay SummaryPON1 is a liver-derived gene that encodes an enzyme involved in protection against oxidative stress, a key contributor to metabolic liver disease and diabetes. In this study, we found that specific combinations of PON1 genetic variants are associated with abnormalities in blood glucose regulation and with markers of liver fibrosis. These associations were dependent on genetic configuration rather than enzyme activity alone, suggesting that PON1 genetic information may help identify individuals at higher risk of metabolic liver disease.

Background and purpose: Excessive sitting and genetic liability to obesity are associated with risk of obesity and hypertension, two significant risk factors for cardiovascular disease. This study aimed to investigate the interactive effects of genetic liability to obesity and excessive sitting on prevalence of hypertension. Methods: Obesity genetic liability was estimated in unrelated individuals of European ancestry (n=208,594) using previously identified genetic variants and their effect sizes for adiposity related traits. Hypertension was defined as systolic blood pressure ? 140 mmHg, diastolic blood pressure ? 90 mmHg, or the use of anti-hypertensive medications. Logistic regression was used to examine the association between obesity genetic liability and across different levels of self-reported sitting time. Results: excessive sitting and increased genetic liability were independently associated with higher odds of hypertension. The greatest odds of hypertension was observed in participants with high sitting time combined with increased genetic liability to obesity (OR=1.29; 95% CI = 1.25, 1.33, P <2 x10-16) compared to individuals with low genetic liability and low sitting time. Interaction analysis identified that in individuals with excessive sitting, the effect of genetic liability of waist circumference on hypertension was greater compared to individuals with low sitting time (P interaction=0.03). Conclusion: Combined excessive sitting and high genetic susceptibility to obesity is associated with greatest odds of hypertension. These findings highlight the importance of lifestyle in offsetting risk imposed by genetic factors.

Objectives To estimate population-level eligibility for glucagon-like peptide-1 receptor agonist (GLP-1RA) medications among adults in Australia, according to Therapeutic Goods Administration (TGA) approved indications for chronic weight management and secondary prevention of cardiovascular disease. Design Cross-sectional analysis of data from the Australian Bureau of Statistics 2022 National Health Survey. Setting, Participants Non-pregnant adults [&ge;] aged 18 years who are usual residents of Australia and living in a private dwelling. Main outcome measures Total number of adults who are eligible for GLP-1RA medications according to TGA approved indications for chronic weight management and secondary prevention of cardiovascular disease, across subgroups defined by body mass index, weight-related comorbidities, and/or socio-demographic factors. Results In total, 39.7% (95% CI 38.4 - 41.0%) of adults in Australia are eligible for GLP-1RA use for chronic weight management, accounting for 7.8 million (95% CI, 7.6 - 8.1 million) individuals. Among those eligible under this indication, 2.9 million (95% CI 2.7 - 3.1 million) adults had no weight-related comorbidities, 3.3 million (95% CI 3.1 - 3.4 million) adults had at least 1 weight-related comorbidity, and 1.7 million (95% CI 1.6 - 1.8 million) adults had at least 2 weight-related comorbidities. The proportion of adults eligible under this indication varied across clinical and sociodemographic factors. Among those eligible under the chronic weight management indication, up to 338.9 thousand (95% CI 271.3 - 406.5 thousand) adults also meet the indication for secondary prevention of cardiovascular disease. Conclusions More than one third of Australian adults are eligible to access GLP-1RAs for chronic weight management, with 3.7-4.3% of adults also qualifying according to the indication for established cardiovascular disease. This study provides a valuable reference to allow policy makers to understand the number of adults in Australia that may benefit from access to GLP-1RA medications under a range of coverage scenarios.

SGLT2 inhibitor (SGLT2i)-induced diabetic hyperketonemia is a life-threatening acute complication of diabetes. While Celastrol has been reported to exert beneficial effects on obesity; its potential role in ketogenesis remains unclear. In this study, Celastrol administration significantly attenuates the fasting-induced elevation of blood {beta}-hydroxybutyrate. Moreover, a 7-day course of Celastrol (1 mg/kg/day) leads to reductions in body weight and fat mass. Mechanistically, Celastrol specifically downregulates HMGCS2 expression and suppressess hepatic ketogenesis through inhibiting PPAR expression in the short term ([&le;] 2 days). However, after prolonged treatment for 7 days, Celastrol modulates both PPARand serum free fatty acids (FFAs) levels. Furthermore, anti-ketogenic effect of Celastrol is abolished in Ppar{square} /{square} mice. Importantly, Celastrol effectively ameliorates SGLT2i-induced hyperketonemia. In summary, Celastrol curbs hepatic ketone overproduction in a PPAR-dependent manner, indicating its protective potential against SGLT2i-induced hyperketonemia.

GLP-1 receptor agonists induce substantial weight loss, but the extent to which lean tissue and physical function are preserved in routine care remains poorly understood. Using an EHR-linked body-composition digital phenotyping pipeline with LLM-based extraction, we performed a large-scale longitudinal analysis of 670,422 first-episode GLP-1RA users, including 456,742 treated with semaglutide and 213,680 treated with tirzepatide. Among these, 7,965 individuals with paired pre- and post-initiation body-composition measurements were analyzed over 12 months. Tirzepatide was associated with greater relative lean body mass (LBM) loss than semaglutide at each measured time point, with excess LBM losses of 1.1%, 1.5%, 1.3% and 2% at 3, 6, 9 and 12 months, respectively. A Depletive GLP-1 metabotype, defined as >20% total body weight (TBW) loss with >5% LBM loss, was significantly more frequent with tirzepatide than semaglutide during the first year of therapy (10.3% versus 6.7%, p<0.001). By contrast, a Prime GLP-1 metabotype, defined as >10% TBW loss with <5% LBM loss, was numerically more frequent with semaglutide than tirzepatide, but not significantly so (12.3% versus 11.8%, p=0.66). Higher drug dose and longer exposure were associated with progressively greater LBM decline in both treatment groups (both p<0.001). Among 3,746 examined EHR phenotypes, baseline musculoskeletal pain emerged as the most significant correlate of greater LBM loss (BH-adjusted q<0.001): cervicalgia (semaglutide, -4.1 percentage points; tirzepatide, -14.3 percentage points) and knee pain (semaglutide, -4.8 percentage points; tirzepatide, -13.4 percentage points), consistent with mobility-limited patients being more vulnerable to lean-tissue depletion during incretin therapy. Analysis of EHR notes for on-treatment functional features showed reduced exercise tolerance was the strongest correlate of greater LBM loss, increasing by 7.2 and 11.1 percentage points in semaglutide- and tirzepatide-treated patients, respectively. An independent analysis of all available Single-cell RNA-seq data from human musculature showed broader GIPR+ cellular distribution than GLP1R+ cells across immune, stromal, vascular, and contractile compartments, providing plausible biological context for the greater LBM loss observed in routine care with tirzepatide (dual GLP1R-GIPR agonist) relative to semaglutide (GLP1R-specific agonist). In this observational study, greater weight-loss efficacy did not necessarily translate into more favorable body-composition outcomes, underscoring the need for clinical decision-making and trial designs that maximize each patient's likelihood of achieving a Prime GLP-1 metabotype.

Obesity-driven metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are shaped by depot-specific adipose tissue dysfunction, including maladaptive expansion and visceral adipose tissue (VAT) fibrosis. Pirfenidone, an anti-fibrotic agent, improves experimental liver disease. However, its actions on adipose depots and adipose-liver crosstalk remain unclear. Here, we identify pirfenidone as a modulator of mechanistic target of rapamycin complex 1 (mTORC1)-dependent adipose tissue remodeling with divergent outputs in subcutaneous and visceral fat. In diet-induced obese MASH mice, pirfenidone decreased subcutaneous adipose tissue (SAT), inhibiting mTORC1-driven lipogenesis and enhancing oxidative lipid metabolism. Pirfenidone attenuated VAT fibrosis by suppressing an mTORC1-mothers against decapentaplegic homolog 3 (SMAD3)-yes-associated protein (YAP) axis and extracellular matrix gene programs. Pirfenidone also lowered hepatic triglycerides, improved steatosis and fibrosis, reduced hepatic mTORC1 activity. Conditioned medium from fibrotic adipocytes induced lipogenic, inflammatory, and pro-fibrotic programs in AML12, which effects that were blunted by pirfenidone. These data reveal adipose tissue-centered actions of pirfenidone that link mTORC1 remodeling to improved obesity-associated liver disease.

Importance: Assessment of cardiovascular health (CVH) during may unmask latent metabolic vulnerability and indicate long-term disease risk. However, the prognostic value of the AHA's Life's Essential 8 (LE8) framework during pregnancy remains uncertain. Objective: To evaluate CVH during using a modified Life's Essential 8 (mLE8) score in association with time to incident cardiometabolic disease. Design: Prospective cohort study with electronic medical record (EMR) surveillance for 7 years postpartum (August 2018-March 2026). Adjusted accelerated time-to-failure models estimated mLE8 associations with incident conditions. Setting: A population-based prenatal cohort recruited from a large academic medical system in South Carolina. Participants: Singleton pregnancies in individuals aged 18 to 44 years without pre-existing diabetes or cardiovascular disease (CVD) Exposures: A 7-component mLE8 score assessed during pregnancy, incorporating hypertensive disorders of pregnancy (HDP), 50-g glucose tolerance test results, pre-pregnancy body mass index, smoking status, sleep adequacy, diet quality, and physical activity. Scores ranged from 0 to 100, with higher scores indicating more favorable CVH. Main Outcomes and Measures: Post-delivery incident cardiometabolic conditions captured through EMRs and classified as chronic hypertensive conditions, chronic metabolic conditions (e.g., dyslipidemia, impaired glucose regulation), and CVD (e.g. cardiac arrest, cardiomyopathy). Time to incident diagnosis was measured in days from delivery. Results: Among 1,225 pregnancies (mean age, 25.0 [5.3] years), 499 incident cardiometabolic events occurred over a median follow-up of 6.2 (2.8) years. Each 10-point higher mLE8 score was associated with a longer time to incident diagnosis of chronic hypertensive conditions (time ratio [TR], 1.26; 95% CI, 1.11, 1.42) and chronic metabolic conditions (TR, 1.20; 95% CI, 1.11, 1.29). Healthier HDP, glucose, BMI, and sleep scores were most strongly associated with longer time to diagnosis of chronic metabolic disease. Results were robust to sensitivity analyses excluding individuals who developed gestational diabetes or HDP. Conclusions and Relevance: In this racially diverse, low-income cohort study of 1,225 pregnancies, better CVH during pregnancy was associated with a longer time to incident post-delivery diagnosis of cardiometabolic conditions. Pregnancy-based CVH assessment may help identify individuals with elevated and emerging cardiometabolic risk who could benefit from early, targeted intervention and enhanced longitudinal surveillance.

Semaglutide is often optimized for weight loss, but whether longer-term cardiovascular benefit tracks achieved weight loss or therapeutic exposure levels remains unclear. Using a federated deidentified U.S. electronic health record network of 29 million patients, including 505,874 semaglutide-treated individuals, we leveraged multimodal AI technologies to analyze 47,199 patients with baseline cardiovascular disease. We quantified dose escalation and weight change during the 0-2-year period after semaglutide initiation (landmark period) and assessed cardiovascular outcomes during the 2-4-year period (post-landmark). In propensity-matched comparisons during the landmark period, semaglutide was associated with lower cardiovascular events than metformin, DPP-4 and SGLT2 inhibitors. Higher maximum semaglutide dose was associated with greater weight loss during the landmark period (3.15% additional weight loss per 1 mg increase; r=0.97, P<0.001), and lower post-landmark risk of all-cause mortality (RR 0.42, p<0.001), composite cardiovascular events (death, myocardial infarction, or stroke; RR 0.51, p<0.001), cerebrovascular disease (RR 0.50, p<0.001), heart failure (RR 0.55, p<0.001), and valvular/rheumatic heart disease (RR 0.71, p=0.025). In contrast, greater achieved weight loss during the landmark period did not show a consistent monotonic association with lower post-landmark cardiovascular risk (All-cause mortality p-value=0.14, composite cardiovascular endpoint p-value=0.55). Integrating insights from a single cell GLP1R expression atlas was used to infer how semaglutide pharmacology may tie into heart-specific signaling, beyond what is reflected by body-weight reduction alone. The strongest prevalence-weighted GLP1R signal was observed in the pancreas, followed by the heart, where GLP1R engagement potential (GEP) was considerable across cardiomyocyte, cardiac endothelial, and rarer immune cell populations. Together, semaglutide cardiovascular benefit appears organized more by maximum dose attained than by achieved weight-loss magnitude, setting the stage for beyond-obesity trial designs that integrate whole-body spatial intelligence.

Background and aims: Direct evidence to connect early life metabolism with cardiometabolic diseases in old age is limited due to the rarity of multi-decadal biochemical follow-up studies. To gain deeper insight into metabolic ageing, we conducted a longitudinal study that integrates serial data on clinical biomarkers, metabolomics and clinical events across the human life course. Methods: Children born in 1962-1992 were included from four European cohorts. Time-series of clinical biomarkers and metabolomics data were available for 8,653 participants (ages 0-49 years, 142 molecular and four physiological variables). Comparable data for 13,795 UK Biobank participants at two visits (ages 40-79 years) were linked with retrospective and prospective records of diabetes and cardiovascular disease. Lifetime metabolic trajectories were reconstructed by unsupervised machine learning and local polynomial regression. Results: A stable stratification in metabolic health emerged in children between ages 3 and 12 years and persisted to old age. We summarized this population pattern by assigning each participant into one of seven metabolic subgroups with characteristic biomarker trajectories. Two subgroups (MetDys TG+ and MetDys TG-) featured increased waist-height ratio from childhood, persistently higher C-reactive protein throughout life and rapidly increasing fasting insulin between 30 and 49 years of age. Both subgroups exhibited high risk for diabetes (HR > 13) and ischemic heart disease (HR > 2.5) when compared against the lowest risk subgroup (High HDL ApoB-). Conclusions: This life-course analysis shows that metabolic dysfunction associated with excess weight gain begins in early childhood and is associated with cardiometabolic morbidity in later life.