Metabolism

Background: A substantial proportion of coronary events originate from angiographically moderate lesions, indicating that stenosis severity alone does not reflect lesion biomechanical risk. Objectives: To test whether adding lesion-adjacent pericoronary adipose tissue (PCAT) and CTCA-derived anatomy-flow descriptors to quantitative plaque assessment improves identification of future culprit lesions, with a prespecified focus on moderate stenosis. Methods: We performed a within-patient, lesion-level case-control analysis in the GeoCAD cohort, including patients undergoing coronary revascularisation during follow-up. Culprit lesions were identified from longitudinal CTCA. Stenosis severity, quantitative plaque composition, and PCAT volume were quantified (MEDIS), and vessel centreline geometry and lesion haemodynamics derived using computational modelling. Incremental prognostic value was assessed using Cox models with drop-one and stepwise workflow analyses, including a prespecified subgroup analysis of moderate stenosis lesions (25 - 49% diameter stenosis). Results: Among 46 patients (212 lesions; 55 culprit), percent area stenosis (%AS) dominated culprit lesion discrimination (HR: 2.01; 95% CI: 1.54 - 2.62; p < 0.001). In 82 moderate-stenosis lesions (30 culprit), %AS provided minimal discrimination ({Delta}C-index: 0.01; p=0.895). Culprit lesions were characterised by greater PCAT volume (HR: 1.75; 95% CI: 1.29 - 2.37; p < 0.001), higher helical flow intensity (HR: 1.35; 95% CI: 1.16 - 1.57; p < 0.001), and lower torsion (HR: 0.50; 95% CI: 0.29 - 0.84; p=0.009). Adding anatomy-flow descriptors improved risk stratification for moderate lesions beyond CTCA stenosis and plaque/PCAT features (p=0.007). Conclusions: In moderate stenosis, lesion-adjacent PCAT and anatomy-flow descriptors provided incremental prognostic information beyond luminal narrowing and plaque composition, supporting integrated CTCA phenotyping to identify high-risk nonobstructive coronary lesions.

This study investigates the individual and combined effects of Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and metformin on glucose regulation in a non-obese, insulin-deficient model of type 2 diabetes. Female Goto-Kakizaki (GK) rats underwent RYGB, SG, or sham surgery. Three weeks postoperatively, animals received metformin (50 mg/kg/day, 5 days/week) or vehicle for three additional weeks. Glucose tolerance was assessed using a standardized meal test, and insulin sensitivity was evaluated by insulin tolerance test. Plasma levels of GLP-1, GIP, insulin, and leptin were measured. RYGB and SG reduced body weight, food intake, and leptin levels, and improved fasting glucose, glucose tolerance, insulin sensitivity, and postprandial incretin and insulin secretion. Metformin alone improved glucose tolerance and insulin sensitivity independently of incretin or insulin changes. When combined with surgery, metformin further reduced postprandial glycemic excursions and advanced the glycemic peak but did not enhance insulin sensitivity or hormone secretion beyond surgery alone. In conclusion, bariatric surgery and metformin independently improve glucose regulation in non-obese diabetic GK rats. Their combination provides additional benefits on postprandial glucose control, despite no additive effects on insulin sensitivity or hormone levels. These findings support the use of metformin as an adjunct to bariatric surgery in insulin-deficient diabetes and highlight the need for longer-term, sex-inclusive studies to enhance translational relevance. NEW & NOTEWORTHYBariatric surgery and metformin each improved glucose regulation in non-obese, insulin-deficient female GK rats. Their combination yielded an additional reduction in postprandial glycemic excursions without further enhancing insulin sensitivity or incretin/insulin secretion. These findings reveal that postprandial glucose dynamics can be modulated independently of hormonal or insulin-sensitivity pathways, highlighting distinct and dissociable mechanisms governing glucose homeostasis in an insulin-deficient model.

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

Administration of ciliary neurotrophic factor (CNTF) reduces food intake and body weight in both humans and experimental animals, where it also ameliorates hyperglycemia, hyperinsulinemia, and dyslipidemia. To exert its anti-obesogenic and anti-diabetogenic effects, CNTF targets brain feeding centers as well as multiple peripheral organs inducing the phosphorylation of the transcription factor signal transducer and activator of transcription 3 (p-STAT3). However, data showing which peripheral cytotypes are specifically targeted by exogenous CNTF in vivo in metabolically relevant organs are currently lacking. Here, we first evaluated the gene expression levels of the subunits of the tripartite CNTF receptor (Cntfr) complex, i.e., the Cntfr, the leukemia inhibitory factor receptor {beta} (Lifr{beta}) and the glycoprotein 130 (gp130), by quantitative real-time PCR in metabolically relevant organs of adult male mice: gastrointestinal (GI) tract, pancreas, liver, visceral and subcutaneous white (WAT) and interscapular brown adipose tissue (iBAT), skeletal muscle and the sciatic nerve. We then quantified p-STAT3 by Western blotting in these organs after intraperitoneal administration of CNTF (0.3 mg/kg) or saline. Finally, we mapped CNTF-responsive cells by immunohistochemistry, followed by morphometric quantification and confocal microscopy in both CNTF- and saline-treated mice. Lifr{beta} and gp130 were ubiquitously detected across all the investigated organs; the Cntfr showed the highest expression levels in the skeletal muscle, sciatic nerve, and iBAT, whereas it was found to be expressed to a lesser extent in the other sites. Administration of CNTF led to a significant increase of p-STAT3/STAT3 protein ratio in all organs examined, except the duodenum, and induced a distinctive pattern of cell nuclear p-STAT3 immunoreactivity. Notably, along the analyzed GI tract CNTF induced nuclear STAT3 phosphorylation in neurons of the submucosal and myenteric plexuses of the enteric nervous system and in contractile cells of the muscularis externa, where the response peaked in the mesenteric gut and colon. In the pancreas, CNTF triggered a higher activation within the endocrine component compared to the exocrine parenchyma. In the liver, CNTF induced STAT3 phosphorylation not only in parenchymal cells but also in sinusoids and resident macrophages. The cytokine activated p-STAT3 in subcutaneous and visceral white adipocytes, but also in brown adipocytes, with a prominent response observed in the beige subcutaneous adipocytes; adipose resident macrophages and endothelial cells of numerous blood vessels were also CNTF-responsive. Lastly, in skeletal muscle, a major site for glucose/lipid utilization, CNTF induced widespread nuclear p-STAT3 immunoreactivity in muscle fibers and in connective and Schwann cells of the peripheral nerves, including the sciatic nerve, supplying the gastrocnemius. In conclusion, our data indicate that CNTF acts across diverse cytotypes within metabolically relevant organs and tissues, likely fostering its peripheral metabolic effects through this cellular heterogeneity.

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. Author summaryInflammation plays a vital role in protecting the body from infection and injury but can also become chronic and consequently detrimental. Systemic inflammation is linked to many common diseases, including heart disease, diabetes, and depression. C-reactive protein and Interleukin-6 are widely used markers of inflammation which can be measured in the blood. Although these markers are often elevated in disease, it is not always clear whether they are a cause, a consequence, or a consequence of other underlying processes. In this study, we used genetic evidence from large population studies to help clarify which traits may have causal influence on levels of these inflammatory markers. By analysing thousands of potential relationships across metabolic, immune, cardiovascular, and mental health traits, we identified several metabolic processes, and related traits such as BMI and Type 2 diabetes, as key drivers of both markers of inflammation. We also found that C-reactive protein appears to reflect a broader range of biological influences than Interleukin-6. Our findings help to clarify which factors are most likely to sit upstream of systemic inflammation. This improved understanding may help guide future research aimed at preventing or reducing inflammation-related disease.

A greater genetic susceptibility has been proposed as an explanation of the greater rates of cardiovascular and metabolic disease in South Asian relative to European populations. We first demonstrate that after accounting for technical artefacts the genetic effects for related traits are largely consistent between ancestral groups, which downplays the role of GxG or GxE interactions driving differential prevalence. If higher genetic susceptibility in South Asians is due to selective pressures acting through adiposity-related traits in the evolutionary past, signatures of selection should be evident at loci associated with cardiometabolic disease and other causally related traits (e.g. fat distribution). We tested for enrichment of several selection statistics (FST, XP-EHH and XP-nSL) at loci associated with a range of traits related to cardiometabolic disease, in comparison to a null distribution of linkage disequilibrium (LD) score and minor allele frequency (MAF) matched SNPs. Loci associated with a subset of these traits (Type 2 diabetes mellitus, trunk fat percentage, body fat percentage and trunk fat mass) exhibited enrichment for FST, consistent with a moderate adaptive explanation for their cross-population differentiation. In contrast, none of the studied traits were enriched for haplotype-based statistics, indicative that cross population genetic divergence is unlikely to have been driven by recent selective sweeps but has rather likely arisen from either ancient selection or recent polygenic selection acting on standing variation.

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.

{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.

BackgroundMetabolically healthy obesity (MHO) is unstable, with up to 80% of individuals progressing to metabolically abnormal obesity (MAO), yet mechanisms underlying this transition remain unclear. African Americans bear a disproportionate burden of obesity-related cardiovascular disease. Circulating extracellular vesicles (EVs) mediate inter-organ communication and may drive MAO-related vascular dysfunction. MethodsAdults of African ancestry were classified as metabolically healthy lean (MHL, n=14), MHO (n=9), or MAO (n=16). Plasma-derived EVs were characterized and their microRNA cargo profiled. Human coronary artery endothelial cells were treated with EVs from each group to assess nitric oxide signaling, oxidative stress, inflammatory activation, and mitochondrial dynamics. ResultsMHO participants exhibited preserved insulin sensitivity and lower inflammation compared with MAO despite comparable adiposity. EVs from MHO carried a distinct microRNA signature enriched in miR-148a-5p, miR-181c-5p, and miR-1255a, linked to antioxidant and matrix regulatory pathways. MAO EVs were enriched in miR-3613-3p, miR-6842-3p, and miR-326, targeting inflammation and insulin resistance pathways. Compared with both MHL and MHO EVs, MAO EVs suppressed endothelial nitric oxide synthase phosphorylation and reduced nitric oxide bioavailability, with increased reactive oxygen species and ICAM-1 expression. MHO EVs induced an intermediate phenotype with disrupted mitochondrial morphology, supporting a graded continuum of endothelial stress. ConclusionsMHO represents a biologically active intermediate state. Circulating EVs from MHO individuals convey molecular signals that impair endothelial and mitochondrial function, predisposing to vascular injury and progression toward MAO. EV-associated microRNAs are mechanistic mediators and candidate biomarkers of metabolic and vascular deterioration in obesity. CLINICAL PERSPECTIVEO_ST_ABSWhat Is New?C_ST_ABSO_LIThis study systematically investigated extracellular vesicles derived from metabolically healthy obese individuals to define direct vesicle effects on endothelial function using integrated omics coupled to functional outputs. C_LIO_LIExtracellular vesicles from metabolically healthy obesity convey a distinct molecular and biological signature that distinguishes lean and metabolically abnormal obesity. C_LIO_LIMetabolic health status, rather than obesity alone, drives extracellular vesicle-mediated endothelial nitric oxide signaling, oxidative stress, inflammation, and mitochondrial dynamics. C_LI What Are the Clinical Implications?O_LIThese findings explain why some individuals with obesity exhibit preserved vascular function while others develop early endothelial dysfunction. C_LIO_LIStratifying obesity by metabolic health status improves cardiovascular risk assessment beyond body mass index alone. C_LIO_LITargeting extracellular vesicle signaling pathways represents a novel strategy to prevent metabolically healthy individuals from progressing to metabolically abnormal obesity. C_LI

BackgroundObesity significantly increases the risk of prognosis and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC). While research on the interactions between obesity and the tumor microenvironment (TME) is mostly confined to a few interactions at a time, leaving a gap in the comprehensive understanding of obesity-driven PDAC. We set out to develop a cell-type-resolved model of obesity-driven PDAC using bulk transcriptomic data to investigate TME changes. MethodsWe conducted an integrated transcriptomic analysis of PDAC patients from the CPTAC-3 cohort (n=140) stratified by BMI. A custom immune and stromal functional gene signature database covering 65 cell types was constructed, followed by LLM-assisted review, overlap control, and validation. BayesPrism deconvolution using matched single-cell references was used to derive expression profiles for each cell type. Stabl, a machine-learning algorithm, was used to identify BMI-associated signatures. Bayesian hierarchical modeling, using both continuous and categorical BMI change, was applied to estimate effect sizes and assess the statistical credibility of the signature changes using the 95% Highest Density Interval (HDI) excluding zero. Virtual multiplex immunofluorescence was generated from whole-slide H&E images using gigaTIME to assess the spatial manifestation of BMI-associated TME changes in tissue ResultsBulk pathway analysis showed that ECM homeostasis and primary immunodeficiency pathways deteriorated with increasing BMI. However, Bayesian modeling revealed cell-type-specific, non-linear dynamics. Stromal populations in overweight (OW) individuals were altered, with changes in ECM synthesis and inflammatory signaling that stabilized rather than intensified during obesity. Immune compartments also showed diverse trajectories: CD4+ T cells remained functional in OW but collapsed in obesity; CD8+ T cells progressed linearly from activation to chronic exhaustion. NK cells exhibited non-monotonic behavior, and monocyte and B cell lineages became impaired prior to clinical obesity. Cell-cell interaction analysis showed a shift from a T cell and dendritic cell-centric adaptive interactome in normal weight patients to a neutrophil-dominated inflammatory network in OW. Spatial analysis showed stromal-trapped CD8+ T cells were compressed closer to the tumor boundary with rising BMI. ConclusionsOverweight status represents a critical tipping point in tumor microenvironmental reprogramming, challenging linear models of obesity-associated immune modulation and suggesting that early metabolic interventions may prevent PDAC functional deterioration. Model is available at https://obese-pdac-model.streamlit.app/ O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/721695v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@b1c8cdorg.highwire.dtl.DTLVardef@1f61b7forg.highwire.dtl.DTLVardef@876c60org.highwire.dtl.DTLVardef@dc32b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

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.

BackgroundThe 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. MethodsWe 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. ResultsConditioning on the primary sentinel variant rs12213929 (upstream of GLP1R, {beta} = 0.11; 95% CI 0.09-0.14; p = 1.94x10-17), we identified a secondary variant (rs13216992, intron of GLP1R) independently associated with BMI ({beta} = 0.10; 95% CI 0.07-0.13; p = 7.88x10-14). 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 < 2x10-16). 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. ConclusionsThe 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.

Lactation is associated with a protective effect against breast and ovarian cancer as well as against cardiovascular diseases suggesting a systemic effect. Here, we show that the serum of lactating mice and breastfeeding mothers have targeted antineoplastic effects, while serum from virgin mice and matched post-partum but non-lactating women do not. The effect is specific to cancer cells expressing Pappalysin-A (PAPP-A), a target that is shared among diseases affected by breastfeeding. RNAseq revealed that lactating serum inhibits mitochondrial function and we found that PAPP-A alone lowers mitochondrial function, suggesting that lactation serum acts by exploiting the metabolic vulnerability of these cancer cells. Using serum proteomics, we identified corticotropin release factor (CRF) as being unique to serum of lactating women and we show that CRF alone mimics the mitochondrial and anti-tumorigenic effect of lactating serum. Blocking the CRF receptor, inhibits the protective effect of lactating serum. Since CRF has shown efficacy in the clinic in other settings, our findings raise the possibility to extend its use to mimic or enhance the protective effect of breastfeeding. SummaryWe show that the serum from lactating women has anti-cancer activity and used multi-omics approaches to identify corticotropin release factor as a peptide able to mimic the effect of lactating serum by targeting cells with low mitochondrial activity.

OBJETIVEFood intake, energy expenditure, and metabolic homeostasis depend on hypothalamic neurons responses to peripheral signals, such as leptin, involving the primary cilium (PC). The PC is crucial for signal transduction and is dynamically regulated by assembly/disassembly or reabsorption of its microtubules-based axoneme. Absence or reduction in the length of PC is associated with obesity and type-2 diabetes (T2D). In other cellular systems, PC reabsorption is primarily regulated by calcium-mediated activation of the Aurora kinase A (AurkA)/histone deacetylase C6 (HDAC6) axis, which promotes axonemal disassembly. Here, we explore the role of Galectin-8 (Gal-8), a glycan-binding protein, in regulating PC structure and signaling related to metabolic parameters in hypothalamic neurons. METHODSGal-8 effects were assessed in hypothalamic Clu-177 cells by analyzing the PC presence and length by immunofluorescence, PC dynamics, and intracellular calcium changes by in vivo cell imaging, activation of FAK, Src, AurkA, HDAC6 and STAT3 by immunoblot, and Gal-8 interactions with {beta}1-integrins by pull-down assays. Gal-8-KO mice were used to evaluate PC length in hypothalamic neurons, metabolic phenotype, and responses to Gal-8 intranasal administration. RESULTSIn Clu-177 cells, Gal-8 induced PC reabsorption and reduced responsiveness to leptin signaling towards STAT3 activation. PC reabsorption involves glycan-mediated Gal-8 interactions with a5b1 and a3b1 integrins, activation of FAK and Src leading to calcium influx through L-type calcium channels (LTCC), and subsequent AurkA/HDAC6 axis activation. Gal-8-KO mice showed longer PC in hypothalamic neurons, higher STAT3 activation, decreased body weight and food intake, improved glucose tolerance, higher locomotor activity, and a glycolytic respiratory exchange rate (RER). Daily intranasal Gal-8 administration for 4 days restored hypothalamic PC length and STAT3 signaling, as well as RER in Gal-8-KO mice to the level of WT mice. CONCLUSIONSEndogenous Gal-8 is required to maintain PC structure and leptin signaling in hypothalamic neurons, impacting body weight, energy balance, and glucose homeostasis. The mechanism involves calcium influx via LTCC downstream of b1-integrin/FAK/Src signaling and subsequent AurkA/HDAC6 axis activation. Both Gal-8 and the AurkA/HDAC6 axis may offer new therapeutic opportunities for treating metabolic diseases characterized by ciliogenesis impairment, including obesity and type-2 diabetes.

BackgroundCardiometabolic diseases arise from metabolic dysfunction that develops decades before clinical onset. Conventional genetic risk models are typically derived in middle-aged or older populations, where genetic effects are confounded by cumulative environmental exposures, chronic comorbidities, and clinical interventions. Whether the life stage at which genetic liability is modelled influences the biological signal captured by polygenic scores remains unclear, particularly in underrepresented populations. We therefore tested whether genetic liability modelled in early adulthood, a period of relative physiological stability, is associated with cardiometabolic risk across the life course in Asian populations. MethodsWe developed a polygenic score for metabolic syndrome, GenMetS, using data from 1,368 Singaporean women aged 18-45 years. The model integrates 15 established polygenic scores for metabolic traits and applies elastic-net penalized regression to optimize variant weights. GenMetS was evaluated in five cohorts comprising 670,952 individuals aged 0-94 years across population-based and disease-enriched settings, including Asian and European ancestry groups. Associations with metabolic traits, cardiometabolic diseases, multimorbidity, and early-life growth patterns were assessed. ResultsIn Asian populations, GenMetS explained 5.0-12.4% of the variance in metabolic syndrome in adults and 10.3% in children, with negligible performance in European populations (R{superscript 2} < 0.001). Higher GenMetS was associated with increased odds of cardiometabolic diseases, including type 2 diabetes, heart failure, and stroke (odds ratios 1.32-1.52 per standard deviation). In UK Biobank participants of Asian ancestry, GenMetS improved discrimination of cardiometabolic multimorbidity beyond age alone. Associations were consistent across sexes. In children, higher GenMetS was associated with obesogenic growth trajectories and increased abdominal adiposity. ConclusionsGenetic liability to metabolic dysfunction modelled in early adulthood captures a stable biological signal associated with metabolic traits, disease risk, and multimorbidity from childhood to adulthood in Asian populations. These findings indicate that the life stage of model derivation shapes the biological signal captured by polygenic scores and support the development of life-stage- and ancestry-informed approaches for cardiometabolic risk assessment and prevention.

Background: C-terminal binding protein 2 (CtBP2) has been implicated in metabolic regulation, but its association with specific measures of adiposity and lipid profiles in humans remains unclear. This study examined the relationship between circulating CtBP2 levels and key components of metabolic syndrome, focusing on body fat distribution and lipid markers. Methods: Data from 508 participants (259 men, 249 women) from a publicly available dataset were analyzed. Serum CtBP2 concentrations were measured using ELISA. Associations with obesity markers (BMI, waist circumference, waist-to-hip ratio) and lipid profiles (triglycerides, HDL cholesterol) were assessed using Spearman correlation and linear regression, adjusting for age and sex. Results: CtBP2 levels showed weak but statistically significant positive correlations with all measures of adiposity, with the strongest association observed for waist circumference ({rho} = 0.150, p < 0.001), followed by BMI ({rho} = 0.120, p = 0.007) and waist-to-hip ratio ({rho} = 0.098, p = 0.027). No significant correlations were found with triglycerides or HDL cholesterol. In the regression model predicting BMI, age, and sex were significant predictors, while CtBP2 demonstrated a trend toward association ({beta} = 0.080, p = 0.052). Conclusion: Circulating CtBP2 appears to be modestly associated with measures of adiposity, particularly abdominal fat, but not with lipid abnormalities. These findings suggest a potential role for CtBP2 in obesity-related metabolic dysregulation and underscore the need for further mechanistic studies to clarify its clinical relevance.

PurposeLeft ventricular hypertrophy (LVH) is a major complication of chronic hypertension and an independent risk factor for cardiovascular morbidity and mortality. There are currently no clinically validated markers available to identify hypertensive individuals at risk for developing LVH. In hearts of hypertensive rats, we previously described metabolic changes that precede LVH development, including in branched-chain amino acid (BCAA) metabolism. This study investigated whether cardiac leucine uptake, measured with dynamic 5-[18F]fluoroleucine positron emission tomography-computed tomography ([18F]FLE-PET/CT), was impaired and could serve as an in vivo marker for hypertension-induced LVH development. ProceduresWe synthesized [18F]FLE following established radiochemistry protocols and performed dynamic [18F]FLE-PET/CT imaging in 3-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) control rats (n = 4 per group). Cardiac magnetic resonance (CMR) imaging was conducted on the same animals for structural co-registration. A dual-output reversible two-tissue compartment model with spill-over (SP) and partial volume (PV) corrections was developed to quantify the first-pass rate constant (K1) and total distribution volume (Vt = K1/k2) for [18F]FLE. Protein expression of L-type amino acid transporter 1 (LAT1) and branched-chain keto acid dehydrogenase (BCKDH) phosphorylation status were assessed by immunoblotting of isolated heart tissue. ResultsSHR demonstrated markedly lower first-pass leucine uptake rates (K1) and total distribution volumes (Vt) compared with WKY rats, consistent with reduced cardiac BCAA uptake. Concurrently, LAT1 (SLC7A5) expression was significantly reduced in SHR hearts compatible with decreased leucine uptake. Elevated BCKDH phosphorylation at Ser293 in SHR hearts indicated diminished BCKDH enzymatic activity and impaired BCAA catabolism. ConclusionsDynamic cardiac [18F]FLE-PET imaging successfully detects decreased leucine uptake in hypertensive rat hearts at 3 months of age, before LVH is established at 5 months. Reduced cardiac leucine uptake may thus serve as a surrogate marker for impaired cardiac BCAA metabolism and early in vivo indicator of cardiometabolic dysfunction that precedes LVH. The imaging approach holds translational potential for identifying hypertensive patients at risk for LVH progression.

Obesity affects one in three adults and is complicated by adipose inflammation, lipotoxicity and cell death. We previously identified RIPK1 as a genetic determinant of human obesity risk and adipose inflammation. Because RIPK1 is the apical kinase in the necroptosis pathway upstream of RIPK3 and the executioner protein MLKL, and emerging evidence links MLKL to lipid metabolism, MLKL has surfaced as a potential metabolic regulator. However, conflicting findings in Mlkl knockout mice fed a high fat diet have left its therapeutic relevance unresolved. MLKL has not been previously targeted through therapeutic knockdown in vivo in the context of diet-induced obesity. Here, we evaluated two independent MLKL antisense oligonucleotides (ASOs) in high fat diet (HFD)-fed C57BL/6J mice. In a 24-week progression model, MLKL ASO markedly reduced body weight, fat mass and hepatic steatosis compared with controls, while preserving lean mass. MLKL knockdown also lowered the respiratory exchange ratio, indicating a shift toward increased fat oxidation. In the intervention model, once obesity was established after 12 weeks of HFD feeding, both MLKL ASOs, and similarly, two independent RIPK1 ASOs, reversed weight gain and improved systemic glucose control. In vitro, MLKL-CRISPR/Cas9 knockout blocked 3T3-L1 adipogenesis, indicating a requirement for MLKL during adipocyte differentiation. However, in mature adipocytes, MLKL siRNA reduced palmitic acid-induced lipid accumulation, increased isoprenaline-stimulated lipolysis, and prevented TNF-mediated suppression of insulin-mediated AKT signalling and glucose uptake. Collectively, these findings demonstrate that partial MLKL suppression reprograms whole-body energy metabolism, enhances insulin sensitivity and limits diet-induced adiposity. MLKL, therefore, represents a promising and mechanistically novel therapeutic target for obesity and insulin resistance.

Childhood obesity remains a pressing global health challenge, yet the impact of dynamic adiposity changes during active developmental window retains poorly understood. Leveraging longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (N=8519 at baseline; N=1873 at 4-year follow-up), our study reveals distinct neurodevelopmental implications of central fat dynamics during adolescence. At baseline, central fat indices (body roundness index, BRI / waist-to-height ratio, WHtR) outperformed BMI in predicting cognitive deficits, showing robust associations with impaired inhibitory control and episodic memory. The prediction effect was partially mediated by cortical changes in prefrontal and temporal regions. Longitudinally, the rate of fat accumulation ({Delta}) emerged as a critical predictor: faster adiposity accrual predicted attenuated cortical thinning (i.e., slower development) in parietal lobes and poorer executive function at follow-up, while baseline adiposity showed no significant effects on the follow-up brain morphology or cognitive development. Notably, subgroup analyses uncovered that obese adolescents with central fat reduction exhibited accelerated cortical thinning in posterior cingulate (change difference p=0.006-0.029) alongside rapid improvement in inhibitory control (Flanker slope difference p<0.05), whereas those with persistent adiposity showed delayed thinning in the postcentral gyrus. The study reveals that central fat (BRI/WHtR) is closely linked to neurocognitive risks, and longitudinal fat accumulation--rather than baseline adiposity--drives cortical alteration. Notably, fat reduction activated adaptive neural change in obese adolescents, underscoring the importance of weigh regulation during neurodevelopment.

Adipokines are key metabolic hormones that modulate cardiometabolic risk through multiple distinct biological pathways. To delineate these pathways, we systematically mapped adipokineassociated variants to putative effector genes (V2G) across{square}1,669 human traits in three ancestries from the Million Veteran Program. Grouping the variants by their associations with insulinresistance-related traits yielded six discrete variant clusters, including a "Lipodystrophy" cluster characterised by lower bodymass index but higher waisttohip ratio, fasting glucose, and insulin levels. V2G mapping implicated TGFB2 and VEGFA as candidate effector genes in the Lipodystrophy cluster. VEGFA also appeared in a distinct "Thyroid-adiposity" cluster that was strongly associated with increased insulin resistance and decreased thyroid function. The Thyroid-adiposity cluster comprised variants that are thyroid eQTLs, unlike those in the Lipodystrophy cluster. These findings indicate that VEGFA may influence insulin resistance via two separate mechanisms: abnormal adiposity and altered thyroid function. Although both clusters increased coronary artery disease risk, only the Lipodystrophy cluster increased type{square}2 diabetes risk. Our results highlight mechanistically distinct routes by which adipokines modulate insulin resistance and cardiometabolic disease.