Metabolism

Obesity-driven metabolic syndrome poses a critical global threat, yet standard therapies like GLP-1 receptor agonists trigger substantial lean mass wasting, with muscle loss accounting for up to 40% of reduced weight. Here we identify a non-canonical metabolic application for dronedarone hydrochloride, an anti-arrhythmic benzofuran derivative. In diet-induced and ob/ob obese mice, short-term dronedarone hydrochloride administration dose-dependently reduces food intake, clears visceral and subcutaneous adiposity, and reverses steatohepatitis. Head-to-head trials show that dronedarone hydrochloride achieves glycemic control and fat clearance non-inferior to semaglutide, tirzepatide, and empagliflozin, but uniquely and completely preserves skeletal muscle mass. Mechanistically, dronedarone hydrochloride operates independently of central hypothalamic appetite-regulating neuropeptides and the peripheral leptin pathway. By decoupling fat reduction from sarcopenia, our findings establish dronedarone hydrochloride as a muscle-sparing therapeutic candidate for metabolic syndrome.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease, with weight loss as the pivotal therapeutic strategy. However, the metabolic and molecular adaptations underlying rapid weight loss remain incompletely defined. In this pilot study, women with obesity and MASLD but without diabetes consumed a very low-calorie diet (VLCD) for 8 weeks. Clinical parameters, hepatic steatosis measured by controlled attenuation parameter (CAP), circulating metabolites, and microRNAs (miRs) were assessed before and after the dietary intervention. Integrated correlation and hierarchical clustering analyses were performed to identify molecular networks associated with clinical improvement. VLCD was well tolerated, resulting in significant weight loss (~11%) with ~80% adherence. Significant improvements in metabolic parameters were observed, including fat mass, waist circumference, blood pressure, insulinemia, HOMA-IR, HbA1c, and triglycerides, with unchanged liver enzymes. Hepatic steatosis decreased markedly, as indicated by a reduction in CAP, while stiffness remained unchanged. Metabolomic profiling revealed elevated ketone bodies and broad reductions in amino acid levels, consistent with enhanced fatty acid oxidation and a catabolic metabolic state. Correlation analysis identified distinct metabolite signatures associated with hepatic steatosis, with changes in CAP positively associated with changes in amino acids and inversely associated with changes in ketone bodies and tricarboxylic acid cycle intermediates. Circulating miRs underwent selective rather than global remodeling, with only a limited subset showing strong associations with clinical parameters, including CAP and HOMA-IR. Specifically, VLCD altered the circulating levels of miR-148a-3p, miR-140-3p, miR-10b-5p, and miR-345-5p. Integration of metabolomic and miR datasets identified coordinated metabolite-miR modules involving glucose metabolism, branched-chain amino acid catabolism, mitochondrial metabolism, purine metabolism, microbial metabolites, and cellular redox pathways. These findings demonstrate that improvement in hepatic steatosis during VLCD-induced weight loss is accompanied by coordinated remodeling of circulating metabolite-miR networks. Integrated multi-omics analysis identifies candidate molecular signatures associated with metabolic adaptation and highlights circulating miR-metabolite modules as potential biomarkers of therapeutic response in MASLD.

Insulin resistance (IR) is a hallmark feature of Type 2 Diabetes Mellitus and a well-established risk factor for coronary heart disease (CHD), yet the pathways through which IR contributes to CHD remain incompletely understood. To comprehensively describe the genetic architecture of IR, we collected three direct IR indicators--- fasting insulin (N = 151,013), the Modified Stumvoll insulin sensitivity index (N = 53,657), and pro-insulin (N = 45,861), and conducted joint analysis on them using Linkage Disequilibrium (LD) Score Regression and factor analysis. A single latent IR factor was generated which captures 60.5% of the shared genetic variance. Based on the IR factor, a multivariate GWAS was conducted within Genomic Structural Equation Modelling and then we built a polygenic risk score (PRS) of IR for the UK Biobank European cohort (N = 407,767; 55,729 CHD cases and 352,038 controls). Then we performed the association study to quantify the relationship between genetically predicted IR and CHD. Causal mediation analyses were also performed through 2,923 plasma proteins (Olink) and 168 metabolites (Nightingale NMR), followed by serial-mediation models (IR -> protein -> metabolite -> CHD) over all prescreened pairs. Single-mediator screening nominated 938 proteins and 159 metabolites; this yielded 3,669 significant "protein -> metabolite -> CHD" serial-mediation pathways, from which 33 broadly-acting core mediating proteins were prioritized. These acted predominantly through the large and very large high-density lipoprotein (HDL) particle subclasses: 30 of the 33 core proteins and all 14 HDL-subclass metabolites formed 306 pathways, of which 303 (99.0%) amplify the CHD risk. These results map a proteomic and metabolomic axis linking the genetic component of IR to CHD and highlight HDL lipoprotein-subclass biology as a candidate therapeutic and biomarker space.

Mechanical homeostasis plays a central role in promoting and preserving optimal structure and function in the adult aorta. Although pathogenic variants can compromise homeostatic processes, it appears that intramural cells yet attempt to compensate for some genetically induced changes. In particular, lysyl oxidase is higher in the adult Marfan aorta compared with the age-matched control aorta. Here, we block lysyl oxidase in adult Fbn1C1041G/+ Marfan syndrome mice after stimulating aortic disease progression via induced hypertension. Whereas hypertension alone increases aortic dilatation, concurrent blocking of lysyl oxidase results in a dramatic increase in disease severity, driving an otherwise mild aortic phenotype in adult male Fbn1C1041G/+ Marfan mice to aneurysmal dilatations as well as dissection and rupture, with frequent premature death. Deposition and cross-linking of fibrillar collagens, among other extracellular matrix constituents, can represent a protective compensation against severe disease in the Marfan aorta. The present study emphasizes the need clinically to avoid compromising new collagen deposition and suggests that strategies to augment collagen cross-linking could be beneficial.

Introduction: Lipids are considered both drivers and biomarkers of cardiometabolic diseases. As glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for diabetes and obesity management, it is crucial to understand how they affect the related comorbidities through the circulating lipidome. This study investigated the lipidomic changes induced by liraglutide treatment when compared to placebo in people with type 2 diabetes (T2D) to characterise lipid remodelling and its association with clinical outcomes. Research design and methods: This post-hoc study analysed plasma samples using liquid chromatography-mass spectrometry (LC-MS/MS) from LIRAFLAME, a randomised, double-blind, placebo-controlled, parallel-group trial. A hundred people with T2D received up to 1.8 mg of liraglutide or placebo once daily for 26 weeks. Plasma samples were collected at baseline, week 13 and week 26. Results: Liraglutide treatment resulted in a statistically significant increase in multiple lysophospholipid subclasses, including LPCs, LPC(O)s, LPC(P)s, LPEs, and LPE(P)s, observed at 13 weeks and sustained at 26 weeks compared to placebo. These increases were not mediated by the change in BMI. Triglyceride concentrations decreased at 13 weeks, while fatty acid levels declined at 26 weeks, consistent with enhanced lipid remodelling. The increase in LPC(O)s was associated with favourable decreases in ALAT, MCP-1, and UACR, suggesting anti-inflammatory effects with hepatic, renal, and cardiovascular benefits. Conclusions: Compared to placebo, 26 weeks of liraglutide treatment resulted in a favourable lipidomic shift from a triglyceride-rich profile towards one enriched in lysophospholipids. This lipid remodelling was associated with improvements in hepatic, renal, and inflammatory markers.

Background. Type 2 diabetes (T2D) and coronary artery disease (CAD) frequently co-occur, yet the biological pathways that jointly determine risk remain incompletely understood. Most genetic studies have examined shared risk from a single-disease perspective, limiting insight into the mechanisms that generate discordant risk between conditions. Methods. We applied PLACO to multi-ancestry GWAS data of T2D and CAD to identify shared loci, prioritising shared causal signals using colocalisation. Shared variants were clustered by their associations with 77 cardiometabolic traits, and cluster-specific genetic risk scores (GRS) were tested for association with 17 clinical biomarkers and 1,254 binary outcomes in 378,772 UK Biobank (UKB) participants. Two-sample Mendelian randomisation (MR) was used to test the causal role of liver fat. Results. We identified 149 loci shared between T2D and CAD; most novel loci had discordant effects (35 of 42), in contrast to the predominantly concordant signals reported previously. Clustering 187 independent shared variants revealed seven mechanistic clusters, three of them centred on liver fat and defined by discordant T2D?CAD effects. Enrichment analyses and cluster-GRS associations in UKB highlight associations between higher liver fat and T2D risk with a cardioprotective lipid profile and reduced CAD risk. Genetically higher liver fat increased T2D risk but lowered CAD risk in MR analyses; partitioning liver fat instruments by their effect on ApoB-containing lipoproteins indicates that the CAD effects are determined more by effects of circulating ApoB rather than liver fat itself. Conclusions. Liver fat largely sets the direction of T2D risk, whereas the fate of that lipid, retained in the liver with low circulating ApoB or exported as ApoB-containing lipoproteins, sets the direction of CAD risk. This liver-centric partitioning provides a mechanistic framework for the discordant cardiometabolic effects of hepatic lipid and lipid-lowering pathways, with implications for precision prevention.

Background Anthropometric measures do not adequately capture heterogeneity in body fat distribution and corresponding cardiometabolic risk, whereas magnetic resonance imaging (MRI) enables precise differentiation and quantification of adipose tissue compartments and ectopic fat. We aimed to validate previously derived MRI-based body composition subphenotypes and their cardiometabolic risk profiles in two independent European cohorts. Methods Using deep learning-based image analysis, we quantified bone marrow, visceral, subcutaneous, cardiac, renal sinus, hepatic, skeletal muscle, and pancreatic fat in the imaging substudies of two population-based cohorts: the German National Cohort (NAKO, N=29,314, age range 19-74 years) and the UK Biobank (N=36,109, age range 40-69 years). Body composition subphenotypes, previously identified by k-means clustering, were evaluated using a rigorous statistical cluster validation framework with method-based and results-based approaches. In NAKO, cross-sectional associations between subphenotypes and estimated cardiovascular disease risk scores were examined using linear regression. In UK Biobank, longitudinal associations between subphenotypes and incident cardiometabolic outcomes, ascertained through hospital record linkage, were analysed using Cox regression. Findings All five body composition subphenotypes were robustly validated across both cohorts, and showed distinct fat distribution patterns and cardiometabolic risk profiles: I "lean", II "average adiposity", III "bone and muscle adiposity", IV "hepato-abdominal adiposity", and V "general and pancreatic adiposity". Subphenotypes I-III showed progressive adipose tissue remodelling patterns likely reflecting ageing trajectories. The "hepato-abdominal adiposity" subphenotype showed highest risk of incident diabetes, whereas the "general and pancreatic adiposity" subphenotype showed highest overall cardiovascular disease burden and metabolic impairment. Interpretation MRI-derived body composition subphenotypes represent distinct fat distribution patterns that reflect ageing- and disease-related processes, which supports the potential of body composition phenotyping for improved cardiometabolic risk stratification and targeted prevention.

Obesity is a significant public health concern. Early-onset obesity in the context of rare disease can reflect genetically-mediated pathology or elevated susceptibility through indirect mechanisms. Mapping the diverse characteristics and needs of young people with obesity in the rare disease population is a first step toward mechanistic and translational research. We carried out a retrospective comparative analysis of demographic, genotypic, phenotypic and health service utilisation data for young people with obesity (cases: n=500) and without obesity (controls: n=11,444) from the UK 100,000 Genomes Project rare disease cohort. Cases and controls were recruited prior to genomic diagnosis, across clinical disorder categories. We observed significant association between socioeconomic deprivation and obesity risk. Young people with obesity had significantly higher utilisations of acute care and mental health services, indicating an overall higher health burden. A curated panel of 519 candidate obesity-associated genes demonstrated aggregate association with obesity, although no single gene reached significance. Phenotypic comparison between cases and controls highlighted increased multi-organ and neurological system involvement, highlighting the overlap between neurodevelopmental and obesity risks. Within the case group, we conducted cluster analysis to identify early-onset obesity groups with different phenotypic profiles, potentially arising from different causal pathways - this identified six obesity subgroups of interest, with differing involvement of neurodevelopmental and other systems. Our study confirms that obesity co-occurs with a wide range of factors within the rare disease population, and is associated with significant physical and mental health needs, requiring holistic lifelong care.

Complement factor D, also known as adipsin, is produced by adipose tissue, and the liver that links metabolic regulation with innate immunity. Despite its established systemic functions, the regulation of hepatic adipsin expression and its contribution to metabolic disease remain poorly defined. Here, we show that hepatic adipsin protein abundance is markedly increased in individuals with type 2 diabetes (T2D), and positively correlates with glycated hemoglobin, despite unchanged mRNA expression. Concordantly, hepatic adipsin protein levels were elevated in multiple murine models of hyperglycemia, including type 1 diabetes (T1D), T2D, and following fasting-refeeding transitions. In cultured hepatocytes, glucose exposure induced a rapid, dose-dependent increase in adipsin protein without altering transcript abundance, demonstrating post-transcriptional regulation. Mechanistically, glucose stimulates adipsin translation via dephosphorylation of eukaryotic initiation factor 2 (eIF2), and activation of the mammalian target of rapamycin, mediated by the 5' untranslated region of adipsin mRNA. Functionally, hepatocyte-specific depletion of adipsin impaired postprandial glucose tolerance, with reduced glucose uptake and a marked downregulation of glucose transporter type 2 (GLUT2). Taken together, these findings identify hepatic adipsin as a glucose-responsive translational target that couples nutrient availability to metabolic adaptation, revealing a new layer of regulation with potential relevance to diabetes pathogenesis. HighlightsO_LIHepatic adipsin protein increases in type 2 diabetes and correlates with glycemic status independent of mRNA expression. C_LIO_LIGlucose induces adipsin translation through eIF2 dephosphorylation and mTOR activation. C_LIO_LImTOR controls adipsin synthesis via structured 5'UTR of adipsin mRNA. C_LIO_LILiver-specific adipsin depletion impairs post-prandial glucose tolerance by downregulating GLUT2. C_LIO_LIHepatic adipsin acts as a glucose-responsive effector of glycemic control. C_LI

BACKGROUNDLysine methyltransferase SET7 activates gene expression through mono- methylation of histone H3 at lysine 4 (H3K4me1) and modulates protein function via mono- methylation of non-histone proteins (Kme1). However, its role and molecular targets in endothelial dysfunction associated with cardiometabolic disorders remain unknown. METHODSEndothelial-specific Setd7 knockout (Setd7EC-KO) mice were generated and endothelial function assessed in WT and Setd7EC-KO mice after high-fat diet (HFD). Human aortic endothelial cells (HAECs) were used to investigate SET7 expression and function under metabolic stress. SET7-dependent histone and non-histone targets were identified by proteomic and ChIP analyses. Insights from these datasets guided the design of bioinformatic, molecular, and functional studies to define their regulatory mechanisms. Clinical relevance was evaluated in human arteries. RESULTSHFD selectively increased endothelial SET7 expression in WT mouse aortas. Despite comparable metabolic abnormalities, Setd7EC-KO mice were protected from HFD- induced endothelial dysfunction, oxidative stress, and inflammation. In HAECs, high glucose emerged as the strongest inducer of SET7 expression, promoting pro-inflammatory and pro- oxidant gene expression, monocyte adhesion, and ROS generation. These effects were reproduced by overexpression of catalytically active SET7 and reversed by its inhibition or silencing. Proteomic and ChIP analyses revealed that SET7-dependent H3K4me1 activates transcription of spliceosome components, linking aberrant mRNA splicing to endothelial inflammation and oxidative stress. Moreover, Kme1-proteomics identified endothelial nitric oxide synthase (eNOS) as a direct SET7 substrate. Bioinformatic analyses and mutagenesis experiments demonstrated that SET7-mediated mono-methylation of eNOS at K494 disrupts calmodulin (CaM) binding and impairs NO synthesis. These molecular signatures were also observed in internal mammary arteries from patients with vascular disease and hyperglycemia. CONCLUSIONSSET7 drives endothelial dysfunction through a dual mechanism: 1) H3K4me1-dependent activation of splicing machinery triggering inflammation and oxidative stress, and 2) eNOS mono-methylation at K494 reducing NO bioavailability. Targeting SET7 may therefore represent a promising avenue to safeguard endothelial homeostasis in cardiometabolic disease. GRAPHIC ABSTRACTA graphic abstract is available for this article.

The GLP-1-based obesity drug semaglutide lowers bodyweight primarily by increasing satiation and satiety, whilst also reducing food reward and commonly causing nausea. The brainstem dorsal vagal complex (DVC) has been identified as a key site of action for these phenotypic components of semaglutides anorectic effect. However, which GLP-1 receptor (GLP-1R) populations within the DVC are recruited to mediate these phenotypic components, and whether they are dissociable, are translationally important but unresolved questions. We addressed these using metabolic and behavioural phenotyping, combined with activity-dependent genetic labelling ( Sema-TRAP) and chemogenetic manipulation of semaglutide-recruited brainstem circuits. Semaglutide potentiated satiation and satiety, caused behavioural proxies of nausea, and suppressed motivation for Western diet, in a largely sex-independent manner. It activated a substantial proportion of GLP-1R-expressing neurons in the brainstem area postrema (AP), but surprisingly most semaglutide-activated neurons in the nucleus tractus solitarius (NTS) did not express GLP-1R. Chemogenetic reactivation of Sema-TRAP neurons in the NTS alone was sufficient to recapitulate the acute effects of semaglutide on satiation, nausea, food reward, and bodyweight. Knockdown of GLP-1R expression in the AP before Sema-TRAPing abolished the recruitment of Sema-TRAPNTS neurons which elicited all these effects, while leaving the effects of semaglutide on satiety and bodyweight intact. These data demonstrate that semaglutide recruits dissociable anorectic circuits to suppress eating via distinct behavioural mechanisms, with non-GLP-1R NTS neurons downstream of GLP-1RAP representing potential therapeutic targets to tune GLP-1-based obesity drugs towards a better-tolerated effect profile.

Fructooligosaccharides (FOS) are prebiotic fibers that influence gut microbiota and host metabolic function. In a diet-induced obesity (DIO) mouse study, FOS supplementation was compared with PBS-treated obese controls. Blood glucose was markedly lower at Day 42 (221.9 {+/-} 7.8 vs 138.3 {+/-} 9.0 mg/dL), and remained lower at Day 56. FOS reduced body-weight gain from 8.4 {+/-} 0.9 g in PBS controls to 2.6 {+/-} 0.2 g, corresponding to an approximate 69.5% reduction in gain over Days 1-70. Cumulative feed consumption was not significantly different between PBS and FOS cages, suggesting that the observed metabolic effects were not explained simply by reduced food intake. These data support our thesis that FOS works as an active metabolic ingredient acting through the gut-liver-metabolic axis. Thus, in the present study, dietary FOS supplementation produced marked improvements in glucose homeostasis in a severe DIO model characterized by diabetic-range hyperglycemia that more closely resembles poorly controlled human type 2 diabetes. HIGHLIGHTSO_LIFructooligosaccharide (FOS) normalized glucose levels in a severe DIO model that mimics poorly controlled human type 2 diabetes. C_LIO_LIDay-42 blood glucose was reduced by [~]37.7% in FOS-treated DIO mice. C_LIO_LIFOS reduced body-weight gain by [~]69.5% versus controls over 70 days. C_LIO_LIMetabolic benefits occurred without a statistically significant reduction in feed intake. C_LIO_LIFindings support a gut-liver-metabolic mechanism rather than simple caloric restriction. C_LIO_LIData position FOS as an active metabolic ingredient with potential utility in diabetes and metabolic health. C_LI

Obesity is a global epidemic characterized by metabolic dysfunction, with white adipose tissue playing a pivotal role in these processes. Noncoding RNAs, such as long non-coding RNAs (lncRNAs) and short non-coding RNAs (e.g., microRNAs), have been identified as an emerging class of regulatory molecules that can influence metabolic function. Here, the Dleu2/miR-15a/16-1 cluster (known as 13q14-Minimal Deleted Region, i.e., MDR), which encodes the lncRNA Dleu2 and miR-15a/16-1, a previously unrecognized player in metabolic function, is shown to contribute to obesity and insulin resistance. Using a combination of phenotypic and molecular approaches, this study establishes that MDR governs metabolic regulation for the first time. In a nutshell, this study identifies a new role of a lncRNA-miRNA cluster, previously implicated exclusively in cancer, in the regulation of obesity, thereby extending its biological significance beyond oncology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/745519v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@424a1borg.highwire.dtl.DTLVardef@f6e3eorg.highwire.dtl.DTLVardef@10ebf0borg.highwire.dtl.DTLVardef@120803c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDeletion of MDR contributes to obesity, insulin resistance, and impaired energy metabolism C_LIO_LILoss of MDR reduces circulating adiponectin levels, indicating metabolic dysfunction C_LIO_LIMDR regulates satiety signaling in visceral adipose tissue and increases serum leptin levels C_LIO_LIMDR modulates several unrecognized new transcriptional regulators in obesity C_LIO_LIFirst evidence to establish the metabolic role of MDR beyond cancer biology C_LI

BackgroundMetabolic dysfunction is characterized by dysregulated lipid metabolism, lipotoxicity, insulin resistance, and chronic low-grade inflammation, contributing to obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Multi-target therapeutic strategies that restore lipid homeostasis are of growing interest. Patolakaturohiniyadi Kashayam (PKR), a classical Ayurvedic polyherbal formulation, was investigated for its potential to modulate lipid metabolism and ameliorate metabolic dysfunction. MethodsAn integrated approach combining network pharmacology, in vitro, lipidomics, and in vivo studies was employed. Hub gene identification and KEGG pathway enrichment were performed to elucidate molecular targets. Anti-steatotic and anti-adipogenic effects were assessed in hepatocytes and adipocytes, followed by lipidomic profiling. Efficacy was further evaluated in a high-fat high-fructose diet (HFHFD)-induced animal model. ResultsNetwork pharmacology identified key targets including TP53, AKT1, IL6, TNF, and STAT3, enriched in pathways related to lipid metabolism, inflammation, and metabolic regulation. PKR significantly reduced lipid droplet accumulation and intracellular triglyceride levels in vitro. Lipidomics revealed suppression of diacylglycerol-mediated lipotoxicity and restoration of phospholipid balance, characterized by increased lysophospholipids and phosphatidylethanolamines with normalization of phosphatidylcholine species. In vivo, PKR reduced body, liver, and adipose tissue weights, improved serum lipid profiles, and decreased AST and ALT levels. Histological analyses demonstrated reduced lipid accumulation and inflammation, along with preservation of adipose tissue architecture. PKR also improved glucose tolerance and significantly elevated plasma GLP-1 levels. ConclusionPKR exerts potent anti-steatotic and anti-obesogenic effects through coordinated regulation of lipid metabolism, inflammation, and incretin signalling, highlighting its potential as a multi-target therapeutics for metabolic dysfunction.

Type 2 Diabetes mellitus (T2DM) is a metabolic syndrome characterized by hyperglycemia and various complications. Current drugs are limited by side effects and resistance, necessitating novel targets and therapies. Previous studies have shown that MK-83, a synthetic agonist of transient receptor potential mucolipin 1 (TRPML1/ MCOLN1), a lysosomal Ca2+ channel, activates adenosine 5'-monophosphate-activated protein kinase (AMPK), a key therapeutic target in diabetes. However, whether targeting TRPML1 can treat T2DM remains unclear. In this study, we found that transgenic overexpression or pharmacological activation of TRPML1 finely controls AMPK phosphorylation via a Ca2+-CaMKK{beta}-dependent mechanism. This activation promotes glucose transporter 4 (GLUT4) translocation and dramatically increases intracellular glucose uptake. Conversely, genetic inactivation or pharmacologically inhibition of TRPML1 blocks both AMPK activation and glucose uptake. More importantly, pharmacological activation of TRPML1 in vivo dramatically alleviates hyperglycemia in db/db mice (a T2DM model), as evidenced by random blood glucose levels, fasting blood glucose levels and HbA1c levels. Furthermore, other hallmark features of db/db mice-including impaired oral glucose tolerance, reduced insulin tolerance, and elevated ALT and AST levels- were all ameliorated upon TRPML1 activation. Hence, targeting lysosomal TRPML1 channel represents a promising therapeutic strategy for T2DM, with highly specific TRPML1 agonists as potential anti-diabetic agents.

The insulin-like growth factor (IGF)/IGF-binding protein (IGFBP) axis has been implicated in diabetes mellitus and the associated burden of cardiovascular complications. Higher circulating levels of IGFBP-1 and IGFBP-2 have been established as markers of protection from incident type 2 diabetes, yet their associations with cardiovascular disease remain unclear. Utilising the UK Biobank (UKB) resource to integrate disease outcomes, plasma proteomics and MRI data, we examined associations of IGFBP-1 and IGFBP-2 with incident diabetes and cardiovascular disease. Approximately 50,000 UKB participants with plasma proteomic measurements for IGFBP-1 and IGFBP-2 were included. Multivariate Cox regression models revealed that participants in the highest quartiles of IGFBP-1 and IGFBP-2 had a substantially lower risk of incident diabetes (hazard ratio (HR) = 0.31 and 0.32 respectively), but, paradoxically, had increased risks of incident macrovascular disease, all-cause and cardiovascular-related mortality (HR = 1.81 and 2.39). Both proteins were negatively associated with HbA1c levels, triglyceride/HDL ratio and abdominal adiposity, yet positively associated with NT-proBNP, troponin I, cardiac chamber size and aortic dimensions. In summary, negative associations of IGFBP-1 and IGFBP-2 with incident diabetes mellitus did not translate to a reduced cardiovascular risk, suggesting potentially complex actions of IGFBP-1 and IGFBP-2 in the pathophysiology of cardiometabolic disease.

BackgroundCancer-associated cachexia is characterized by progressive loss of skeletal muscle and adipose tissue driven by systemic inflammation and metabolic dysregulation. AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, but its role in cachexia and its therapeutic potential remains incompletely defined. We investigated AMPK signaling during cachexia and whether pharmacological AMPK activation alone or combined with ghrelin could ameliorate disease manifestations. MethodsCachexia was induced in male C57BL/6 mice by Lewis lung carcinoma (LLC) implantation. Additional models included fibrosarcoma (CHX and MN/MCA1) and chronic lymphocytic choriomeningitis virus (LCMV) infection. AMPK was activated using AICAR and BC1618 (AB), alone or combined with ghrelin (AB+G). Metabolic, inflammatory, and functional outcomes were assessed in hypothalamus, skeletal muscle, adipose tissue, and serum. ResultsLLC-bearing mice developed cachexia characterized by reduced body weight, lean and fat mass, hypophagia, and elevated circulating IL-6 and corticosterone. Cachectic LLC mice displayed increased Il6 and Il1{beta} expression in hypothalamus, skeletal muscle, and white adipose tissue (WAT). Furthermore, AMPK activation failed to increase in hypothalamus or peripheral tissues despite profound energy deficit. A similar defect in AMPK responsiveness was observed in CHX and LCMV models, indicating a conserved feature of cachexia. AB treatment in LLC mice reduced circulating IL-6 and corticosterone levels and decreased skeletal muscle atrogene expression and IL-6/STAT3 signaling, partially preserving muscle mass, fiber size, and grip strength. However, food intake remained low, and WAT was largely unresponsive, maintaining elevated Il6 expression and tissue loss. Ghrelin alone increased food intake in LLC mice but did not ameliorate the cachectic phenotype. In contrast, AB+G restored food intake and prevented loss of lean and fat mass. LLC AB+G mice exhibited reduced hypothalamic Il6 and serotonin transporter (Slc6a4) expression, normalized adipocyte morphology and serum leptin levels, decreased adipose Il6 and Atgl expression and reduced WAT sympathetic innervation. AB+G further lowered circulating corticosterone levels, and provided greater protection against muscle wasting, with increased Pgc1 expression and improved muscle function. Neither intervention affected tumor growth or tumor inflammatory gene expression. ConclusionsCancer cachexia is associated with a central and peripheral failure to appropriately activate AMPK signaling in response to the energetic stress imposed by cachexia. Combined AMPK activation and ghrelin administration exerted complementary effects on energy homeostasis, inflammation, and tissue wasting, resulting in greater protection against cachexia than either intervention alone. These findings support combined AMPK-ghrelin targeting as a promising therapeutic strategy for cancer cachexia.

Background/Objectives: Childhood appetitive traits are heritable behavioural phenotypes hypothesized to link genetic susceptibility to obesity risk. Yet their genetic architecture and role in mediating polygenic adiposity risk remain poorly understood. Methods: We conducted the largest survey of childhood eating behaviour to date, allowing us to perform genome-wide association studies of six appetitive domains derived from 18 items of the parent-reported Children's Eating Behaviour Questionnaire in up to 31,018 eight-year-old children from the Norwegian Mother, Father and Child Cohort Study (MoBa). A trio-based design enabled decomposition of direct and indirect genetic effects on appetite and BMI. Results: We identified ten independent genome-wide significant loci for childhood eating behaviour, primarily across Food Responsiveness, Satiety Responsiveness, and Food Fussiness, eight of which lie at established childhood or adult BMI loci. Food Responsiveness and Satiety Responsiveness showed both phenotypic and genetic correlations with BMI trajectories from early childhood through adolescence. Statistical mediation analyses indicated that 22.1% and 10.4% of the aggregated genetic association with BMI at age 8 could be decomposed through these traits, respectively. Locus-specific patterns further suggested mechanistic pathways, with the FTO locus acting predominantly via Food Responsiveness, and the ADCY3 locus via Satiety Responsiveness. Trio analyses demonstrated that both BMI and eating behaviour associations were predominantly explained by children's inherited alleles, with minimal contribution from indirect effect from parental adiposity, although parental genetic liability influenced reporting of Satiety Responsiveness. Conclusions: Childhood appetitive traits capture a substantial proportion of genetic susceptibility to adiposity through distinct eating behaviour pathways (under standard mediation assumptions). These effects are primarily driven by the child's own genotype rather than indirect parental influences, positioning appetite as a plausible, biologically grounded target for early obesity prevention.

Adipose tissue dysfunction drives obesity-associated insulin resistance, but whether expanding adipocyte lipid storage can improve metabolic health remains unclear. Here, we generated adipocyte-specific Pten knockout mice (PtenAKO) using Adipoq-Cre to determine how chronic Pten loss affects adipose tissue remodeling and systemic metabolism. PtenAKO mice exhibit increased adiposity and adipocyte hypertrophy under chow and high-fat diet feeding, yet showing lower blood glucose and insulin levels, enhanced insulin sensitivity, and reduced hepatic lipid accumulation during basal growth and diet-induced obesity without systemic metabolic deterioration. Despite lipid enrichment in brown adipose tissue, Pten-deficient adipocytes maintain UCP1 expression, OXPHOS protein abundance, and mitochondrial ultrastructure. Transcriptomic analysis of inguinal white adipose tissue reveals activation of adipogenesis, lipid metabolism, insulin response, oxidative phosphorylation, lipid storage, vascular and extracellular matrix pathways, together with suppression of immune and inflammatory programs. Mechanistically, Pten deficiency increases Cav1 expression, caveolae abundance, collagen expression, and extracellular matrix remodeling, suggesting coordinated structural adaptation to support adipocyte expansion. These findings demonstrate that adipocyte Pten deficiency promotes metabolically healthy adipose expansion by enhancing lipid storage capacity, preserving adipocyte function, and reducing inflammation.

Endothelial dysfunction is a hallmark of numerous vascular pathologies and is strongly influenced by mechanobiological forces within the vascular microenvironment. While the effects of shear stress have been extensively investigated, the mechanisms by which elevated hydrostatic pressure regulates endothelial junctional organisation remain sparsely investigated. Here, we employed a microfluidic platform to investigate the combined effects of low shear stress (1.4 dyne/cm2) and elevated hydrostatic pressure (~3972 Pa) on endothelial junctional dynamics. Elevated hydrostatic pressure induced marked remodelling of VE-cadherin junctions, characterised by formation of serrated, finger-like structures accompanied by increased YAP1 nuclear localisation and reduced YAP1-VE-cadherin cytoplasmic colocalisation compared to shear stress alone conditions. Further, elevated hydrostatic pressure also demonstrated an increase in cytoplasmic accumulation of EPS8, an actin adaptor protein, and increased cytoplasmic EPS8-VE-cadherin colocalisation. These observations were accompanied by functional changes marked by increased endothelial permeability, and enhanced THP-1 monocyte adhesion, thus suggesting activation of mechanosensitive pathways linked to dynamic junctional reorganisation. Inhibition of PI3K at elevated hydrostatic pressure exhibited a thin VE-cadherin patterning and increased cytoplasmic EPS8-VE-cadherin colocalisation, thus demonstrating a prominent role for PI3K signalling in regulating the junction organisation. Interestingly, Piezo-1 activation using Yoda1 produced context-dependent effects. Under shear stress alone, Yoda1 promoted YAP1 nuclear translocation, reduced YAP1-VE-cadherin colocalisation, increased endothelial permeability but strikingly did not impact THP-1 adhesion compared to shear stress alone conditions. In contrast, under elevated hydrostatic pressure conditions, Yoda1 significantly reduced both endothelial permeability and THP-1 adhesion while increasing YAP1-VE-cadherin colocalisation and decreasing YAP1 nuclear accumulation. Collectively, these findings identify a previously underappreciated elevated hydrostatic pressure-Piezo-1-PI3K signalling axis that regulates endothelial barrier integrity and pro-adhesive endothelial activation through coordinated regulation of VE-cadherin, YAP1, and EPS8. These results highlight elevated hydrostatic pressure as a unique mechanobiological stimulus, distinct from that of shear stress alone and provide novel insights into mechanisms underlying microvascular dysfunction.