Metabolism

High-fat, high-sucrose (HFHS) diets are established risk factors for obesity. In the intestine, sucrose is hydrolyzed into glucose and fructose, with fructose being taken up by epithelial cells and phosphorylated by ketohexokinase (KHK). We hypothesized that KHK is required for the obesogenic effects of HFHS diets and performed genetic and pharmacologic experiments in mice using diet-induced obesity (DIO) models. We show that genetic loss of KHK prevents HFHS-induced weight gain and intestinal villus elongation. Moreover, pharmacologic inhibition of KHK (KHKi) promotes weight and fat loss during continued HFHS feeding in DIO mice and enhances weight loss and weight maintenance during and after incretin-mimetic therapy. The anti-obesogenic effects of KHKi were associated with delayed intestinal lipid absorption, reprogramming of lipid metabolism in the distal intestinal epithelium, and reduced absorption of unsaturated dietary fats. Together, these findings identify fructose metabolism as a key regulator of intestinal lipid handling and suggest that fructose promotes obesity, in part, by enhancing intestinal lipid absorption and metabolism.

Consumption of high fat diet (HFD) is linked to reduced cardiac vagal motor output, a main contributor to progression of cardiovascular disease. HFD for 15 days increases extrasynaptic or tonic gamma aminobutyric acid (GABA) current in cardiac projecting neurons in the dorsal motor nucleus of the vagus (CVNDMV), which contributes to dampening cardiac parasympathetic output. However, the mechanism underlying this increased inhibition is unknown. Here, we hypothesize that increased activity of protein kinase C {delta} isoform (PKC{delta}) enhances tonic GABA current in CVNDMV after HFD. Whole-cell patch-clamp recording of retrogradely labeled CVNDMV demonstrated that pan inhibition of PKC activity with GFX, and isoform specific inhibition of PKC{delta} with rottlerin normalize 15-day HFD-induced increases in tonic GABA current, suggesting that PKC{delta} mediates enhanced tonic inhibition. This effect persisted in the presence of dynasore, a clathrin-mediated endocytosis blocker, indicating that the normalization effect of PKC{delta} inhibition on tonic current in HFD is likely independent of clathrin-mediated endocytosis. Furthermore, no differences in PKC{delta} mRNA or protein expression were observed between NFD and HFD, suggesting a post-translational mechanism underpinning increased tonic GABA current after 15 days of HFD. Altogether, this study provides evidence that HFD-induces increased PKC{delta} activity, but not expression, leading to increased tonic GABAergic inhibition in CVNDMV. This increase PKC{delta} activity could explain the cardiac vagal motor output dampening in CVD and be developed into treatments targeting PKC{delta} for CVD.

The intermittent energy restriction (iER) represents an effective dietary strategy for improving metabolic diseases including metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM), yet the underlying mechanisms remain elusive. In this study, we integrated human clinical data, mouse models, and in vitro experiments to investigate the role of iER in modulating the gut-liver axis in comorbid MASLD and T2DM. We demonstrate that an iER diet improves hyperglycemia, hepatic steatosis and decreases the abundance of gut pathogen Klebsiella pneumoniae, which is strongly associated with reductions in blood endotoxin, lipopolysaccharide (LPS) levels, suggesting a potential role of K. pneumoniae-derived LPS in mediating effects of the iER on hepatometabolic improvements. We confirm that K. pneumoniae-derived LPS exacerbates lipid accumulation and inflammation using an in vitro model. Mechanistically, we reveal a core target of protein lysine acetylation (Kac), hydroxyacyl-CoA dehydrogenase -subunit (HADHA) Lys353 in the liver of db/db mice through a multi-omics analysis. The iER decreases HADHA-K353 acetylation and enhances its enzyme activity. A Kac-mimicking mutation (K353R) increases its enzyme activity and stability, blocks its binding to the inflammasome adaptor ASC, and alleviates lipid accumulation and inflammation in K. pneumoniae-derived LPS induced in vitro model. This study provides novel insights into the potential benefits of the iER in comorbid MASLD and T2DM.

A new definition of clinical obesity was introduced by the 2025 Lancet Diabetes & Endocrinology Commission to characterize excess body fat and dysfunctional adiposity beyond body mass index (BMI). We performed the first genome-wide analysis (GWAS) of 151,642 cases of clinical obesity and 128,874 controls without obesity from the All of Us Research Program and UK Biobank spanning five ancestry groups and compared these results to GWAS for BMI. We identified 127 independent loci associated with clinical obesity, 63 of which did not share any significant association with BMI. We highlight rs15285 as the most discordant variant, with larger effect size and significance for clinical obesity compared to BMI (delta Z: +6.35, delta -log10 P: 17.67). This variant is located in the LPL gene, colocalized to expression quantitative loci for lipoprotein lipase, and associated with elevated triglyceride levels and proteomic markers of insulin resistance and inflammation. Next, we constructed a clinical obesity polygenic score, which had improved association with cardiovascular risk factors and proteomic markers of inflammation (interleukin-6, fibroblast growth factor 21, hepatic growth factor) and insulin resistance (adiponectin, resistin, leptin, and leptin receptor) over a BMI polygenic score. Stratifying individuals into low, intermediate, and high inherited obesity risk groups, we found that clinical obesity polygenic risk reclassified 35% of individuals compared to BMI polygenic risk. Clinical obesity polygenic risk improved discrimination for myocardial infarction, heart failure and stroke over BMI polygenic risk. We replicated the significant improvement in cardiovascular risk prediction of clinical obesity polygenic scores in Atherosclerosis Risk in Communities, Multi-Ethnic Study of Atherosclerosis, Framingham Heart Study, and Women Health Initiative. These findings demonstrate that clinical obesity captures genetic loci distinct from BMI that are biologically and clinically relevant to cardiovascular health and can improve cardiovascular genetic risk prediction.

G-protein-coupled receptor 75 (GPR75) has emerged as an important mediator in diet-induced obesity (DIO) and a promising therapeutic target for anti-obesity drugs. However, the anatomical location of GPR75 in the brain remains unclear, hindering the understanding of GPR75 biology in DIO. Here, we generated a new GPR75-GFP-Ires-Cre knockin mouse strain, in which the Cre expression is driven by the endogenous GPR75 promoter and the GFP is fused with the C-terminal of the GPR75 protein. Both Cre and GFP were confirmed to be colocalized with the endogenous GPR75 expression. In addition, the GPR75-GFP fusion protein remains functionally normal with unaltered susceptibility to DIO. Moreover, using this mouse strain, we found that GPR75 is broadly expressed throughout the brain and mainly localized to the cytoplasm of brain neurons. This new genetic tool can therefore be used to study the neural basis for GPR75 in mediating DIO.

Background: Genome-wide association studies (GWAS) have identified hundreds of loci associated with body fat distribution, yet the causal genes and regulatory mechanisms through which these variants exert their effects remain largely unknown. Expression quantitative trait locus (eQTL) colocalization provides a powerful framework for identifying genes whose expression is genetically coregulated with complex traits. Methods: We performed a genome-wide colocalization analysis integrating waist-hip ratio adjusted for body mass index (WHRadjBMI) GWAS summary statistics from 694,649 individuals (Pulit et al., 2019) with subcutaneous adipose tissue eQTLs from the Genotype-Tissue Expression (GTEx) Project v8 (N = 581 donors). GWAS coordinates were lifted from GRCh37 to GRCh38 to enable direct alignment with GTEx data. We incorporated CAVIAR fine-mapping results to overcome the limitation of FDR-significant eQTL filtering. Colocalization was assessed using the approximate Bayes factor framework (coloc.abf) across 335 independent genome-wide significant loci. Results: Of 2,897 locus-gene pairs tested, 489 (16.9%) showed strong colocalization (PP.H4 > 0.8) and 618 (21.3%) showed moderate evidence (PP.H4 > 0.5). The strongest colocalization was observed for SNX10 (sorting nexin 10; PP.H4 = 1.000), a recently characterized regulator of adipocyte differentiation and female-specific diet-induced obesity. Other top hits included DGKQ (diacylglycerol kinase theta; PP.H4 = 0.9999999), an emerging pharmacological target for insulin resistance, and CBX3 (chromobox 3; PP.H4 = 0.9999974), an epigenetic regulator linked to cardiovascular disease. Established adiposity genes including GRB14 (PP.H4 = 0.681) and KLF14 (PP.H4 = 0.590) were recovered, validating our approach. Several loci exhibited extensive allelic heterogeneity, with 50 genes colocalizing at a single chromosome 3 locus. Conclusions: Our analysis provides a comprehensive map of adipose tissue gene regulatory mechanisms underlying genetic risk for body fat distribution. The identification of SNX10, DGKQ, and CBX3 as high-confidence candidate causal genes advances the translation of GWAS associations into mechanistic understanding and therapeutic targets for obesity-related cardiometabolic disease.

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.

The hepatic urea cycle is consistently suppressed in liver disease and hepatocellular carcinoma (HCC), but whether loss of individual enzymes contributes to disease initiation and progression remains unknown. Using mice with hepatocyte-specific deletion of argininosuccinate synthase 1 (ASS1), the urea cycle enzyme that condenses citrulline and aspartate into argininosuccinate, we investigated the role of ASS1 in diet and carcinogen-induced liver disease progression. We found that complete loss of hepatic Ass1 is lethal, but high fat diet extends lifespan. Unexpectedly, animals with approximately 85% loss of hepatic Ass1 are completed protected from diet-induced obesity, liver steatosis, fibrosis, and HCC. We determined that hepatic Ass1 loss activates fatty acid oxidation in peripheral oxidative tissues leading to increased energy expenditure and protection from disease phenotypes. Moreover, targeting Ass1 after obesity onset promotes weight loss and reverses liver steatosis. These findings implicate hepatic ASS1 as a novel regulator of whole-body lipid metabolism that can be targeted to prevent obesity, liver disease, and HCC.

The vascular endothelium maintains homeostasis by acting as a selective barrier, permitting the exchange of nutrients, immune cells, and signaling molecules while restricting pathogens. It further regulates vascular function by generating and sustaining mechanical tension. Aging and disease alter the vascular environment and disrupt the regulation of endothelial tension, contributing to vascular diseases such as hypertension and atherosclerosis. Although endothelial mechanics are influenced by the cellular environment, the mechanisms that enable endothelial cells (ECs) to maintain tension over time remain poorly understood. Here, we demonstrate that confluent human umbilical vein endothelial cells (HUVECs) sustain stable tension for at least three days in the absence of external chemical or mechanical stimuli, indicating the presence of an intrinsic, active mechanism for long-term tension maintenance. Imaging of an EC multicellular ensemble shows a collective phenomenon where diacylglycerol release consistently precedes a rise in intracellular contractility. This contractility propagates to neighboring cells, wherein we identify a Gq-G-protein-coupled receptor (GqGPCR) signaling pathway as a key regulator driving force generation in ECs. The persistence of this signaling sequence in the absence of exogenous agonists suggests a force-induced-force-generation mechanism that coordinates tension maintenance across the monolayer. Together, these findings demonstrate that ECs actively regulate tension through continuous GqGPCR signaling, revealing tension maintenance as a dynamic, collective process. This work provides new insight into how vascular tissues preserve mechanical homeostasis and suggests potential therapeutic targets for vascular endothelial dysfunction and age-related vascular stiffening. New and NoteworthyThis study reveals that endothelial cells actively maintain mechanical tension through continuous GqGPCR signaling rather than passive mechanical properties. We demonstrate that DAG signaling consistently precedes contractility increases, even without chemical stimulation, suggesting that intercellular forces alone can activate this pathway. This "force-induced-force-generation" mechanism represents a potential therapeutic target for vascular dysfunction. Our findings reframe tension maintenance as a dynamic, collectively regulated process in the vascular endothelium.

Vascular ischemia is characterized not only by hypoxia but also by acidosis, which affects endothelial cells (ECs) due to increased H+ production from glycolysis and a deficit in H+ washout. We recently documented that an acidic environment facilitates the flip-flop transport of the non-ionized form of fatty acids (FAs) across the plasma membrane of cancer cells. In this study, we investigated how acidosis influences the capacity of highly glycolytic ECs to manage FAs and participates to endothelial dysfunction. We first tracked lipid droplet (LD) formation using Oil Red O staining and holotomographic microscopy. Purified monounsaturated oleate but also a mixture of FAs that reflect in vivo serum composition, resulted in dose- and time-dependent LD accumulation through FA transporter-independent mechanisms. Acid-exposed ECs exhibited enhanced mitochondrial respiration fueled by FAs, and endoplasmic reticulum (ER) stress, as indicated by the expression of ATF4 and CHOP. This phenotype was further associated with elevated reactive oxygen species production, which correlated with reduced nitric oxide (NO) availability. FA removal from EC culture media promoted lipolysis from LDs, supported by ATGL lipase induction which however slowed under acidic conditions. While ER stress persisted upon FA washout, NO availability was restored to levels comparable to those in FA-unexposed ECs. This observation coincided with dynamic mobilization of antioxidant defenses in acid-exposed ECs, as evidenced by low levels of reduced glutathione and enhanced cystine uptake, alongside a decrease in carnitine and FA-fueled mitochondrial respiration. Collectively, these data underscore the vulnerability of ECs to passive FA capture promoted by local acidosis, thereby contributing to a silent source of endothelial dysfunction in the postprandial state or during chronic exposure to elevated lipid levels.

Cells deploy adaptive programs to maintain homeostasis under stress, yet mechanisms counteracting damage triggered by transmembrane signaling remain poorly defined. Using a hyperaldosteronism model, we examined how autophagy regulates aldosterone-mediated mineralocorticoid receptor (MR) activation. In human umbilical vein endothelial cells (HUVECs), aldosterone induced autophagy, as evidenced by elevated Beclin-1, an increased LC3-II/LC3-I ratio, and reduced SQSTM1/p62. Aldosterone also promoted MR translocation from the cytosol to the nucleus. Co-immunoprecipitation and immunofluorescence revealed direct interaction and colocalization between MR and Beclin-1, as well as enhanced MR-lysosome association. Domain mapping showed that the Beclin-1 middle domain (161-241 AA) binds the MR C-terminal region (601-984 AA). Bioinformatic prediction and ChIP-qPCR confirmed that MR occupies the promoters of IL-1{beta}, IL-6, and TNF- upon aldosterone stimulation. Beclin-1 overexpression attenuated MR nuclear translocation, promoter binding, and inflammatory cytokine expression, whereas Beclin-1 knockdown reversed these effects. In vivo, aldosterone-infused Beclin-1 transgenic (Becn1-tg) mice exhibited lower blood pressure, reduced aortic medial thickening, and attenuated cardiac hypertrophy relative to wild-type controls, with no difference in body weight. Our findings identify Beclin-1 as a critical negative regulator of aldosterone signaling through an autophagy-dependent negative feedback loop. By interacting with MR and directing it toward lysosomal sequestration, Beclin-1 limits MR nuclear translocation and transcriptional activity, thereby mitigating aldosterone-induced vascular inflammation and cardiovascular injury. HighlightsAldosterone activates autophagy and promotes MR-Beclin-1 interaction in HUVECs Beclin-1 binds the C-terminal MR domain and directs MR to lysosomal degradation Beclin-1 overexpression suppresses MR nuclear translocation and cytokine gene activation Beclin-1 transgenic mice are protected from aldosterone-induced cardiovascular injury

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.

BackgroundDecreased hepatic removal of low density lipoproteins (LDL) and increased apolipoprotein B (apoB) production cause hypercholesterolemia, a major causal risk factor of atherosclerotic cardiovascular disease (ASCVD). By a genome-wide siRNA screen, we previously identified subunits of the Coat protein I (COPI) complex to limit LDL uptake into Huh-7 hepatocarcinoma cells. MethodsThese findings were validated by targeted in vitro experiments as well as genetic association studies in humans and three mouse models with mutated or disrupted COPI genes. ResultsSilencing of COPA, COPB1, COPB2, ARCN1, COPG1, and COPZ1 in Huh-7 cells resulted in decreased uptake of LDL and aberrant glycosylation and altered cell surface abundance of the LDL receptor (LDLR) as well as increased apoB secretion and cellular lipid storage. Single nucleotide polymorphisms of ARCN1 were associated with lower ARCN1 expression and higher levels of LDL-cholesterol (LDL-C). Rare variants of COPA and COPG1 were enriched among patients with LDL-C > 5 mmol/L. Patients and mice carrying other rare immunopathogenic missense variants of COPA and COPG1 did not present with elevated plasma levels of LDL-C, while hepatic knockdown of murine Copg1 increased the concentrations of non-HDL-cholesterol in plasma and triglycerides in the liver. ConclusionsThe COPI coatomer regulates LDLR activity and apoB secretion as well as lipid content of liver cells. Loss of function of some variants of COPI genes are associated with higher LDL-C levels.

Obesity is one of the most prevalent diseases worldwide. Increasing thermogenesis to enhance energy expenditure has emerged as a promising therapeutic strategy. In an effort to identify new regulatory targets in thermogenic adipocytes, we found that SOX8 is correlated with obesity and serves as a novel marker of classical brown adipocytes in both humans and mice, upregulating during acute cold exposure. Functional studies further demonstrated that adipocyte-specific knockdown of SOX8 leads to obesity and metabolic dysfunction in mice. Mechanistically, SOX8 directly interacts with USP7 and stabilizes PGC-1 by reducing its K48-linked polyubiquitination. AAV-Rec2-mediated SOX8 overexpression initially enhanced energy expenditure, improved insulin sensitivity, and alleviated metabolic dysfunction in HFD-fed mice. However, prolonged SOX8 overexpression induced compensatory metabolic maladaptation, characterized by reduced energy expenditure, impaired glucose homeostasis, and mitochondrial structural disruption. These findings reveal a novel SOX8-USP7-PGC-1 regulatory axis in brown adipocytes, and reveal a previously unrecognized time-dependent effect of sustained thermogenic activation, highlighting SOX8 as a promising therapeutic target for obesity and metabolic syndrome.

Background: Repeated metabolic-bariatric surgery (MBS, r-BS) represents 10-25% of all MBS procedures and is commonly performed for recurrent weight gain after initial weight loss. How weight loss followed by regain reshapes adipose tissue biology remains unclear. We hypothesized that women undergoing r-BS exhibit a distinct adipose tissue signature compared with those undergoing primary bariatric surgery (p-BS). Methods: We analyzed subcutaneous and visceral adipose tissues (SAT, VAT, respectively) from women undergoing either p-BS, or r-BS with documented >15% weight loss after prior MBS. Tissues were assessed histologically, molecularly, and functionally (activation of human microglia cells (HMC3) by SAT secretome). Results: Consistent with other cohorts, women undergoing r-BS (n=21) trended to be older (47.2 vs. 40.5 y, p=0.06) than those undergoing p-BS (n=35), with a lower BMI (42.3 vs. 45.6 kg/m2, respectively, p=0.103), and a trend for improved cardiometabolic risk parameters such as fasting insulin, CRP and HDL-c. Adipose tissue histological features (adipocyte size, fibrosis, macrophage and crown-like structure abundance) were similar, while adipose mast cells were slightly (though insignificantly) more prevalent in r-BS. A single-nucleus RNA-seq-based deconvolution algorithm applied to bulk RNA-seq confirmed the absence of a major shift in adipose tissue cell-type composition. Yet, it uncovered a unique SAT transcriptome, with activation of inflammatory pathways in r-BS. Consistently, SAT explants from r-BS secreted higher protein concentrations of NFkB-regulated cytokines IL6 and IL8. Biological impact of the more inflammatory secretome was demonstrated by its increased ability to activate human microglia cells. Conclusions: Prior BS with significant weight loss-regain in women is associated with an inflammatory SAT transcriptome and secretome, possibly reflecting altered adipose-brain endocrine communication.

Central glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling is required for the efficacy of GIP-based obesity therapeutics, yet how distinct subpopulations of GIPR neurons shape appetite remains undefined. Here we show that GIPR neurons in adjacent brainstem nuclei, the area postrema (AP) and nucleus tractus solitarius (NTS), exert opposing control over ingestion. We find GIPRAP neurons dampen post-ingestive satiation, permitting hyperphagia, whereas GIPRNTS neurons are anorectic. In line with this model, we show Gipr expression in AP, but not NTS, neurons is necessary for appetite suppression following GIPR antagonism. Additionally, we reveal that GIPR neurons in the AP and NTS occupy distinct gut-brain circuits, and are differentially sensitive to obesity-driven circuit remodelling. These data offer a framework for understanding how current GIPR agonist and antagonist strategies elicit weight loss.

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

White adipose tissue and pancreatic islets play central roles in the regulation of metabolic homeostasis. Although ectopic lipid accumulation is established as a driver of impaired insulin secretion, the acute contribution of adipocyte lipolysis to islet function remains poorly documented. Here, we investigated a mouse model with inducible adipocyte-specific deletion of both adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), which leads to defective adipocyte lipolysis. Despite preserved ex vivo islet function, these mice displayed a marked reduction in insulin secretion in response to stimulation of adipocyte {beta}3-adrenoceptors, as well as following glucose and arginine challenges. Mechanistically, we identified non-esterified fatty acids as critical mediators of lipolysis-driven insulin secretion, engaging pancreatic signaling of the free fatty acid receptors FFAR4 (a.k.a. GPR120) and FFAR1 (a.k.a. GPR40). The regulation of insulin secretion by adipocyte lipolysis was preserved in high-fat diet-induced obesity. These findings identify an underappreciated adipose-islet crosstalk that couples adipocyte lipolysis to insulin secretion and links lipid and glucose metabolism.

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.

While standard high fat diets cause hyperphagia and obesity in mice, high fat-low carbohydrate ketogenic diets (KDs) reduce food intake and body weight. Because the basis for this difference is still unclear, we systematically altered the macronutrient content of a standard KD and found that feeding C57BL/6J (B6J) mice a KD with 5% protein resulted in hypophagia, weight loss, and hypoglycemia, whereas the same diet with 10% protein led to increased adiposity and glucose intolerance. However, these effects were strain-dependent as C57BL/6NJ (B6NJ) weighed similar amounts on the two diets leading us to investigate the molecular mechanisms. When fed the KD-5% diet, B6J but not B6NJ mice showed increased levels of two anorexigenic factors, GDF15 and LCN2, and loss of function of either blunted the weight loss of B6J mice fed the diet. B6J mice harbor mutations in Nnt (Nicotinamide nucleotide transhydrogenase) and Nlrp12 (NLR family pyrin domain containing 12), both of which are wildtype in B6NJ mice. B6J mice fed the KD-5% diet showed the RNA signature of oxidative and integrated stress responses (ISR) and restoring NNT function in liver reduced the levels of GDF15. RNA-seq also revealed that B6J but not B6NJ mice had the RNA signature for hepatic inflammation and a knockout of Nlrp12 led B6NJ mice to lose weight on the KD-5% diet with increased levels of LCN2. Suppression of oxidative stress with N-acetylcysteine (NAC) reduced expression of both GDF15 and LCN2 and prevented the weight loss associated with the KD-5% protein diet in B6J mice, whereas inhibition of the integrated stress response with ISRIB only attenuated the GDF15 axis. Collectively, these findings explain why B6J mice lose weight on a ketogenic diet and reveal a critical interplay between macronutrient composition and genetic background leading to increased levels of GDF15 and LCN2 to induce hypophagia. Finally, these data suggest that the response to different diets among humans might be similarly variable based on genetic variation and macronutrient composition, suggesting the possible need for personalized dietary interventions.