Bariatric surgeries improve cardiovascular health through modulation of plasma lipid profiles. Among these procedures, single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) yields marked metabolic benefits; however, its impact on atherosclerosis has not yet been defined. This study aimed to assess the impact of SADI-S on atherosclerosis development in a mouse model of atherosclerotic disease. Low-density lipoprotein receptor–deficient (Ldlr−/−) male mice were fed a high-fat diet for 12 weeks and subsequently underwent either SADI-S or sham laparotomy. Mice were then transitioned to a cholesterol-enriched Western diet from 6 to 12 weeks post-surgery. Atherosclerotic burden was quantified histologically as the ratio of Oil Red O–positive plaque area to total aortic root surface. SADI-S induced a sustained 30

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

Background The incidence of heart failure is approximately 2.5-fold higher in patients with type 2 diabetes than in non-diabetic individuals. Diabetic cardiomyopathy is characterized by diastolic dysfunction and left ventricular hypertrophy. The diabetic heart exhibits insulin resistance, leading to impaired glucose uptake and oxidation and, consequently, to intracellular glucose overload and glucotoxic stress. To further investigate the mechanisms underlying diabetic cardiomyopathy, we have previously examined the cardiac phenotype of lipodystrophic and severely insulin-resistant seipin knockout mice. These mice developed left ventricular hypertrophy associated with chronic activation of the hexosamine biosynthetic pathway, which promotes over-O-GlcNAcylation of cardiac proteins. Methods To assess the causal role of chronic activation of the hexosamine biosynthetic pathway in cardiac dysfunction in seipin knockout mice, we used adeno-associated virus-mediated cardiac overexpression of O-GlcNAcase, the enzyme responsible for removing O-GlcNAc moieties. Cardiac properties were evaluated by echocardiography. O-GlcNAcylated proteins were enriched using wheat germ agglutinin pull-down followed by proteomic analysis. Pharmacological inhibition and genetic modulation were used to investigate the role of β-catenin signalling. Results Cardiac overexpression of O-GlcNAcase corrected cardiac hypertrophy, as assessed by echocardiography, and improved insulin sensitivity in seipin knockout hearts. Proteomic analyses identified 28 proteins with increased O-linked N-acetylglucosamine modification in seipin knockout mice. Among these, β-catenin emerged as a candidate mediator, as expression of its target genes was increased in seipin knockout mice and normalized upon O-GlcNAcase overexpression. Increased β-catenin activity was associated with enhanced O-GlcNAcylation. Pharmacological inhibition of β-catenin using ICG-001 prevented cardiac hypertrophy in seipin knockout mice. Increased β-catenin O-GlcNAcylation and activity were also observed in two other murine models of diabetic cardiomyopathy. Selective enhancement of β-catenin O-GlcNAcylation was sufficient to induce hypertrophy in cultured cardiomyocytes. Conclusion These findings indicate that β-catenin O-GlcNAcylation contributes to cardiac remodelling in insulin-resistant states. This mechanism may extend beyond the seipin deficient specific model and could represent a potential target for the treatment of cardiac hypertrophy associated with type 2 diabetes.

Abstract Adipocyte dysfunction is a major driver of obesity-associated cardiometabolic disease, underscoring the need to understand how lipid storage and mobilization are regulated and disrupted. The ER-anchored protein Seipin governs lipid droplet (LD) biogenesis and ER-LD and ER–mitochondria (MAM) contacts, and its loss impairs calcium transfer and causes lipodystrophy. Here, we investigated whether Seipin coordinates MAM and ER-LD remodeling during adipocyte lipid handling. In subcutaneous adipose tissue from inducible Seipin-knockout mice, electron microscopy and proximity ligation assays revealed that feeding reduces MAMs while increasing ER-LD and mitochondria-LD contacts, a remodeling abolished by Seipin deficiency. Lipid loading elevated tripartite MAM-LD contacts in controls but not knockouts. Fluorescence recovery after photobleaching showed that impaired triglyceride transfer to LDs in Seipin-deficient cells was rescued by the MAM-LD-stabilizing peptide ‘Linker-ER-Mi’, in a calcium-dependent manner. During adipogenesis and lipid loading, MAM-LD contacts increased, whereas MAM-cytosolic mitochondria contacts declined; however, obesity blunted this remodeling. Furthermore, disrupting membrane contact sites impaired lipid flux, lipolysis, and insulin signaling. Taken together, these findings identify MAM-LD as regulators of adipocyte metabolic flexibility.

Adiponectin (Adpn) is a potent insulin-sensitizing adipokine with therapeutic promise for type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). Its clinical use is limited by challenges in producing stable, bioactive high-molecular weight forms. Adipocyte-derived extracellular vesicles (EVs) naturally carry oligomeric Adpn on their surface, enhancing hormone stability and activity. Here, we engineered EVs displaying membrane-anchored Adpn (EVPP-Adpn) and control EVs lacking Adpn (EVCTL), and evaluated their metabolic effects in high fat diet (HFD)-induced obesity mice.EVPP-Adpn were purified from HEK293T cells stably transfected with a chimeric Adpn fused to a transmembrane domain and a pilot peptide (PP) directing it to EVs ; EVCTL were produced from non-transfected cells. HFD-fed male and female mice received intraperitoneal EV injections for six weeks.EVPP-Adpn improved glucose tolerance and insulin sensitivity, promoted adipocyte lipid storage through insulin-regulated lipogenesis and alleviated MASH features (liver steatosis, inflammation and fibrosis). EVPP-Adpn lowered circulating ceramides and reduced FGF21, indicating improved hepatic metabolism, and activated AKT and AMPK pathways in liver and skeletal muscle, consistent with increased adiponectin signaling.These results demonstrate that surface-anchored Adpn EVs restore tissue-specific insulin signaling and improve obesity-related metabolic dysfunctions, highlighting their potential as a novel biotherapeutic strategy for T2D and MASH.

Hepatic daily rhythms are coordinated by feeding and the molecular circadian clock, ensuring metabolic homeostasis. Disrupted feeding schedules promote circadian misalignment and metabolic diseases but the underlying mechanisms remain scarce. Post-translational modifications have emerged as key regulators of circadian metabolic outputs. Here, we show that the mitochondrial enzyme Acyl-CoA synthetase family member 3 (ACSF3) oscillates in phase with different feeding schedules to drive rhythmic lysine-malonylation and coordinate daily hepatic metabolism. Hepatic Acsf3 knockdown drastically affected lysine-malonylation rhythms, decreased fasting glycemia, insulin sensitivity, and AKT phosphorylation, indicative of perturbed glucose homeostasis. Concomitantly, Acsf3 knockdown shifted lipid oxidation from mitochondria to peroxisomes, enhanced lipogenesis and triglyceride synthesis, while increasing diurnal autophagy. Multi-omics profiling uncovered specific lysine-malonylation targets in glycolysis, the tricarboxylic acid (TCA) cycle, fatty-acid oxidation and autophagy. Our findings uncover hepatic ACSF3 as a pivotal molecular nexus that integrates feeding time with dynamic protein lysine-malonylation and orchestrates the diurnal rhythm of liver metabolism.

BACKGROUND:Methylglyoxal (MGO) is a potent glycating agent that contributes to the pathogenesis of diabetes. However, MGO is unstable in plasma without demanding sample preparation at blood collection, limiting its clinical utility as a biomarker. We aimed to discover reliable MGO-glycated albumin (ALB)-derived biomarkers and to assess their association with new-onset diabetes (NOD) in people with prediabetes. METHODS:Bottom-up mass spectrometry-based proteomics was used to discover peptide biomarkers of MGO-glycated ALB, including MGO-derived hydroimidazolone (MGH)-ALB219-225, which proved to be biologically stable and reliable for large-scale analyses in human plasma. After assay validation, the IT-DIAB (Innovation Thérapeutique DIABète) prospective study, conducted in 300 individuals with impaired fasting plasma glucose (FPG) levels (110 to 125 mg/dL, 6.1 to 6.9 mmol/L), was used to assess the association between plasma MGH-ALB219-225 and NOD, defined as FPG ≥126 mg/dL (7 mmol/L), using Kaplan-Meier curves and Cox models. RESULTS:In total, 113 participants of the IT-DIAB study developed NOD during a median follow-up of 5 years. There was a graded association between the baseline plasma MGH-ALB219-225 concentration and incident NOD (log-rank P < 0.0001), in contrast to a lack of association for plasma MGO and total or glycated ALB (commercial kit). After adjustment for age, sex, body mass index, FPG, hemoglobin (Hb) A1c, and ALB, the plasma levels of MGH-ALB219-225 were associated with NOD (hazard ratio [HR] per one SD [95% CI] = 1.50 [1.26-1.78]; P < 0.0001). CONCLUSIONS:MGH-ALB219-225 is a novel and stable peptide biomarker of MGO-glycated ALB, whose plasma levels are positively associated with an increased risk of NOD in individuals with prediabetes, independently of traditional risk factors. ClinicalTrials.gov Registration Number: NCT01218061.

AIMS:Postprandial hyperlipidaemia (PPL), characterized by elevated triglyceride (TG) concentrations after a meal, is common in type 2 diabetes (T2D) and is often recognized as an independent cardiovascular risk factor. Here, we aimed to assess the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition by alirocumab on PPL in patients with T2D. MATERIALS AND METHODS:EUTERPE is a randomized, double-blind, placebo-controlled cross-over trial conducted in male patients with T2D. Participants received sequentially two sequences of 10-week treatment (alirocumab 75 mg Q2W or placebo s/c) with a wash-out period of 10 weeks. The primary end-point was the percentage reduction in plasma TG response after an oral fat load (incremental area under the curve [iAUC]0-8h TG). Secondary end-points included mass spectrometry-based apolipoprotein measurements and nuclear magnetic resonance (NMR)-based lipoprotein profiling. RESULTS:Fourteen participants were included: age 59 ± 9 years, BMI 32.8 ± 5.5 kg/m2, HbA1C 6.7 ± 0.5%. Compared to placebo, alirocumab did not reduce PPL (iAUC0-8h TG: -5% [CI 95%: -28, +25], p = 0.68). Alirocumab decreased fasting non-HDL cholesterol (-38.5 ± 5.6%, p = 0.0003), remnant cholesterol (-20.0 ± 13.3%, p = 0.04), apoB100 (-21.2 ± 6.4%, p = 0.004) and apoE (-15.3 ± 6.6%, p = 0.02) concentrations. NMR analyses showed that alirocumab decreased both postprandial VLDL2 cholesterol (-42% [-55, -25], p < 0.001) and IDL cholesterol (-26% [-38, -12], p = 0.0007), without effect on VLDL1 cholesterol or TG concentrations. CONCLUSIONS:Inhibition of PCSK9 by alirocumab did not reduce PPL in T2D, confirming that PCSK9 controls remnant cholesterol catabolism rather than intestinal chylomicron production.

Introduction The use of biological heart valves (BHV) is constantly growing but their durability remains a main concern. Structural valve degeneration (SVD) occurs gradually and seems to reiterate, at least in part, the processes described in native valve stenosis. Lipoprotein (a) [Lp(a)] has been described as one of the main triggers of native valve calcification but its association with SVD remains unclear. Objective We aim to determine whether Lp(a) plasma levels and/or the Lp(a) polymorphic sizes, determined by the apolipoprotein (a) [apo(a)] Kringle-IV copy number, were associated with SVD. Method Three hundred and thirty-two patients with BHV for at least 4 years from the Translink study were included. SVD was assessed on echocardiography and computed tomography. Lp(a) concentration was determined by immunoturbidimetry method and the apo(a) Kringle-IV copy number by liquid chromatography-tandem mass spectrometry. Univariable and multivariable models, adjusted for clinically relevant and statistically significant variables, were used to determine the independent association between Lp(a) concentrations and/or apo(a) Kringle-IV copy numbers with SVD. Results Among the 332 patients included in this study, 76 (23%) presented clinically significant SVD on echocardiography. Bioprosthetic valve calcification was significantly higher in patients with versus without SVD (128 [24–259] vs 42 [0–150] mm3, P=0.005). Low apo(a) Kringle-IV copy number was associated with an increased risk of SVD (OR=2.71 [1.34–5.50], P=0.006), but not Lp(a) concentration (OR=0.99 [0.84–1.15], P=0.85). This association remained significant (OR=3.21 [1.31–7.84], P=0.01) after multivariable adjustments including Lp(a) concentration. The analysis of the transprosthetic mean gradient and bioprosthetic valve calcification provided consistent results (all P≤0.05). Conclusion This cross-sectional study from the Translink trial demonstrates the association between Lp(a) polymorphic size and SVD, highlighting a potential therapeutic option to limit the occurrence of SVD in selected patients who underwent AVR with surgical or transcatheter BHV.

AIMS:LIPC encodes hepatic lipase (HL), a liver-bound protein with both phospholipase and triglyceride lipase activity, and involved in the catabolism of circulating lipoproteins. We recently identified the gain-of-function variant HL-E97G, with selectively increased phospholipase activity, as a new genetic cause of familial combined hypocholesterolaemia in humans. The role of HL in the development of atherosclerosis remains controversial. In this context, the action of HL-E97G on the development of atherosclerosis remains unknown. METHODS AND RESULTS:To evaluate the lipid-lowering and anti-atherogenic properties of HL-E97G vs. wildtype HL (HL-WT) in hypercholesterolaemic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, and to assess dependence of these effects on the LDL receptor (LDLR) pathway in LDLR-deficient (Ldlr-/-) mice. APOE*3.Leiden.CETP mice or Ldlr-/- mice received an intravenous injection of AAV8 expressing either eGFP (control), HL-WT or HL-E97G (3 × 1011 GC/mouse) while being fed pro-atherogenic diets. Plasma cholesterol levels were measured monthly, and aortic atherosclerotic lesion sizes were assessed at termination. HL-E97G largely decreased plasma total cholesterol exposure in APOE*3-Leiden.CETP mice (-63% vs. control; -58% vs. HL-WT), resulting at least in part from increased uptake of (V)LDL by the liver, accompanied by a marked decrease in atherosclerotic lesion size (-98% vs. control; -97% vs. HL-WT) in the aortic root. Importantly, HL-E97G also strongly reduced plasma cholesterol exposure in Ldlr-/- mice (-80% vs. control; -77% vs. HL-WT), and decreased atherosclerotic lesion size in the aortic root (-54% vs. control; -41% vs. HL-WT) and the aortic arch (-73% vs. control; -70% vs. HL-WT). CONCLUSIONS:HL-E97G strongly reduces plasma cholesterol levels, by increasing the uptake of (V)LDL, to decrease atherosclerosis development in mice independently of the LDLR pathway. These data suggest that modulating HL function is a promising tool in patients with familial hypercholesterolaemia.

Obesity is a major risk factor for cardiometabolic diseases, with adipocyte dysfunction playing a central role. In individuals living with obesity, adipose tissue (AT) enters a state of metabolic inertia, reducing its capacity to store excess lipids and promoting ectopic lipid accumulation in non-adipose tissues—thereby contributing to cardiometabolic complications. Understanding the mechanisms that regulate lipid storage and mobilization in adipocytes—and how these are disrupted in obesity—is critical for addressing these complications. Generalized lipodystrophy, the most severe form of primary adipocyte dysfunction, is caused in approximately 50% of cases by mutations in the BSCL2 gene encoding Seipin, an endoplasmic reticulum (ER) protein essential for lipid droplet (LD) biogenesis and maintenance. Seipin also localizes to ER/mitochondria contact sites (MAM), where it regulates calcium exchange and mitochondrial function. This study aimed to determine whether Seipin’s recruitment to MAM and ER/LD contact sites overlaps and to assess the consequences of Seipin dysfunction on membrane contact site (MCS) dynamics and adipocyte metabolism. Using in situ proximity ligation assays (PLA) and transmission electron microscopy (TEM), we observed altered MCS involving the ER, LDs, and mitochondria in Seipin-deficient models. Functional assays revealed that Seipin knockdown impairs triglyceride transfer to LDs, an effect that was rescued by the MAM-reinforcing synthetic peptide, the Linker-ER-Mi. Further, we investigated how MCS remodeling influences adipocyte metabolic flexibility. Using TEM and PLA in both mouse AT and 3T3-L1 adipocytes, here, we show that lipid loading increases contacts involving the lipid droplet (LD), specifically ER/LD and mitochondria/LD (Mi/LD) contacts. However, lipid loading exerts opposite effects on MAM subtypes: oleic acid increases the MAM involving mitochondria in close contact with the LD, the MAM-LD, while decreasing the MAM involving cytosolic mitochondria, the “classical” MAM-CM contacts. Notably, this adaptive MCS remodeling was blunted in the AT of diet-induced obese mice. Genetic disruption of MCS in 3T3-L1 adipocytes led to altered lipid flux, impaired lipolysis, and reduced insulin signaling. Collectively, our findings demonstrate that MAM-LD contacts are central to adipocyte metabolic flexibility and lipid handling, and that their dysregulation in obesity may underlie the metabolic inflexibility characteristic of this condition. ### Competing Interest Statement The authors have declared no competing interest. ANR, ANR-21-CE14-0024 MAMA

OBJECTIVE:This proof-of-concept study evaluated the impact of adding semaglutide as an adjuvant therapy to sleeve gastrectomy (SG) on weight loss and metabolic outcomes in obese mice. METHODS:C57Bl6/J male received for 12 weeks high-fat diet and 20% fructose-enriched water, then they were randomized to undergo SG or a Sham surgery and were subsequently treated with either semaglutide or a vehicle for 8 weeks. Mice were weighed weekly, and food intake, plasma glucose levels, and adipose tissue weights were measured. RESULTS:Both SG and semaglutide alone significantly reduced body weight compared with Sham surgery (-22.9%, p = 0.049 and -28.2%, p = 0.003, respectively). SG and semaglutide combination resulted in the greatest reduction (-30.0%, p = 0.003). Food intake was only significantly decreased in the semaglutide group. Although SG has no significant effect, semaglutide alone and in association with SG significantly decreased the plasma glucose concentration. The combination also led to a significant reduction in plasma cholesterol levels (-37.5% ± 4.8% vs. 5.6% ± 6.8%, p = 0.023). Liver steatosis was reduced in all treated groups. CONCLUSIONS:Adding semaglutide to SG potentiates weight loss and metabolic benefits of surgery in obese mice, but no more than with semaglutide alone. These findings support further investigation of combined surgical and pharmacological approaches in obesity treatment.

Lipoproteins are biochemical complexes of apolipoproteins and lipids that primarily mediate the transport of lipids through the circulation, from sites of absorption or synthesis to those of use, storage, or excretion. In type 2 diabetes (T2D), disruptions in lipoprotein metabolism are key drivers of complications and strongly contribute to atherosclerotic cardiovascular disease (ASCVD). As a result, ASCVD remains the leading cause of death in T2D, with significantly higher prevalence than in non-diabetic individuals. Protein post-translational modifications (PTMs) have emerged as key contributors to organ failure mechanisms, with specific PTMs closely linked to the pathogenesis of T2D. Several reports also emphasized the value of plasma apolipoproteins for the early prediction of ASCVD in cardiometabolic diseases. Thus, apolipoproteins, and especially their structurally post-translational modified forms, offer new insights into the molecular mechanisms of lipoprotein dysfunction and may enhance the specificity of ASCVD risk stratification in T2D. This review outlines major apolipoprotein PTMs identified in T2D, many of which can now be quantified in biological samples, particularly via mass spectrometry. We also discuss their role in lipoprotein metabolism dysfunction and their potential value in assessing ASCVD risk in T2D, highlighting their growing potential as clinical biomarkers in population-based cohort studies.

Despite a growing therapeutic arsenal, atherosclerotic cardiovascular disease remains the major cause of mortality worldwide. Hepatic lipase, encoded by the gene LIPC (lipase C, hepatic type), is a protein that has recently regained interest in this context. In this review, we provide a comprehensive overview of the versatile roles of hepatic lipase in lipoprotein metabolism, with a focus on the recently discovered LIPC-E97G (point mutation replacing glutamic acid with glycine at position 97) variant. Specifically, we discuss the roles of hepatic lipase in the metabolism of high-density lipoproteins and apoB-containing lipoproteins, as elucidated through in vitro, in vivo, and genetic studies. We also explore the complex interplay between the antiatherogenic and proatherogenic effects of hepatic lipase, highlighting a predominance of antiatherogenic functions for hepatic lipase. Lastly, we briefly discuss how the knowledge on the function of hepatic lipase can potentially be harnessed for the treatment of atherosclerotic cardiovascular disease.

AIM:Observational studies in the general population suggest that low concentrations of lipoprotein (a) [Lp(a)] are associated with an increased risk of type 2 diabetes. Here, we aim to determine whether Lp(a) plasma concentration and Kringle-IV (K-IV) repeat polymorphism were associated with new-onset diabetes (NOD) in individuals with prediabetes. METHODS:IT-DIAB is an observational, prospective study including 303 participants with impaired fasting glucose (fasting plasma glucose [FPG]: 110-125 mg/dl) followed annually for 5 years. The primary endpoint was the development of NOD, defined as a first FPG value ≥ 126 mg/dl during follow-up. Lp(a) concentrations were measured by immunoturbidimetry, apo(a) concentrations and the number of K-IV domains by mass spectrometry. Survival analyses for NOD were modeled using Kaplan-Meier curves and a multivariable Cox model, after binarization on threshold values of Lp(a) or K-IV. RESULTS:Among the participants, 113 (37%) developed NOD during follow-up. The concentrations of Lp(a) and the number of K-IV domains were not significantly different according to NOD status. Similarly, the percentage of patients with a non-detectable (≤ 7 nmol/l) or elevated (>125 nmol/l) Lp(a) concentration was similar between those with or without NOD: 68.1 vs 63.7% (P = 0.46) and 8.8 vs 8.9% (P > 0.99), respectively. Kaplan-Meier curves and Cox models did not show any association between Lp(a) concentration (threshold 7 nmol/l and 125 nmol/l) or number of K-IV domain (threshold 23) and the risk of NOD. CONCLUSION:In a high-risk population, Lp(a) concentration or polymorphic size do not appear to be substantially associated with type 2 diabetes risk.

The global rise in obesity poses a major public health challenge. While chronic energy surplus is a well-established driver of weight gain and obesity, the mechanisms linking adipose tissue (AT) expansion to cardiometabolic complications remain incompletely understood. In obese individuals, dysfunctional AT loses its capacity to store excess lipids, leading to ectopic fat accumulation and contributing to cardiometabolic complications such as type 2 diabetes. However, the molecular events that drive the transition from healthy to dysfunctional adipocytes are poorly defined. At the opposite end of the adiposity spectrum, lipodystrophies represent a heterogeneous group of disorders characterized by selective loss of AT, often accompanied by severe metabolic disturbances. Despite these contrasting adipose phenotypes, both obesity and lipodystrophy result in similar metabolic complications. In this study, we investigated whether AT in these two contrasting conditions shares a common molecular signature. We performed an unbiased comparative transcriptomic analysis of AT from lipodystrophic BSCL2-deficient and obese mice, identifying a shared signature of 129 genes. Using publicly available datasets, we replicated this signature and refined it to 102 genes whose expression is consistently altered in both obese and lipodystrophic adipose tissue. Correlation network analysis, gene ontology, and literature-based refinement revealed that these genes fall into nine functional categories: lipogenesis, adipocyte differentiation, carbohydrate metabolism, mitochondrial function, amino acid metabolism, reactive oxygen species, metabolic processes, immune response, and a group with no clear functional association. Most of these genes’ expression levels correlated strongly with insulin sensitivity across lipodystrophic and obese mice, as well as human samples. Finally, 52 genetic loci containing these genes harbor variants associated with type 2 diabetes, including 11 loci where genetic associations directly influence candidate gene expression levels. In conclusion, our findings demonstrate that a shared “energetic collapse” of adipocytes, characterized by profound metabolic inflexibility in pathways spanning glucose utilization, lipogenesis, and amino acid catabolism, represents a common pathogenic mechanism underlying adipose tissue dysfunction in both obesity and lipodystrophy. This convergent molecular signature underscores the critical role of intrinsic adipocyte metabolic health in systemic energy homeostasis and insulin sensitivity.