Metabolism[JOURNAL]
Sun
200 papers
Serotonin 2C receptors inhibit hypothalamic CRH neurons to suppress appetite.
Yoo ES, Yu J, Sa M … +2 more , Lee CJ, Sohn JW
Metabolism · 2026 Jan · PMID 41203197 · Publisher ↗
OBJECTIVES: The serotonin 2C receptor (Htr2c) is one of the plausible targets for the development of appetite suppressants. Previous studies have demonstrated the complexity of neuronal circuitry underlying the appetite-...
OBJECTIVES: The serotonin 2C receptor (Htr2c) is one of the plausible targets for the development of appetite suppressants. Previous studies have demonstrated the complexity of neuronal circuitry underlying the appetite-suppressing effects of Htr2c stimulation. To develop a safe and effective anti-obesity medication targeting Htr2c, we need to better understand how Htr2c agonists suppress appetite. In this study, we focused on the effects of Htr2c agonists on corticotropin-releasing hormone (CRH) neurons to identify the contribution of humoral components to the suppression of fasting-induced food intake. METHODS: We used the Crh-ires-cre mice to fluorescently label CRH neurons for whole-cell patch-clamp recordings (Crh-ires-cre::tdTomato mice) and to delete Htr2c selectively in CRH neurons by breeding with Htr2c mice (Crh-ires-cre::Htr2c mice). We also injected Htr2c-targeting short hairpin RNA (shRNA) into the paraventricular nucleus of the hypothalamus (PVH) of Crh-ires-cre mice to knock down Htr2c selectively in CRH neurons within the PVH (CRH neurons). Using these model mice, we tested the effects of WAY161503, a selective Htr2c agonist, on CRH neuronal activity ex vivo as well as fasting-induced food intake and plasma corticosterone (CORT) levels in vivo. RESULTS: WAY161503 inhibited the activity of CRH neurons. The appetite-suppressing effects of WAY161503 were significantly attenuated when Htr2c was deleted selectively in CRH neurons. On the other hand, WAY161503 promoted the reduction of plasma CORT levels during fasting-induced refeeding via Htr2c expressed by CRH neurons. Importantly, when mice were pretreated with RU486, a glucocorticoid receptor antagonist that blocks CORT action, WAY161503 suppressed food intake whether CRH neurons expressed functional Htr2c or not. Finally, we characterized the expression of single-minded 1 (Sim1) messenger RNA (mRNA), Crh mRNA, and Htr2c mRNA in PVH neurons, which may help to explain the effects of Htr2c stimulation on fasting-induced refeeding. CONCLUSIONS: Our results demonstrate that Htr2c expression in the CRH neurons is necessary for the appetite-suppressing effects of WAY161503 during fasting-induced refeeding. Importantly, we found that WAY161503 suppresses the hypothalamic-pituitary-adrenal (HPA) axis and promotes the reduction of plasma CORT levels, thereby enabling the appetite-suppressing effects of Htr2c stimulation during fasting-induced refeeding. To our knowledge, this study is the first to highlight the necessity of coordination between neural and humoral pathways for the suppression of fasting-induced food intake by Htr2c agonists.
Sphk2 suppresses ferroptosis in ischemic hearts by promoting HSP90AA1-mediated TFEB nuclear translocation, lysosome biogenesis and lysosome-autophagy pathway-dependent lipid-ROS clearance.
Gong T, Wang D, Jin Y … +20 more , Chen L, Qiu N, Qiu W, Zheng N, Lv Y, Ding S, Yuan J, Wu J, Lin L, Yang C, Abudureyimu M, Wang X, Yesitayi G, Xu L, Zhang P, Hu W, Zhao G, Ma L, Zou Y, Wang S
Metabolism · 2026 Jan · PMID 41203196 · Publisher ↗
BACKGROUND: Lipid peroxidation and iron overload-mediated cardiac ferroptosis play a critical role in myocardial ischemic injury and remodeling. Sphingosine kinase 2 (Sphk2) is implicated in lipid metabolism and cell sur...
BACKGROUND: Lipid peroxidation and iron overload-mediated cardiac ferroptosis play a critical role in myocardial ischemic injury and remodeling. Sphingosine kinase 2 (Sphk2) is implicated in lipid metabolism and cell survival, yet its role in myocardial infarction (MI) remains elusive. Given the critical function of ferroptosis in ischemic injury, we investigated whether Sphk2 protects the heart by regulating this novel cell death pathway. METHODS: Sphk2 expression was assessed in human failing hearts and a murine MI model. Sphk2 mice and AAV9-mediated cardiac-specific Sphk2 overexpression were used to assess cardiac function by echocardiography, remodeling by Masson's trichrome staining and molecular events. RESULTS: Sphk2 was significantly downregulated in human and murine failing hearts. Sphk2 mice exhibited exacerbated cardiac dysfunction, fibrosis and ferroptosis post-MI. Inhibition of CD36 signaling attenuated lipid uptake and ischemia-induced ferroptosis in Sphk2 mice, whereas pharmacological activation of TFEB restored autophagosome-lysosome function and further suppressed ferroptosis. Mechanistically, Sphk2 deficiency impaired the interaction with and stability of HSP90, leading to suppressed TFEB nuclear translocation, lysosomal biogenesis, and autophagic clearance of lipid peroxides. This exacerbated ferroptosis and ischemic injury via lipid-ROS accumulation and oxidative stress. Crucially, cardiac-specific overexpression of Sphk2 in knockout mice restored HSP90-TFEB signaling, ameliorated ferroptosis, and fully rescued cardiac function and remodeling after MI. CONCLUSION: Our study unveils a novel role of Sphk2 in stabilizing HSP90 to activate TFEB-dependent lysosomal function, thereby mitigating lipid peroxidation and ferroptosis following ischemic injury. Our findings establish a direct causal link between Sphk2 deficiency and ischemic heart failure, which highlights the therapeutic potential of Sphk2 restoration in treating ischemic heart disease.
SLC22A6-dependent lactylation of H3K9 aggravates endothelial dysfunction and atherosclerosis.
Ma Y, Feng S, Jiang Y … +6 more , Jiang J, Liu R, Ma Y, Yin X, Bian H, Zhu R
Metabolism · 2026 Feb · PMID 41197766 · Publisher ↗
BACKGROUND: Atherosclerosis, a leading cause of cardiovascular morbidity and mortality, is driven by endothelial dysfunction. While metabolic reprogramming toward glycolysis in endothelial cells exacerbates disease progr...
BACKGROUND: Atherosclerosis, a leading cause of cardiovascular morbidity and mortality, is driven by endothelial dysfunction. While metabolic reprogramming toward glycolysis in endothelial cells exacerbates disease progression, the role of lactate-derived lactylation in atherogenesis remains poorly understood. METHODS: We performed RNA-seq on aortic tissues from atherosclerotic mice to identify differentially expressed genes, along with Seahorse XF metabolic flux analysis. Endothelium-specific solute carrier family 22 member 6 (Slc22a6) knockout and AAV-delivered acyl-CoA synthetase short-chain family member 1 (Acss1) knockdown mice were established on an ApoE background. Integrated multi-omics (RNA-seq, CUT&Tag, metabolomics) elucidated downstream regulatory networks, and in vivo pharmacological inhibition validated key pathways. RESULTS: Our study reveals a marked elevation of histone H3 Lysine 9 Lactylation (H3K9la) relative to acetylation in atherosclerotic aortic tissue, potentially via SLC22A6-mediated glycolytic enhancement and lactate uptake. Additionally, endothelial-specific knockout of Slc22a6 attenuates H3K9la-driven endothelial dysfunction and atherosclerosis. Integrated RNA-seq and CUT&Tag analyses identify that upregulated ACSS1 and E1A binding protein p300 (EP300) drive H3K9la, which transcriptionally activates stearoyl-CoA desaturase 1 (SCD1), thereby exacerbating endothelial dysfunction. Pharmacological inhibition of H3K9la or SCD1 alleviates endothelial dysfunction and atherosclerosis in vitro and in vivo. We further establish the clinical relevance of lactate, SLC22A6, and ACSS1 in atherosclerosis. CONCLUSIONS: Our findings unveil a metabolism-epigenetics-transcription regulatory axis in endothelial pathophysiology, thus providing novel therapeutic strategies for atherosclerosis by targeting the SLC22A6-dependent ACSS1-H3K9la-SCD1 pathway.
Lifestyle intervention is more effective in high 1-hour post-load glucose than in prediabetes for restoring β-cell function, reducing ectopic fat, and preventing type 2 diabetes.
Wang Y, Sandforth A, Jumprtz-von Schwartzenberg R … +12 more , Ganslmeier M, Cheng Y, Sandforth L, Katzenstein S, Machann J, Schick F, Kantartzis K, Preissl H, Fritsche A, Stefan N, Bergman M, Birkenfeld AL
Metabolism · 2026 Jan · PMID 41192753 · Publisher ↗
BACKGROUND: High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glu...
BACKGROUND: High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glucose regulation (IGR) and is amendable to greater lifestyle intervention (LI) benefit. METHODS: In the Tübingen Lifestyle Intervention Program, 317 people with either NGR, IGR or isolated high 1 h-PG without IGR underwent LI for 9 months to achieve ≥5 % weight loss. RESULTS: Before LI initiation, insulin sensitivity and β-cell function declined progressively from NGR (n = 106) to high 1 h-PG (n = 96) and to IGR (n = 115). Visceral adipose tissue (VAT) volume and liver fat content increased from NGT to high 1 h-PG and to IGR. LI improved insulin sensitivity and ß-cell function in the high 1 h-PG group to levels observed in NGR together with a marked reduction in hepatic fat content. Compared to the IGR group, T2D risk was reduced by 80 % (37-96 %, p = 0.005) in the high 1 h-PG group during a 12-year follow-up period. The odds of remission to complete normoglycemia were doubled in the high 1 h-PG group compared to the IGR group (2.18 [1.13-4.28], p = 0.021). CONCLUSION: High 1 h-PG indicates an intermediate metabolic state with pathophysiological changes more severe than in NGR but milder than in IGR. In people with high 1 h-PG, LI significantly improved insulin sensitivity and β-cell function and reduced ectopic lipid deposition and the risk of developing T2D compared to IGR. These findings highlight the value of 1 h-PG as a clinically useful biomarker, providing a critical window for early intervention to reverse core metabolic defects driving prediabetes and T2D.
Hepatic steatosis associates with leukopoietic activity and atherosclerotic inflammation: mechanistic insights into cardiovascular risk.
Abohashem S, Aldosoky W, Abbasi T … +10 more , Dar T, Rollings R, Tung B, Hammad B, Saeed F, Ali A, Takx RAP, Ghoshhajra BB, Tawakol A, Osborne MT
Metabolism · 2026 Jan · PMID 41192752 · Full text
BACKGROUND: Hepatic steatosis (HS) is associated with an increased risk of major adverse cardiovascular events (MACE). However, the underlying mechanisms linking HS to MACE remain incompletely understood. This study aime...
BACKGROUND: Hepatic steatosis (HS) is associated with an increased risk of major adverse cardiovascular events (MACE). However, the underlying mechanisms linking HS to MACE remain incompletely understood. This study aimed to investigate the role of the leukopoietic-arterial axis in mediating the relationship between imaging markers of HS and MACE. METHODS AND MATERIALS: This longitudinal retrospective cohort study included 445 individuals without active cancer, liver disease or alcohol abuse, or baseline cardiovascular disease who underwent clinical F-FDG-PET/CT imaging. Hepatic glucose uptake (HGU), uptake in the bone marrow (BM) and spleen (as a marker of leukopoiesis), and activity in the aorta (as a measure of arterial inflammation, ArtI) were evaluated. Hepatic and splenic attenuations were analyzed to assess hepatic attenuation index (HAI) and determine nonalcoholic fatty liver disease (NAFLD) status. Metabolic Dysfunction Associated Steatotic Liver disease (MASLD) was defined based on NAFLD status and other metabolic criteria. MACE was adjudicated. RESULTS: In fully adjusted models, HGU associated with heightened BM (standardized β [95 % confidence interval]: 0.353 [0.276, 0.430], p < 0.001) and spleen activities (0.548 [0.475, 0.621], p < 0.001) as well as ArtI (0.529 [0.453, 0.605], p < 0.001). Similar associations were observed for HAI and MASLD or NAFLD status. Notably, these associations remained significant after adjusting for other confounders and among individuals without MASLD/NAFLD. A total of 28 individuals developed MACE over 4 years median follow-up. Furthermore, the leukopoietic-arterial activity mediated the link between imaging markers of HS (i.e., HGU, HAI, MASLD) and MACE, (p < 0.05). CONCLUSION: Our study suggests an important role for the leukopoietic-arterial axis in HS and MACE. These findings may inform therapeutic avenues for reducing the cardiovascular risk associated with HS. STRUCTURED ABSTRACT: This study examines the connection between hepatic steatosis (HS) and major adverse cardiovascular events (MACE) through the leukopoietic-arterial axis. Among 445 patients without history of liver disease or alcohol abuse, imaging markers of hepatic steatosis (i.e., hepatic glucose uptake (HGU)), and metabolic dysfunction associated steatotic liver disease (MASLD), associated with increased activity in bone marrow and spleen, and atherosclerotic plaques. These associations persisted irrespective of MASLD status and after adjusting for relevant confounders. Heightened uptake in leukopoietic tissues and the arteries mediated the relationship between HS markers (i.e., HGU, MASLD) and MACE development. These findings shed light on novel mechanistic pathways and potential targets for interventions to reduce the burden of HS-related CVD.
Lysine potentiates insulin secretion via AASS-dependent catabolism and regulation of GABA content and signaling.
Muñoz F, Gao Q, Mattanovich M … +8 more , Trost K, Hodek O, Lindqvist A, Wierup N, Fex M, Moritz T, Mulder H, Cataldo LR
Metabolism · 2026 Jan · PMID 41167553 · Publisher ↗
Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane de...
Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored. Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including AASS, ALDH7A1, DHTKD1, and HADH, were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing AASS in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in Aass-KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted. Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector. Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.
Pros and cons of different dietary patterns for the treatment of metabolic dysfunction-associated steatotic liver disease.
Palumbo P, Di Betto G, Menozzi R … +2 more , Koek GH, Buzzetti E
Metabolism · 2026 Jan · PMID 41151689 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming the most prevalent hepatic disorder, affecting up to 33 % of the global population. An altered lifestyle, characterized by extended physical in...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming the most prevalent hepatic disorder, affecting up to 33 % of the global population. An altered lifestyle, characterized by extended physical inactivity and increased consumption of highly caloric food, often low in nutritional value, is recognised as one of the main contributing factors for MASLD. Cornerstone for MASLD treatment is a healthy lifestyle, starting from diet. However, the most appropriate dietary pattern for the treatment of MASLD remains a subject of debate. The aims of this narrative review are therefore to explore the mechanisms through which nutrition influences MASLD pathogenesis and to evaluate different dietary patterns for MASLD treatment, highlighting their advantages and limitations. Multiple dietary patterns-including the Mediterranean Diet (MD), the Dietary Approaches to Stop Hypertension (DASH), the Low-Carb Diet (LCD), the Ketogenic Diet (specifically the Very Low-Calorie Ketogenic Diet, VLCKD), the Low-Fat Diet (LFD), Vegetarian Diets (VDs), and Intermittent Fasting (IF)-are reviewed, with a focus on their efficacy on MASLD and the ameliorating of the associated cardiometabolic risks factors (CMRF).
SRSF1 is essential for pancreatic β-cell proliferation and the maintenance of glucose homeostasis in mice.
You X, Peng Q, Qian W … +5 more , Xie Z, Lin Y, Gai Y, Ye J, Feng Y
Metabolism · 2026 Jan · PMID 41138848 · Publisher ↗
BACKGROUND: β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β...
BACKGROUND: β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β-cell proliferation issues and dysfunction is crucial. SRSF1 is a central regulator of cell proliferation and survival, but its influence on β-cell proliferation and glucose control remains unclear. This study aims to investigate the role of SRSF1 in β-cell proliferation and its impact on glucose regulation. By examining the consequences of SRSF1 deficiency in pancreatic β-cells, we seek to elucidate the mechanisms linking SRSF1 to β-cell maintenance and function. METHODS: Mice with pancreatic β-cell-specific deletion of SRSF1 and a Rosa26-tdT lineage reporter were generated. Pancreatic sections were analyzed using immunostaining for insulin, glucagon, somatostatin, Ki67, tdT, proinsulin, TUNEL, and ER stress markers, as well as HE staining. Glucose tolerance tests, glucose and insulin measurements were performed in knockout and control mice. RNA-seq analyzed gene expression changes in 4-month-old islets, while scRNA-seq assessed cellular heterogeneity and gene expression profiles in 10-month-old mice islets. Knockdown assays and puromycin labeling experiments measured new protein synthesis. RESULTS: SRSF1 deficiency resulted in glucose intolerance and impaired insulin secretion, worsening with age. At early stages, knockout islets exhibited reduced β-cell proliferation accompanied by compensatory α-cell expansion. By 4 months, RNA-seq analysis showed downregulation of ribosome biogenesis and cell cycle genes, along with upregulation of α-cell determinants and progenitor-associated factors. Histological examination further revealed a decreased β-cell fraction, an increased α-cell fraction, and a small subset of α-cells co-expressing somatostatin, indicative of transient, stress-associated phenotypic plasticity. scRNA-seq identified ER stress and altered β-cell fate in knockout β-cells from 10-month-old mice. Notably, these changes were absent in 4-month-old knockout islets, indicating ER stress as a secondary response to proliferative defects from SRSF1 deficiency. Mechanistically, SRSF1 employs mechanisms similar to MYC to promote β-cell proliferation, with its effects on β-cells through the regulation of MYC expression. CONCLUSIONS: SRSF1 is essential for β-cell proliferation and function through MYC-mediated pathways. Its deficiency disrupts β-cell homeostasis and contributes to metabolic dysfunction in mice, underscoring its importance in preserving functional β-cells and maintaining glucose balance.
Angiopoietin-like protein 8 mediates inflammation and fibrosis of tubular cells in diabetic kidney disease progression by interacting with Akt2.
Pan L, He Y, Xiang Y … +13 more , Mao B, Meng X, Guo Y, Wang Z, Kan R, Wang S, Shen X, Pan T, Liu Z, Xie J, Yang Y, Li D, Yu X
Metabolism · 2026 Jan · PMID 41110501 · Publisher ↗
BACKGROUND AND AIMS: Angiopoietin-like protein 8 (ANGPTL8), an important regulator of glucose and lipid metabolism, has recently been shown to be associated with renal function decline in patients with diabetic kidney di...
BACKGROUND AND AIMS: Angiopoietin-like protein 8 (ANGPTL8), an important regulator of glucose and lipid metabolism, has recently been shown to be associated with renal function decline in patients with diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain unclear. This study aimed to elucidate the novel role of ANGPTL8 in DKD progression. METHODS: The renal expression of ANGPTL8 was measured in patients and murine models with DKD. Proximal tubule-specific Angptl8 knockout mice were generated to elucidate the role of ANGPTL8 in the pathogenesis of DKD. In vitro, ANGPTL8 was inhibited in human proximal tubular epithelial cells (PTECs) under high glucose plus palmitic acid (HGPA) stress. ANGPTL8 interacting proteins were screened using the human proteome microarray and validated by complementary interaction assays. Functional validation employed the Akt2 small interfering RNA and the specific Akt2 inhibitor in vitro and proximal tubule-specific Akt2 knockout mice in vivo. RESULTS: ANGPTL8 expression was significantly increased in renal proximal tubules during DKD. Proximal tubule-specific Angptl8 knockout ameliorated tubular injury and reduced tubular inflammation and fibrosis in DKD mice. In vitro, ANGPTL8 inhibition protected human PTECs against HGPA-induced inflammation and epithelial-mesenchymal transition (EMT). Mechanistically, intracellular ANGPTL8 directly binds to and activates Akt2, triggering downstream NF-κB pathway activation and GSK3β inhibition. Akt2 inhibition abolished ANGPTL8's pathogenic effects in vitro and in vivo. CONCLUSIONS: Our findings demonstrate for the first time that elevated tubular ANGPTL8 promotes tubular inflammation and fibrosis during DKD by interacting with Akt2, highlighting the ANGPTL8-Akt2 axis as a promising target to prevent DKD progression.
Pancreas meets brain: β-hydroxybutyrate as a novel "β-cellular" metabolism therapy.
Lopa C, Pietrangelo D, Santulli G … +6 more , Gambardella J, Rubattu S, Stefan-Lifshitz M, Garcia CN, Jankauskas SS, Lombardi A
Metabolism · 2026 Jan · PMID 41109663 · Publisher ↗
β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once c...
β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.
METTL1-mediated m7G methylation of FoxO1 regulates lipid metabolism in metabolic dysfunction-associated fatty liver disease.
Du J, Li Y, Zhu X … +9 more , Gao J, Zhang Y, Wang C, Han D, Qiao L, Kou B, Guo R, Zhang H, Lin J
Metabolism · 2026 Jan · PMID 41101688 · Publisher ↗
Metabolic dysfunction-associated fatty liver disease (MASLD) is characterized by the accumulation and degeneration of lipids in hepatocytes, presenting a complex pathogenesis that complicates drug development. In this st...
Metabolic dysfunction-associated fatty liver disease (MASLD) is characterized by the accumulation and degeneration of lipids in hepatocytes, presenting a complex pathogenesis that complicates drug development. In this study, we found that methyltransferase-like 1 (METTL1) is upregulated in the livers of both MASLD mice and clinical samples. Hepatocyte-specific depletion of METTL1 inhibits lipid synthesis and promotes lipid oxidation, alleviating metabolic disorders in high-fat diet (HFD)-induced MASLD mice. Conversely, overexpression of METTL1 enhances lipid synthesis while suppressing lipid oxidation. Mechanistically, METTL1 regulates the stability and protein expression levels of FoxO1 mRNA by methylating the Exon1 region of FoxO1, as demonstrated by m7G sequencing. Additionally, we found that overexpression of FoxO1 counteracts the protective effects of METTL1 deficiency on metabolic disorders in MASLD mice. Moreover, we identified a potent small-molecule inhibitor of METTL1, specifically Homatropine Methylbromide (HtMBm), which significantly ameliorated HFD-induced MASLD. Overall, our study suggests that METTL1 plays a crucial role in the progression of MASLD and highlights the therapeutic potential of targeting METTL1 to modulate fatty acid metabolism in this condition.
A melanocortin 4- and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity.
Ashlaw EF, Elfers CT, Chichura KS … +9 more , Miranda IC, McGivney A, Chepurny OG, Holz GG, Mullins G, den Hartigh LJ, Liu Y, Roth CL, Doyle RP
Metabolism · 2026 Jan · PMID 41093057 · Full text
Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatmen...
Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatment discontinuation. Such concerns are greater still in children and adolescents. Thus, there remains a clinical unmet need to develop obesity and/or T2D mellitus therapies with significantly improved tolerability. Herein, we examined a polypharmacy approach combining melanocortin (MC) 4-, and GLP-1-receptor agonism in a single monomeric peptide based on α-MSH and Exendin-4 to bind and stimulate different peptide receptors in vitro, and to drive reductions in body weight and food intake in up to 7 weeks of treatment in comparison to semaglutide and tirzepatide as standard of care positive controls in diet-induced obese rats. Despite the monomeric peptide GLP-1-/MC4-receptor multiple agonist (KCEM1) being a non-lipidated, weaker GLP-1R agonist compared to semaglutide and tirzepatide, reductions in calorie intake and body weight were similar in all three groups after daily subcutaneous injections of the three peptides. In addition, KCEM1 offered superior glycemic control during glucose tolerance testing. In gene expression analyses, KCEM1, but not semaglutide or tirzepatide, significantly increased expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1 in skeletal muscle, while it reduced genetic markers of inflammation in different tissues, including inflammatory markers IL-6 and TNF-α in liver tissue. Furthermore, KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Overall, these data extend emerging concepts around the use of multi-receptor polypharmacy to treat metabolic syndrome.
Glucoprivation-induced nutrient preference relies on distinct NPY neurons that project to the paraventricular nucleus of the hypothalamus.
Rattanajearakul N, Kondoh K, Fu O … +4 more , Okamoto S, Kobayashi K, Nakajima KI, Minokoshi Y
Metabolism · 2026 Jan · PMID 41077338 · Publisher ↗
BACKGROUND: Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection. METHODS: Male mice were subjected to glucoprivation thro...
BACKGROUND: Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection. METHODS: Male mice were subjected to glucoprivation through the intraperitoneal (i.p.) administration of 2-deoxy-d-glucose (2DG) and were examined for food selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) in a diet choice paradigm. This involved the chemogenetic or optogenetic modulation of the neural activity of AMP-activated protein kinase (AMPK)-regulated corticotropin-releasing hormone (CRH) neurons, melanocortin-4 receptor (MC4R) neurons in the paraventricular nucleus of the hypothalamus (PVH), and neuropeptide Y (NPY) neurons projecting to the PVH. RESULTS: Glucoprivation induced by 2DG administration in mice influenced two distinct neural pathways in the PVH that separately promote the intake of an HCD or an HFD. Injection of 2DG activated PVH-projecting NPY neurons in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM), resulting in a rapid increase in HCD intake through stimulation of PVH AMPK-regulated CRH neurons and recovery from glucoprivation. In contrast, PVH-projecting NPY neurons in the NTS, VLM, and arcuate nucleus of the hypothalamus (ARC) promoted HFD intake by inhibiting MC4R neurons in the PVH, reflecting the strong innate preference for an HFD in mice. The ARC NPY neurons specifically promoted HFD selection. CONCLUSION: Our findings reveal a previously unrecognized mechanism for food selection between HCD and HFD during glucoprivation.
NSD2 exacerbates metabolic dysfunction-associated steatotic liver disease progression by suppressing TFEB-mediated autophagy-lysosomal pathway.
Qiao Y, Zhang Y, Sun C … +7 more , Jin Q, Qu P, Li Z, Qiu Y, Meng H, Peng D, Peng L
Metabolism · 2026 Jan · PMID 41075932 · Publisher ↗
OBJECTIVES: Impaired autophagy is increasingly recognized as a key contributor to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, its underlying molecular mechanisms remain...
OBJECTIVES: Impaired autophagy is increasingly recognized as a key contributor to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, its underlying molecular mechanisms remain largely undefined. Emerging evidence implicates epigenetic regulators in modulating autophagic pathways in metabolic diseases. Therefore, this study aimed to elucidate the role of a histone methyltransferase, nuclear receptor binding SET domain protein 2 (NSD2), in regulating autophagy and its contribution to MASLD progression. METHODS: NSD2 expression levels were evaluated in liver tissues from patients with MASLD and mouse models. Functional studies were conducted using hepatocyte-specific Nsd2 knockout and overexpression mouse models, along with cleavage under targets and tagmentation analysis in hepatocyte cell lines. Additionally, the effects of pharmacological NSD2 inhibition using NSC663284 were evaluated in human liver organoids. Autophagy, hepatic steatosis, and related epigenetic changes were assessed through molecular and histological techniques. RESULTS: NSD2 expression was markedly elevated in both patient livers and murine models, correlating positively with disease severity. Hepatic NSD2 deficiency alleviated diet-induced autophagy impairment and steatosis, while NSD2 overexpression exacerbated these pathologies. Mechanistically, NSD2 epigenetically suppressed TFEB transcription by promoting trimethylation of histone H4 at lysine 20, impairing autophagy. Pharmacological inhibition of NSD2 with NSC663284 similarly alleviated hepatic steatosis in human liver organoids. CONCLUSION: NSD2 acts as a key epigenetic suppressor of TFEB-mediated autophagy in the liver, promoting lipid accumulation and MASLD progression. Targeting NSD2 represents a promising therapeutic strategy for MASLD.
Hepatic aconitase 1 redirects citrate flux to suppress lipogenesis and ameliorate hypercholesterolemia.
Li L, Wang Y, Du Z … +16 more , Yu H, Yang Y, Zhang Z, Duan Y, Han L, Hu C, Du Y, Sun H, Sun X, Xing J, Gao X, Chen D, Wang Y, Hua X, Li J, Qin Y
Metabolism · 2026 Jan · PMID 41067489 · Publisher ↗
BACKGROUND AND AIMS: Targeting key enzymes in hepatic de novo lipogenesis (DNL) presents a promising strategy for treating hypercholesterolemia. However, the precise regulatory mechanisms governing hepatic DNL remain inc...
BACKGROUND AND AIMS: Targeting key enzymes in hepatic de novo lipogenesis (DNL) presents a promising strategy for treating hypercholesterolemia. However, the precise regulatory mechanisms governing hepatic DNL remain incompletely understood. Cytosolic citrate plays a crucial role in DNL, with aconitase 1 (ACO1), a key enzyme in citrate metabolism, potentially influencing lipid metabolism. The aim of this study was to clarify the role of hepatic ACO1 in regulating both hepatic and systemic lipid homeostasis. METHODS: ACO1 expression and activity were assessed in liver tissues from multiple hypercholesterolemic animal models. Using liver-specific genetic manipulation, we examined the effects of hepatic ACO1 knockout and overexpression on hypercholesterolemia and atherosclerosis. Targeted metabolomics and stable isotope-based flux analysis were used to profile hepatic substrate utilization patterns. RESULTS: Hepatic ACO1 expression was significantly reduced in both hypercholesterolemic patients and animal models. Hepatocyte-specific ACO1 deletion exacerbated dyslipidemia, while ACO1 overexpression improved hypercholesterolemia, hepatic steatosis, and atherosclerosis in mouse models. Mechanistically, ACO1 overexpression redirected cytosolic citrate metabolism toward α-ketoglutarate, thereby limiting acetyl-CoA availability for DNL and suppressing fatty acid and cholesterol synthesis. These lipid-lowering effects were dependent on ACO1 enzymatic activity, as catalytically inactive ACO1 mutants failed to replicate the observed benefits. CONCLUSION: Our findings identify hepatic ACO1 as a critical regulator of lipid metabolism homeostasis. Promoting ACO1-mediated citrate redirection effectively mitigates hypercholesterolemia and atherosclerosis by suppressing hepatic DNL, highlighting ACO1 as a potential target for lipid-lowering therapies.
ALDH2 deficiency aggravates vascular injury-induced restenosis by enhancing vascular smooth muscle cell proliferation through SLC38A2-mediated upregulation of glutamine uptake.
Hou D, Yang K, Liu Y … +8 more , Du H, Yue H, Xu F, Sang W, Zhao X, Sun Y, Xu F, Chen Y
Metabolism · 2026 Jan · PMID 41067488 · Publisher ↗
BACKGROUND AND AIMS: Vascular injury-induced restenosis is an important cause of poor long-term prognosis in patients with coronary artery disease (CAD). Although aldehyde dehydrogenase 2 (ALDH2) deficiency has been link...
BACKGROUND AND AIMS: Vascular injury-induced restenosis is an important cause of poor long-term prognosis in patients with coronary artery disease (CAD). Although aldehyde dehydrogenase 2 (ALDH2) deficiency has been linked to poor outcomes in CAD patients, the precise mechanisms through which ALDH2 influences vascular injury-induced restenosis remain elusive. Herein, we attempted to explore the role of ALDH2 in modulating vascular smooth muscle cell (VSMC) proliferation and vascular injury-induced restenosis. METHODS AND RESULTS: Immunofluorescence and immunoblotting revealed that ALDH2 expression was significantly decreased in VSMCs in human stenotic coronary segments and injured mouse femoral and carotid arteries. Global ALDH2 knockout and VSMC-specific ALDH2 knockout exacerbated injury-induced neointima formation, whereas VSMC-specific ALDH2 overexpression reduced neointima formation. Endothelial cell (EC)-specific ALDH2 knockout had little effect on injury-induced neointima formation. Mechanistic studies revealed that ALDH2 deficiency facilitated VSMC proliferation by upregulating the expression of the glutamine transporter SLC38A2, which is a novel ALDH2 target gene. Further bioinformatics analysis, luciferase assays, and ChIP-qPCR revealed that ALDH2 deficiency increased SLC38A2 expression via activating transcription factor 4 (ATF4) and that ATF4 knockdown largely reversed the ability of ALDH2 deficiency to promote VSMC proliferation. Moreover, ALDH2 deficiency promoted the accumulation of 4-HNE adducted proteins, thereby activating ATF4, which subsequently increased SLC28A2 transcriptional activity in VSMCs. Importantly, downregulation of SLC38A2 by adeno-associated virus serotype 2 (AAV2) shRNA or by the inhibitor MeAIB has promising therapeutic potential in limiting VSMC proliferation and neointima formation. Finally, we demonstrated that VSMC proliferation was aggravated and that neointima formation occurred in ALDH2 mutant mice. CONCLUSION: Our study elucidates a novel mechanism through which ALDH2 deficiency aggravates neointimal formation by enhancing VSMC proliferation through an increase in glutamine uptake, suggesting a promising translational strategy for the prevention of vascular injury-induced restenosis.
Mitochondrial phosphopantetheinylation is required for oxidative metabolism.
Norden PR, Wedan RJ, Preston SEJ … +7 more , Canfield M, Graber N, Longenecker JZ, Pentecost OA, McLaughlin E, Hart ML, Nowinski SM
Metabolism · 2026 Jan · PMID 41061852 · Full text
4'-Phosphopantetheinyl (4'PP) groups are essential co-factors added to target proteins by phosphopantetheinyl transferase (PPTase) enzymes. Although mitochondrial 4'PP-modified proteins have been described for decades, a...
4'-Phosphopantetheinyl (4'PP) groups are essential co-factors added to target proteins by phosphopantetheinyl transferase (PPTase) enzymes. Although mitochondrial 4'PP-modified proteins have been described for decades, a mitochondrially-localized PPTase has never been found in mammals. We discovered that the cytoplasmic PPTase aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT) is required for mitochondrial respiration and oxidative metabolism. Loss of AASDHPPT results in failed 4'PP modification of the mitochondrial acyl carrier protein and blunted activity of the mitochondrial fatty acid synthesis (mtFAS) pathway. We found that in addition to its cytoplasmic localization, AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 20 amino acids of the protein. Our data show that this novel mitochondrial localization of AASDHPPT is required to support mtFAS activity and oxidative metabolism. We further identify five variants of uncertain significance in AASDHPPT that are likely pathogenic in humans due to loss of mtFAS activity.
Semaglutide, the first approved GLP-1 receptor agonist for the management of metabolic dysfunction-associated steatohepatitis.
Boutari C, Hill MA, Mantzoros CS
Metabolism · 2026 Jan · PMID 41047002 · Publisher ↗
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Phenome-wide associations of coffee intake in the human phenotype project.
Dai J, Dai W, Heianza Y … +1 more , Qi L
Metabolism · 2026 Jan · PMID 41047001 · Full text
OBJECTIVE: Coffee is one of the most widely consumed beverages globally and has been linked to favorable health outcomes. However, its system-wide relationships with human biology and the underlying mechanisms remain poo...
OBJECTIVE: Coffee is one of the most widely consumed beverages globally and has been linked to favorable health outcomes. However, its system-wide relationships with human biology and the underlying mechanisms remain poorly characterized. This study aimed to investigate the relationship between coffee consumption and continuous glucose monitoring (CGM) metrics and other biological systems in healthy adults. RESEARCH DESIGN AND METHODS: In the Human Phenotype Project, 8666 generally healthy Israeli adults provided two weeks of real-time dietary logs, from which coffee intake was estimated. Participants wore CGM devices throughout this period, and multimodal data spanning 11 additional systems (e.g., gut microbiome, serum lipidomics, and body composition) were collected. We employed machine learning approaches to quantify the extent to which each system reflected coffee intake. We performed linear regression to identify individual traits associated with coffee intake, with false discovery rates < 0.05 considered significant. RESULTS: This cross-sectional study identified continuously-monitored glucose regulation and gut microbial composition as the most reflective systems of coffee intake, with further analyses revealing favorable glycemic profiles spanning diverse aspects of glucose regulation with increasing coffee intake, and Clostridium phoceensis (i.e., Lawsonibacter asaccharolyticus) as the most significant species positively associated with coffee intake. Additionally, coffee intake was favorably associated with traits across body composition, serum lipidomics, and hepatic, hematopoietic, and renal systems. CONCLUSIONS: This study found that habitual coffee intake was linked to multifaceted favorable glucose control captured by CGM and favorable profiles across multiple biological systems, providing mechanistic insights that may guide precision nutrition strategies for diabetes prevention.
Administration of the K channel activator SKA-31 improves long-term endothelial function, blood pressure regulation and cardiac performance in rats with type 2 diabetes.
Mishra RC, Khaddaj Mallat R, John CM … +8 more , Belke DD, Hamm L, Singh L, Kim T, George G, Chen YX, Wulff H, Braun AP
Metabolism · 2026 Jan · PMID 41043591 · Publisher ↗
OBJECTIVE: Our goal in the present study was to examine whether long-term administration of the selective K channel activator SKA-31 would mitigate the development/severity of type 2 diabetes (T2D)-associated cardiovascu...
OBJECTIVE: Our goal in the present study was to examine whether long-term administration of the selective K channel activator SKA-31 would mitigate the development/severity of type 2 diabetes (T2D)-associated cardiovascular (CV) complications in adult male Goto-Kakizaki (GK) rats with spontaneous T2D. METHODS: Adult male T2D GK rats instrumented with radio-telemeters were administered either vehicle or the K channel activator SKA-31 (10 mg/kg) at ~14 weeks of age by daily intraperitoneal injection for 12 consecutive weeks. In vivo and ex vivo analyses of CV function, immune system status, vascular signaling and metabolic hormones were performed following treatment. RESULTS: Vehicle-treated T2D GK rats exhibited gradual increases in systolic and diastolic blood pressure, whereas SKA-31 administration led to lower mean arterial pressure, along with improvements in cardiac function (i.e., ejection fraction, fractional shortening) and structure (i.e., end systolic and diastolic volumes), as determined by echocardiography. SKA-31 treatment in vivo further improved vascular endothelial function in small mesenteric arteries, as determined by arterial pressure myography, and increased the protein expression of vasodilatory signaling molecules in the vascular wall. Prolonged SKA-31 treatment did not impair vasodilatory responsiveness in skeletal muscle and coronary arteries, elicit a pro-inflammatory profile in T2D GK rats or produce any adverse histological effects in brain, kidney or liver. CONCLUSIONS: The results of our study demonstrate that low-dose administration of the K channel activator SKA-31 improved CV function in an established rat model of spontaneous T2D and reveal a potential novel strategy to oppose CV-related morbidity in T2D.
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