Metabolism[JOURNAL]
Sun
200 papers
Unravelling the obesity paradox in cancer: An umbrella review of protective associations and evidence credibility across 13 malignancies.
Yu L, Yuan J, Meng M … +4 more , Pan H, Ge L, Wang L, Li X
Metabolism · 2026 Feb · PMID 41338475 · Publisher ↗
BACKGROUND: The "obesity paradox" in cancer remains controversial amid inconsistent meta-analyses. This umbrella review re-analyses evidence across 13 malignancies using pre-specified credibility criteria to clarify asso...
BACKGROUND: The "obesity paradox" in cancer remains controversial amid inconsistent meta-analyses. This umbrella review re-analyses evidence across 13 malignancies using pre-specified credibility criteria to clarify associations. METHODS: We conducted an umbrella review of systematic reviews and meta-analyses investigating obesity and cancer incidence or prognosis. PubMed, Embase, and Cochrane Library were searched from inception to August 2025. Evidence credibility was graded using the following criteria: statistical significance, heterogeneity, 95 % prediction intervals, small-study effects, excess significance bias, and methodological quality assessment. FINDINGS: Based on 33 included articles (comprising 145 associations across 13 cancer types), only two associations met the convincing evidence criteria: higher BMI was associated with a reduced incidence of oral cancer (relative risk [RR] = 0.93, 95 % CI: 0.91-0.96), and excess weight was associated with a reduced incidence of lung cancer in the Chinese population (odds ratio [OR] = 0.68, 95 % CI: 0.59-0.79). Highly suggestive evidence has revealed associations in lung cancer (reduced incidence, fewer surgical complications and prolonged cancer-specific survival), breast cancer (reduced incidence and decreased likelihood of lymph node metastasis), renal cell carcinoma (prolonged overall survival) and prostate cancer (prolonged overall survival). Of the remaining associations, 20 were suggestive, 51 weak, and 53 non-significant. CONCLUSIONS: Only 21 (14 %) meta-analyses provided convincing or highly suggestive evidence, demonstrating potential associations of obesity in specific oncological contexts pertaining to both reduced incidence risk and improved prognostic outcomes. This synthesis also highlights critical gaps in current evidence, emphasising the need for standardised adiposity metrics, more prudent stratification, and rigorous methodology.
FAM83A acts as an amplifier for lipogenic signaling to facilitate the pathogenesis of metabolic dysfunction-associated steatohepatitis.
Zhou Y, Dai Y, Qin M … +7 more , Li Y, Shi L, Chen H, Fan H, Yu Y, Guo L, Xiong J
Metabolism · 2026 Feb · PMID 41338474 · Publisher ↗
BACKGROUND & AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) and its more severe manifestation, metabolic-associated steatohepatitis (MASH), are intimately linked to disturbances in lipid metabolism. A...
BACKGROUND & AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) and its more severe manifestation, metabolic-associated steatohepatitis (MASH), are intimately linked to disturbances in lipid metabolism. Although downstream signaling pathways of epidermal growth factor receptor (EGFR), including extracellular signal-regulated kinase (ERK) and proto-oncogene serine/threonine kinase (RAF1), exhibited heightened activation during MASH progression, their specific roles and underlying mechanisms in driving MASH pathogenesis remain inadequately elucidated. METHODS: A comprehensive transcriptomic analysis was performed to indentify key genes involved in MAFLD development. Murine models with hepatocyte-specific depletion or overexpression of FAM83A were subjected to either a high-fat diet (HFD) for 8 or 14 weeks to simulate simple steatosis (MAFL) and MASH, respectively, or a choline-deficient high-fat diet (CDAHFD) to accelerate MASH progression. RESULTS: FAM83A, recognized as a downstream effector of EGFR that activates the ERK signaling pathway, was predominantly expressed in hepatoctyes and upregulated during MASH pathogenesis in both animal models and clinical patients. Hepatocyte-specific FAM83A knockout delayed MASH progression and mitigated hepatic inflammation and fibrosis. Conversely, overexpression of FAM83A exacerbated MASH pathology, evidence by increased lipid accumulation, inflammation and fibrosis. Mechanistically, insulin induces transcriptional expression of FAM83A, which physically bound to RAF1, enhancing its phosphorylation and subsequent ERK signaling activation. Furthermore, FAM83A-mediated upregulatation of lipogenic gene expression and lipogenesis was significantly inhibited by the treatment of RAF1 inhibitor sorafenib or ERK inhibitor PD98059. CONCLUSIONS: FAM83A promotes MASH pathogenesis by interacting with RAF1 to activate ERK signaling, thereby stimulating fatty acid and cholesterol biosynthesis. Targeting this axis may offer therapeutic potential for MASH and metabolic dyslipidemia.
Meteorin-like protein inhibits vascular smooth muscle cell-derived foam cell formation and atherosclerosis via KIT- endoplasmic reticulum stress signaling.
Chen X, Jiang X, Hou S … +12 more , Lai F, Hu K, Li J, Yang T, Shen X, Chen H, Chen S, Guo X, Zheng Y, Xu T, Su G, Huang R
Metabolism · 2026 Mar · PMID 41325882 · Publisher ↗
OBJECTIVE: Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known met...
OBJECTIVE: Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known metabolic and anti-inflammatory effects, has been linked to cardiovascular protection, but its role in atherosclerosis is not well defined. This study investigated the function of METRNL in VSMC-derived foam cell formation and atherosclerosis and explored the underlying signaling mechanisms. METHODS: ApoE mice were used to investigate the role of METRNL in atherosclerosis. VSMC-derived foam cell formation was evaluated in human VSMC treated with oxidized LDL with or without METRNL supplementation. RESULTS: METRNL levels declined during atherosclerosis progression and were restored during regression. METRNL selectively inhibited foam cell formation in VSMCs-but not in macrophages-by downregulating CD36-mediated cholesterol uptake and suppressing endoplasmic reticulum stress through KIT signaling. Deletion of KIT specifically in smooth muscle cells abolished these protective effects. The transcription factor SP1 was found to bind directly to the METRNL promoter and enhance its expression. Clinically, lower serum METRNL levels were independently associated with increased risk and severity of acute coronary syndrome. CONCLUSION: METRNL protects against VSMC foam cell formation and atherosclerosis by enhancing KIT signaling, thereby reducing ER stress and subsequent cholesterol uptake. These findings position METRNL as a potential therapeutic target and biomarker for atherosclerotic cardiovascular disease.
Molecular code of ferroptosis: emerging multi-dimensional modifications and therapeutic targets in hepatic disorders.
Cai X, Zhang Y, Qin W … +1 more , Li X
Metabolism · 2026 Feb · PMID 41314379 · Publisher ↗
Ferroptosis, a distinct form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a pivotal regulator in the pathogenesis of liver diseases. It functions both as a driver of hepatocyte injury...
Ferroptosis, a distinct form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a pivotal regulator in the pathogenesis of liver diseases. It functions both as a driver of hepatocyte injury in chronic liver disorders and as a therapeutic vulnerability in hepatocellular carcinoma. This review provides a comprehensive analysis of the regulatory networks of ferroptosis, shaped by both epigenetic and post-translational modifications. Specifically, we detailed how RNA and DNA methylation, non-coding RNAs, histone acetylation and post-translational modifications dynamically modulated the expression, stability and activity of ferroptosis-related molecules, especially for glutathione peroxidase 4, solute carrier family 7 member 11, acyl-CoA synthetase long-chain family member 4 and transferrin receptor 1. By dissecting these multilayered regulatory mechanisms, we delineated how distinct modifications operated, either promoting or suppressing ferroptosis across various liver diseases. Furthermore, we summarized recent advances in therapeutic interventions targeting ferroptosis-related pathways, including their pharmacological mechanisms, efficacy in preclinical models and limitations in clinical translation. Special emphasis was also placed on the complexity of modifications, disease-stage specificity and the topology of modification sites in shaping ferroptosis sensitivity. Collectively, this review highlights ferroptosis as a dynamic and therapeutically actionable within liver pathology and underscores the potential of targeting regulatory modifications to refine strategies for disease intervention.
Imeglimin ameliorates MASLD by targeting PEN2 to activate AMPK pathway.
Li J, Zhang R, Zeng X … +9 more , Xu W, Gao L, He S, Wu B, Ma Y, Nie Y, Shirakawa J, Xia H, Li W
Metabolism · 2026 Feb · PMID 41308829 · Publisher ↗
BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent and increasingly chronic liver disorder with increasing global incidence, closely linked to prolonged high-fat d...
BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent and increasingly chronic liver disorder with increasing global incidence, closely linked to prolonged high-fat diet (HFD)-induced metabolic impairment. Although imeglimin, an antidiabetic agent known to improve insulin resistance, has demonstrated therapeutic potential in metabolic diseases, its effects and underlying molecular mechanism in MASLD remain unclear. APPROACH AND RESULTS: In this study, we employed a long-term (48-week) high-fat diet-induced murine model of MASLD to recapitulate human disease progression, then treated those mice with imeglimin for 6 months to investigate its therapeutic effects. Imeglimin treatment improved insulin resistance, restored liver function, attenuated hepatic inflammation, and promoted hepatocyte viability. PEN2, a component of the γ-secretase complex, is identified as the key target of imeglimin. The therapeutic effects of imeglimin are abrogated in liver-specific Pen2-deficient mice or upon pharmacologic inhibition of AMP-activated protein kinase (AMPK), indicating that activation of PEN2-AMPK signaling is required for its beneficial effects. Furthermore, we found that imeglimin also protected human pluripotent stem cell (hPSC)-derived hepatocyte-like cells from free fatty acid (FFA)-induced lipid accumulation. CONCLUSION: Collectively, our findings indicate that imeglimin ameliorates hepatic lipotoxicity by targeting PEN2 to activate AMPK axis, suggesting its potential as a new drug for MASLD treatment in the near future.
TMEM41B contributes to atherosclerosis by promoting lipid synthesis in vascular smooth muscle cells via fatty acid synthase stabilization.
Peng GY, Wei LT, Jing YX … +6 more , Luo HL, Liu ZL, Wei RC, Ning JJ, Chang GQ, Wang M
Metabolism · 2026 Feb · PMID 41297878 · Publisher ↗
Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is signific...
Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. Silencing TMEM41B in VSMCs of apolipoprotein E-deficient (ApoE) mice markedly reduced plaque size and macrophage infiltration. Overexpressing TMEM41B in cultured VSMCs altered intracellular lipid profiles by stabilizing fatty acid synthase (FASN), a crucial enzyme in fatty acid synthesis, via inhibiting its ubiquitination and degradation. The TMEM41B-FASN axis drove lipid synthesis, promoted intracellular lipid storage, and facilitated the release of pro-inflammatory cytokines. Further, in cultured VSMCs, herpes simplex virus (HSV) infection amplified TMEM41B expression via OCT-1-mediated transcriptional activation, linking viral infection to lipid metabolic reprogramming in vitro. These findings expand the current understanding of VSMC-derived foam cell formation and suggest that targeting the TMEM41B-FASN axis may represent a promising therapeutic strategy for AS, particularly in the context of HSV infection.
Metabolic reprogramming in diabetic foot ulcers: mechanisms, therapeutic implications and future perspectives.
Jinyi L, Xianguang D, Yuhan D … +4 more , Haoyue H, Zhongyu X, Lianhui W, Xu J
Metabolism · 2026 Feb · PMID 41285352 · Publisher ↗
As a devastating complication, diabetic foot ulcer (DFU) is characterized by chronic, nonhealing wounds due to vasculopathy and neuropathy. It has emerged as a most challenging chronic disease worldwide, affecting millio...
As a devastating complication, diabetic foot ulcer (DFU) is characterized by chronic, nonhealing wounds due to vasculopathy and neuropathy. It has emerged as a most challenging chronic disease worldwide, affecting millions of people worldwide. The higher mortality and disability rates urgently require innovative therapeutic strategies. Recently, different from nanotechnology, metabolic reprogramming is believed to be associated with the occurrence and progression of various diseases (including cancer, obesity and neurodegenerative diseases). They can alter their cellular metabolism (involving glucose, lipid, and amino acid metabolism) to cope with different external stimuli and pressures. As a novel potential strategy, metabolic reprogramming also exhibits great potential to improve the wound healing of DFU. This review aims to summarize the current knowledge, biological characteristics, and underlying mechanisms of metabolic reprogramming in DFU. And we propose their potential therapeutic implications to improve wound healing and prevent complications in DFU. In addition, we also highlight the current challenges and the future perspectives.
Prenatal caffeine exposure impairs neurodevelopment via glucocorticoid-driven epigenetic cascade suppressing astrocytic ABCG1 and cholesterol transport.
Dai G, Luo M, Dai S … +8 more , Zhou X, Zhu S, Lu M, Han X, Yang F, Yu Y, Wang H, Xu D
Metabolism · 2026 Feb · PMID 41285351 · Publisher ↗
Prenatal caffeine exposure (PCE), stemming from widespread maternal intake of caffeine-containing substances, has emerged as a major pharmacological stressor affecting fetal neurodevelopment. Although epidemiological stu...
Prenatal caffeine exposure (PCE), stemming from widespread maternal intake of caffeine-containing substances, has emerged as a major pharmacological stressor affecting fetal neurodevelopment. Although epidemiological studies have consistently linked PCE to cognitive impairments and emotional deficits in offspring, the underlying mechanisms have long been confined to direct adenosine receptor antagonism, failing to explain the persistent neurodevelopmental consequences. Here, using cross-species models (rat PCE, astrocyte-specific Abcg1 knockout mice, and glucocorticoid-treated zebrafish) and multi-scale analyses, we demonstrate that PCE activates the maternal-fetal glucocorticoid axis, leading to dysregulation of the GR-miR-130b/301b-PPARγ signaling cascade in hippocampal astrocytes. This disrupts expression of the cholesterol transporter- ATP binding cassette subfamily G member 1 (ABCG1), impairing astrocytic cholesterol efflux and depriving neurons of cholesterol-rich microenvironments essential for synaptic development. Abcg1 knockout mice recapitulate PCE-induced synaptic defects, while astrocyte-specific ABCG1 overexpression or miR-130b/301b inhibition rescues neuronal cholesterol supply and synaptic structure. Luciferase assays confirm that miR-130b/301b directly suppress Pparγ-mediated Abcg1 transcription. Our findings identify the GR-miR-130b/301b-PPARγ-ABCG1 axis as a core mechanism of PCE-induced neurotoxicity, establishing astrocytic cholesterol transport as a potential intervention target and providing a shared molecular framework for evaluating central nervous system risks of glucocorticoid-disruptive agents.
Emerging roles of arginine metabolism in skeletal health and disease.
Wang S, Ren Q, Huang Y … +5 more , Ma Y, Zhang X, Liu Y, He B, Yan L
Metabolism · 2026 Feb · PMID 41270967 · Publisher ↗
Arginine, as a semi-essential amino acid, plays a pivotal role in bone metabolism and orthopedic diseases. Beyond its function in protein synthesis, arginine serves as a crucial precursor for Nitric Oxide (NO), polyamine...
Arginine, as a semi-essential amino acid, plays a pivotal role in bone metabolism and orthopedic diseases. Beyond its function in protein synthesis, arginine serves as a crucial precursor for Nitric Oxide (NO), polyamines, and proline, profoundly influencing osteoblast differentiation, osteoclast activation, immune responses, and angiogenesis. Research indicates that abnormalities in arginine metabolism-such as imbalances in NO synthase activity, upregulation of arginase, or abnormal expression of protein arginine methyltransferases-are closely associated with the onset and progression of osteoporosis, rheumatoid arthritis, osteoarthritis, and bone tumors. Simultaneously, the arginine pathway intertwines with oxidative stress, inflammatory responses, and epigenetic regulation, forming a complex "metabolism-immunity-bone" network. In materials science, arginine has been integrated into various biomaterial systems, including Poly (lactic-co-glycolic acid) (PLGA) scaffolds, chitosan hydrogels, hydroxyapatite composites, and RGD-functionalized polymers, significantly enhancing osteogenic, angiogenic, and immunomodulatory capabilities. Despite ongoing research advancements, challenges persist in understanding the environment-dependent effects of arginine, optimizing dosage, and achieving clinical translation. This review systematically summarizes the mechanistic roles of arginine in bone metabolism regulation and its application progress in engineered materials, offering novel therapeutic insights and research directions for preventing and treating diseases such as osteoporosis, arthritis, and bone tumors.
Air pollution exacerbates cardiovascular-kidney-metabolic syndrome and sarcopenia comorbidity via shared genetic-epigenetic mechanisms: A multi-omics and Mendelian Randomization study.
Wei S, Shu Z, Li X … +8 more , Zhong S, Xiao L, Shen R, Lu X, He L, Zhang Y, Quan Y, Huang X
Metabolism · 2026 Feb · PMID 41270966 · Publisher ↗
BACKGROUND: Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly under...
BACKGROUND: Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly understood. METHODS: We integrated genome-wide association study (GWAS) data for CKM components (cardiovascular disease [CVD], chronic kidney disease [CKD], metabolic syndrome), CKM-related cardiovascular events, and sarcopenia diagnostic criteria from European-ancestry cohorts, and conducted meta-analyses harmonizing each phenotype across at least three studies. We employed Mendelian Randomization (MR) to assess potential causal links and genetic correlation analyses (global and local) to quantify shared heritability. Multi-omics analyses included two sequential phases: Phase 1 identified and validated novel shared CKM-sarcopenia genes through integrated methylation (n = 1980) and expression (n = 31,684) analyses, followed by cross-validation using two complementary transcriptome-wide association studies (TWAS). Phase 2 prioritized druggable targets through proteomic analysis across five independent cohorts (deCODE, n = 35,559; UK Biobank Pharma Proteomics Project (UKB-PPP), n = 54,219; Fenland, n = 10,708; FinnGen Olink, n = 619; FinnGen Somascan, n = 828) and integrated colocalization. RESULTS: MR suggested genetically predicted associations between sarcopenia and CKM; genetically slower walking pace was associated with higher CVD risk (OR = 0.85, P = 9.56 × 10) and metabolic syndrome risk (OR = 0.43, P = 3.90 × 10), while conversely, genetically predicted lower appendicular lean mass exhibited inverse associations with heart failure with heart failure and atrial fibrillation. Multi-omics identified key shared genes (ANAPC4, UNC50, TPO), with ANAPC4 methylation sites linked to CVD (cg13918811, P = 0.0212) and reduced muscle mass (cg04009456, P = 0.0049). Blood-based analyses identified 13 air pollution-associated comorbid genes, primarily responsive to PM/NO, with 11 confirmed by cross-tissue validation. Proteomics (F-statistics > 10) revealed potential targets linking CKM/sarcopenia (HP, FCGR3B, GALNT2) and CKM-events/sarcopenia (SERPINA1, FER). CONCLUSION: Ambient air pollution likely promotes CKM-sarcopenia comorbidity chiefly via inflammatory signaling and epigenetic modifications. Our multi-omics integration reveals convergent pathways, candidate driver genes, and differential methylation sites that link these conditions. We propose these targets for environmental mitigation and molecular intervention, which require validation in diverse populations.
DC-SIGN macrophages alleviate metabolic dysfunction-associated steatotic liver disease via fine-tuning TLR4 signaling and inflammatory secretory profiles.
Liu J, Wu H, Zhou L … +14 more , Jin Q, Ji H, Hu B, Wu H, Chen T, Wang X, Hong J, Feng R, Zhang X, Zhou J, Zhang W, Wang X, Qu L, Wan C
Metabolism · 2026 Feb · PMID 41270396 · Publisher ↗
BACKGROUND & AIMS: Innate immune receptors play a pivotal role in modulating immune responses during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to comprehensively...
BACKGROUND & AIMS: Innate immune receptors play a pivotal role in modulating immune responses during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to comprehensively investigate the role of the C-type lectin receptor DC-specific ICAM3-grabbing non-integrin (DC-SIGN) in MASLD progression. METHODS: DC-SIGN expression in liver tissues from patients with MASLD and healthy individuals was examined using immunohistochemical analyses. Immunofluorescence was used to determine DC-SIGN distribution across liver cell types. In vivo, adeno-associated virus (AAV)-mediated transduction of CD68 promoter-driven human DC-SIGN (hDC-SIGN) or a control construct was performed in mice fed either a high-fat, high-cholesterol (HFHC) diet or a normal chow diet (NCD). Additionally, THP-1-differentiated macrophages were used in vitro to investigate the molecular mechanisms by which DC-SIGN modulates Toll-like receptor 4 (TLR4) endocytosis and inflammatory cytokine secretion. RESULTS: DC-SIGN expression was significantly reduced in liver tissues from patients with MASLD and HFHC-fed mice compared to healthy controls and NCD-fed mice. DC-SIGN predominantly co-localized with the macrophage marker CD68. Delivery of CD68 promoter-specific hDC-SIGN markedly ameliorated HFHC-induced liver lipotoxicity, steatosis, inflammation, and fibrosis. Mechanistically, DC-SIGN facilitated macrophage TLR4 endocytosis via direct binding to TLR4, suppressing MyD88-dependent pro-inflammatory responses while activating TBK1-dependent IRF3 signaling. Accordingly, Lewis (Le)-DC-SIGN signaling reduced lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion while simultaneously enhancing anti-inflammatory IL-10 secretion. CONCLUSIONS: DC-SIGN plays a key role in modulating TLR4-dependent inflammation in MASLD, suggesting that targeting macrophage DC-SIGN may be a promising therapeutic approach.
Induction of Yin Yang 1 (YY1) overexpression in mature adipocytes promotes dysfunctional adipose tissue and systemic insulin resistance in mice.
Pedersen L, Gliniak CM, Dale TM … +8 more , Zhu Q, Li C, Funcke JB, Crewe C, Luo J, Palluth L, Zhu Y, Scherer PE
Metabolism · 2026 Feb · PMID 41265559 · Full text
The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been...
The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced weight gain, systemic insulin resistance, and increased liver steatosis in comparison to control littermates. In contrast, brown adipose tissue-specific YY1 overexpression has little effect on mice fed a high-fat diet. In an obesogenic environment, acute ectopic adiponectin promoter-driven YY1 expression promotes weight loss, cell death, and adipose tissue inflammation. Underlying the observed reduction in adipose tissue mass, we find that YY1 controls gene networks related to adipose tissue expansion, lipid anabolic pathways (hypertrophy), and hyperplasia (adipogenesis). Taken together, our results demonstrate novel roles of Yy1 in white adipose tissue. This versatile transcription factor regulates central aspects of white adipose tissue biology that are essential for maintaining whole-body physiology.
Corrigendum to "Addressing the role of 11β-hydroxysteroid dehydrogenase type 1 in the development of polycystic ovary syndrome and the putative therapeutic effects of its selective inhibition in a preclinical model" [Metab Clin Exp 119 (2021) 154749 1-14 [METABOLISM-D-20-01502R3]].
Li X, Hu S, Zhu Q … +12 more , Yao G, Yao J, Li J, Wang Y, Ding Y, Qi J, Xu R, Zhao H, Zhu Z, Du Y, Sun K, Sun Y
Metabolism · 2026 Feb · PMID 41242134 · Publisher ↗
Abstract loading — click title to view on PubMed.
Obesity rewires CD8+ T cell iron metabolism in adipose tissue to fuel metabolic inflammation.
Dai J, Zeng Z, Wang L … +14 more , Yuan W, Rocha KCE, Park J, An G, Wang K, Song J, Xiang Q, Duan Y, Qian C, Beldona V, Lim W, Hui E, Karin M, Ying W
Metabolism · 2026 Feb · PMID 41241023 · Publisher ↗
Sufficient nutrient supply is important for the maintenance of non-lymphoid tissue resident CD8+ T cell homeostasis, but the role of labile iron remains unclear. Here, we find adipose tissue CD8+ T cells exhibit elevated...
Sufficient nutrient supply is important for the maintenance of non-lymphoid tissue resident CD8+ T cell homeostasis, but the role of labile iron remains unclear. Here, we find adipose tissue CD8+ T cells exhibit elevated labile iron and mitochondrial Fe2+ compared to splenic counterparts, driving high ROS and IFNγ production. In obesity, an increase in Fe2+ influx into mitochondria enhances adipose tissue CD8+ cell functions, but weight loss normalizes CD8+ cell iron metabolism. Ncoa4 knockout reduces labile iron, blunting ROS and IFNγ production, while Fth1 knockout elevates Fe2+ and ROS, elevating IFNγ production. CD8+ cell-specific activation of NRF2 restores iron homeostasis by upregulating ferritin and promoting oxidative detoxification, suppressing adipose tissue CD8+ T cell accumulation and IFNγ production. Finally, NRF2 overexpression in CD8+ T cells attenuates obesity-related adipose tissue inflammation and metabolic disorders. These results highlight the crucial role of labile iron supply in adipose tissue CD8+ T cell homeostasis.
HDL dysfunction: a role in the pathogenesis of cardiometabolic syndrome in chronic HIV infection?
Markakis K, Abadi LF, Kombe AK … +2 more , Christodoulides M, Kelesidis T
Metabolism · 2026 Feb · PMID 41238103 · Full text
People living with human immunodeficiency virus (HIV) (PLWH) on antiretroviral treatment (ART) have an increased risk of atherosclerotic cardiovascular disease (CVD) and metabolic syndrome (combinations of adiposity, ins...
People living with human immunodeficiency virus (HIV) (PLWH) on antiretroviral treatment (ART) have an increased risk of atherosclerotic cardiovascular disease (CVD) and metabolic syndrome (combinations of adiposity, insulin resistance, hypertension, and dyslipidemia). Together, CVD and metabolic syndrome constitute the cardiometabolic syndrome. Traditional CVD risk factors and high-density lipoproteins (HDL) alterations seem to contribute to the elevated CVD risk. Cumulative evidence suggests that assessing HDL function instead of HDL cholesterol levels (HDL-C) may be a better way to assess cardiometabolic risk. In HIV infection, HIV-1, ART, and the altered function of organs like the liver, gastrointestinal tract, and immune system affect the proteome, lipidome, and metabolism of HDL, ultimately leading to its dysfunction. However, the impact of altered HDL functions on PLWH remains unclear and whether HDL dysfunction reflects and/or contributes to cardiometabolic syndrome in HIV infection (bidirectional cross talk regarding how HDL function impacts the cardiometabolic syndrome and vice versa). Large cohorts of PLWH with variable CVD risk using independent assays of HDL function are needed to elucidate the bidirectional crosstalk between HDL functions and cardiometabolic syndrome. Developing novel treatments to improve HDL function in PLWH may have multiple beneficial results, reducing chronic inflammation and cardiometabolic risk in PLWH. This review aims to summarize the scientific evidence related to the role of HDL functions in HIV and how therapeutic targeting of HDL dysfunction may contribute to reduced cardiometabolic risk in PLWH.
Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical.
Long J, Liu S, Shi Y … +3 more , Zhang C, Qin L, Ai Q
Metabolism · 2026 Feb · PMID 41238102 · Publisher ↗
The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neur...
The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases-including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)-are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.
BCAA catabolism in TRH neurons of paraventricular nucleus regulates energy expenditure.
Ming X, Tan J, Yuan M … +17 more , Ma X, Zhou F, Wang S, Lyu Q, Xue W, Bo T, Liu Y, Zhang X, Yan F, Hong J, Zheng J, Ning G, Wang W, Wang J, Sun H, Zhou L, Wang X
Metabolism · 2026 Feb · PMID 41224144 · Publisher ↗
The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto aci...
The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto acid dehydrogenase E1α subunit (BCKDHA) expression in the hypothalamus was negatively associated with fat mass. Hypothalamic deletion of BCKDHA (Bckdha) leads to increased fat mass, reduced energy expenditure, and blunted browning of white adipose tissue in mice, with decreases of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus (PVN) and hypothalamic-pituitary-thyroid (HPT) axis activity. Mice with adeno-associated virus-mediated deletion of BCKDHA in the PVN neurons displays a similar metabolic phenotype to Bckdha mice. TRH supplementation ameliorates the abnormal phenotypes of Bckdha mice. Defective BCAA catabolism in the hypothalamus results in hypoacetylation of histone H3 lysine 27 (H3K27) due to decreased acetyl-CoA content, reducing its binding to the Trh promoter. Our study highlights the crucial role of hypothalamic BCAA catabolism in maintaining energy homeostasis through HPT axis.
Calcitonin and procalcitonin: Revisiting the overlooked role of C cells.
Fröhlich E, Wahl R
Metabolism · 2026 Feb · PMID 41218723 · Publisher ↗
Calcitonin (CT) is a hormone produced by C cells in the thyroid gland. Its primary function is to regulate bone turnover. However, it is believed to be of little importance to human physiology because its absence followi...
Calcitonin (CT) is a hormone produced by C cells in the thyroid gland. Its primary function is to regulate bone turnover. However, it is believed to be of little importance to human physiology because its absence following thyroidectomy has no dramatic effects. It was used in the treatment of osteoporosis but has now largely been replaced by bisphosphonates and monoclonal antibodies. However, some studies suggest that CT may have additional functions, such as those related to bone structure, osteoprotection, and pain management. This review summarizes CT synthesis and function and discusses its role and that of its precursor, procalcitonin, as biomarkers. Procalcitonin detection has advantages over some established markers in sepsis management and due to its greater stability, it is also an alternative to CT for managing medullary thyroid carcinoma. Recent research has raised the possibility that procalcitonin could serve as a direct molecular target for treating sepsis. Potential roles of various regulatory peptides released by C cells that may contribute to paracrine fine-tuning of thyroid hormone secretion by follicular thyrocytes are considered. Health-care providers should inform patients that despite optimal thyroxine replacement therapy, subtle symptoms may still occur due to the absence of C cells.
GLP-1RAs and tirzepatide may reduce heart failure risk in obese but not in non-obese patients with cardiovascular or renal disease: A systematic review and meta-analysis.
Zhang J, Guan X, Kong M … +3 more , Xia M, Yu Y, Zhang C
Metabolism · 2026 Feb · PMID 41207615 · Publisher ↗
BACKGROUND: Cardiovascular disease (CVD) and chronic kidney disease (CKD) frequently coexist, with obesity and type 2 diabetes (T2D) being major contributors to adverse outcomes. Glucagon-like peptide-1 receptor agonists...
BACKGROUND: Cardiovascular disease (CVD) and chronic kidney disease (CKD) frequently coexist, with obesity and type 2 diabetes (T2D) being major contributors to adverse outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide have shown cardiorenal benefits beyond glycemic control, but their efficacy across metabolic phenotypes remains unclear. METHODS: This review was prospectively registered in PROSPERO (CRD420251088042). PubMed, Embase, Web of Science, and Cochrane Library were searched (January 2015-July 2025) for RCTs comparing GLP-1RAs or tirzepatide with placebo in patients with cardiovascular or renal disease. Subgroup analyses were performed according to T2D and obesity status. RESULTS: A total of 18 RCTs (n = 97,800) involving eight GLP-1RAs and tirzepatide were included, primarily enrolling patients with established cardiovascular or renal disease. GLP-1RAs significantly reduced the risk of the primary composite outcome (RR 0.88, 95 % CI 0.84-0.91, P < 0.001). GLP-1RAs and tirzepatide also significantly reduced the risk of death from any cause (RR 0.88, 95 % CI 0.84-0.92, P < 0.001), and death from cardiovascular causes (RR 0.88, 95 % CI 0.83-0.93, P < 0.001). Although the overall effect of GLP-1RAs on hospitalization for heart failure was not statistically significant (RR 0.92, 95 % CI 0.78-1.08), a potential benefit was observed in obese patients (P for interaction = 0.02), warranting further investigation. GLP-1RAs showed favorable overall safety profile, with a lower incidence of serious adverse events (RR 0.93, 95 % CI 0.89-0.99, P = 0.01) and cardiac adverse events (RR 0.90, 95 % CI 0.85-0.96, P < 0.01) compared with placebo. CONCLUSION: In patients with cardiovascular or renal disease, GLP-1RAs and tirzepatide provide consistent cardiovascular and renal protection, with a possible benefit in reducing hospitalization for heart failure among individuals with obesity.
Inhibition of microglial Slc2a5 attenuates ischemic brain injury.
Ai D, Qiu B, Chen XJ … +9 more , Li F, Yao D, Mi H, Li JL, Zhou B, Zuo J, Wang Y, Ge WP, Sun W
Metabolism · 2026 Feb · PMID 41205649 · Publisher ↗
Acute ischemic stroke (AIS) is one of the leading causes of mortality and disability globally. Despite its complex pathological mechanisms, effective neuroprotective strategies are still lacking in clinical practice. Mic...
Acute ischemic stroke (AIS) is one of the leading causes of mortality and disability globally. Despite its complex pathological mechanisms, effective neuroprotective strategies are still lacking in clinical practice. Microglia and their metabolic processes play a pivotal role in the pathogenesis of AIS, yet the impact and underlying mechanisms of microglial fructose metabolism remain unclear. In this study, we identified Slc2a5 (also known as Glut5), a crucial regulator of fructose metabolism in microglia, as a key factor contributing to the early progression of AIS. Conditional deletion of Slc2a5 in microglia significantly alleviated brain injury in a mouse model of AIS. Single-cell transcriptomic (scRNA-seq) analysis demonstrated that the deletion of Slc2a5 promoted the differentiation of microglia into stroke-associated subpopulations with neuroprotective properties. Moreover, in vitro experiments indicated that this microglial differentiation process was primarily mediated by the activity of pyruvate kinase M2 (PKM2). Collectively, our findings unveil a novel microglial Slc2a5-mediated fructose metabolism pathway that exacerbates brain injury after AIS. This study provides evidence for SLC2A5 as a promising therapeutic target for the clinical treatment of AIS by offering insights into its critical role in microglial metabolism and neuroprotection.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe