Ceramide regulated intracellular FGF13 impairs adipose nutrient sensing and glucose metabolism
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ABSTRACT:
PROVIDER: PRJNA790647 | ENA |
REPOSITORIES: ENA
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Project description:Although, ectopic ceramide accumulation impairs nutrient sensing in adipocytes, leading to deterioration in energy and glucose homeostasis, the underlying mechanisms remain poorly defined. Using, comparative screen to identify ceramide regulated effector molecule in adipose tissue, we found fibroblast growth factor 13 (FGF13) as one of the critical ceramide-effector molecules that impair nutrient sensing in adipocytes. FGF13 is a cytosolic, non-secreted FGF belonging to a non-canonical FGF family member that comprises of FGF11-FGF14 and do not activate FGF receptors. FGF13 has been implicated in numerous physiological process such as development, cardiac arrythmias, neurological disease and cancer. We demonstrate that FGF13 expression is highly induced in adipose tissue in response to a high fat diet, and its expression is negated by pharmacological and genetic interventions that inhibit ceramide biosynthesis. Inhibition of FGF13 in adipocytes (white, brown and beige), alters adipocyte morphology, prevents the development of obesity, improves glucose homeostasis, insulin sensitivity and resolves hepatic steatosis
2024-12-12 | GSE191233 | GEO
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Project description:Ceramide accumulation impairs adipocytes’ ability to efficiently store and utilize nutrients, leading to energy and glucose homeostasis deterioration. Using a comparative transcriptomic screen, we identified the non-canonical, non-secreted fibroblast growth factor FGF13 as a ceramide-regulated factor that impairs adipocyte function. Obesity robustly induces FGF13 expression in adipose tissue in mice and humans and is positively associated with glycemic indices of type 2 diabetes. Pharmacological or genetic inhibition of ceramide biosynthesis reduces FGF13 expression. Using mice with loss and gain-of-function of FGF13, we demonstrate that FGF13 is both necessary and sufficient to impair energy and glucose homeostasis independent of ceramides. Mechanistically, FGF13 exerts these effects by inhibiting mitochondrial content and function, metabolic elasticity, and caveolae formation, which cumulatively impairs glucose utilization and thermogenesis. These studies suggest the therapeutic potential of targeting FGF13 to prevent and treat metabolic diseases.
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Project description:Angiogenesis is a tightly regulated process essential for both development and disease, yet the role of fibroblast growth factor 13 (FGF13) in vascular remodeling has remained unclear. Here, we identify FGF13 as a key negative regulator of physiological and pathological angiogenesis. Using endothelial cell–specific knockout and overexpression mouse models, combined with retinal vascularization assays, hindlimb ischemia and myocardial infarction models, and in vitro endothelial cell functional assays, we demonstrate that loss of FGF13 enhances, whereas its overexpression impairs, neovascularization. Mechanistically, FGF13 binds to the PAS domain of HIF-1α and facilitates its interaction with RACK1, leading to oxygen-independent degradation of HIF-1α and suppression of downstream angiogenic signaling. Importantly, adenoviral overexpression of HIF-1α reversed the inhibitory effects of FGF13, confirming its essential role in mediating FGF13-driven angiogenic regulation. These findings reveal FGF13 as a critical endothelial-intrinsic brake on angiogenesis and suggest its potential as a therapeutic target in ischemic vascular disease.
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Project description:Angiogenesis is a tightly regulated process essential for both development and disease, yet the role of fibroblast growth factor 13 (FGF13) in vascular remodeling has remained unclear. Here, we identify FGF13 as a key negative regulator of physiological and pathological angiogenesis. Using endothelial cell–specific knockout and overexpression mouse models, combined with retinal vascularization assays, hindlimb ischemia and myocardial infarction models, and in vitro endothelial cell functional assays, we demonstrate that loss of FGF13 enhances, whereas its overexpression impairs, neovascularization. Mechanistically, FGF13 binds to the PAS domain of HIF-1α and facilitates its interaction with RACK1, leading to oxygen-independent degradation of HIF-1α and suppression of downstream angiogenic signaling. Importantly, adenoviral overexpression of HIF-1α reversed the inhibitory effects of FGF13, confirming its essential role in mediating FGF13-driven angiogenic regulation. These findings reveal FGF13 as a critical endothelial-intrinsic brake on angiogenesis and suggest its potential as a therapeutic target in ischemic vascular disease.
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Project description:The purpose of our study was to explore the relevance of the FGF13 protein in a NSCLC cell line
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Project description:The bioactive sphingolipid ceramide, generated by ceramide synthase, is an adaptive stress effector induced in response to various stress stimuli such as aging. In fact, ceramide synthase (CerS) was first discovered in yeast as a longevity assurance gene (LAG1), as the reduced ceramide generation consequent to LAG1 deletion increased longevity. There are six homologues of mammalian LAG1/ceramide synthases (CerS1-6) that generate ceramides with different fatty acid chain lengths with distinct functions and hydrophobicity. Ceramide can be metabolized by sphingosine kinase 1 or 2 for the generation of pro-survival sphingosine 1-phosphate (S1P), which enhances immune cell egress to the blood stream, activating immune function. Ceramide is known to induce mitophagy and cell death. Here we investigated the role of this sphingolipid pathway in immune function, specifically T cell functions, via high throughput expression profiling.
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