Ceramide-FGF13 axis regulate nutrient sensing
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ABSTRACT:
PROVIDER: PRJNA997260 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32756100_1.fastq.gz | Fastqsanger.gz | |||
| SRR32756100_2.fastq.gz | Fastqsanger.gz | |||
| SRR32756101_1.fastq.gz | Fastqsanger.gz | |||
| SRR32756101_2.fastq.gz | Fastqsanger.gz | |||
| SRR32756102_1.fastq.gz | Fastqsanger.gz |
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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: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
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Project description:HEK293T cells were transfected with Flag-FGF13 plasmids, and cells were performed with immunoprecipitation by Flag antibody or IgG (CST, 3900, USA) with protein A/G beads (Meck, LSKMAGAG10, USA). Coimmunoprecipitation was carried out in HEK293T cells and visualized with silver staining by using the beyotime fast silver stain kit (P0017S). Then mass spectrometry was used to detect all the proteins connected with Flag-FGF13. The assay was carried by Shanghai Bioprofile Technology Company Ltd. In brief, the gradient consisted of 5~35% (v/v) acetonitrile in 0.1% (v/v) formic acid at a flow rate of 200 nL/min for 10 min, 35~100% (v/v) acetonitrile in 0.1% (v/v) formic acid at a flow rate of 200 nL/min for 2 min and 100% acetonitrile in 0.1% formic acid at a flow rate of 200 nL/min for 8 min. The eluted peptides were ionized and introduced into a Thermo Fisher LTQ Velos Pro mass spectrometer (Thermo Fisher Scientific, Bremen, Germany) using a Proxeon nanoelectrospray ion source. Survey full-scan MS spectra (from m/z 200~1800) were acquired. A full mass spectrum (m/z 200~1800) was followed by fragmentation of the ten most abundant peaks, using 35% of the normalized collision energy for obtaining MS/MS spectra. All peptide assignments were verified by manual inspection. The information about the proteins connected with Flag-FGF13 was summarized in Supplementary materials: Proteins connect with Flag-FGF13.‘’
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