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GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease | Nature Reviews Endocrinology
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Growth differentiation factor 15 (GDF15) is a member of the TGFβ superfamily whose expression is increased in response to cellular stress and disease as well as by metformin. Elevations in GDF15 reduce food intake and body mass in animal models through binding to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and the recruitment of the receptor tyrosine kinase RET in the hindbrain. This effect is largely independent of other appetite-regulating hormones (for example, leptin, ghrelin or glucagon-like peptide 1). Consistent with an important role for the GDF15–GFRAL signalling axis, some human genetic studies support an interrelationship with human obesity. Furthermore, findings in both mice and humans have shown that metformin and exercise increase circulating levels of GDF15. GDF15 might also exert anti-inflammatory effects through mechanisms that are not fully understood. These unique and distinct mechanisms for suppressing food intake and inflammation makes GDF15 an appealing candidate to treat many metabolic diseases, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular disease and cancer cachexia. Here, we review the mechanisms regulating GDF15 production and secretion, GDF15 signalling in different cell types, and how GDF15-targeted pharmaceutical approaches might be effective in the treatment of metabolic diseases. The expression of growth differentiation factor 15 (GDF15) is increased under conditions of cellular stress as well as by metformin and exercise. This Review highlights mechanisms of GDF15 production and secretion, GDF15 signalling, and the relevance of GDF15 in obesity and metabolic diseases.
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nature portfolio journals permissions reprints growth/differentiation factor-15/macrophage-inhibiting cytokine-1 nature portfolio privacy policy chr=19&end=18549986&phenotype=whradjbmi&start=18435541 advertising author information authors liver disease research social media long-acting mic-1/gdf15 molecules inflammation-induced central mediator org/ensg00000187871-gfral/blood glossary wellcome open res scientific statement tgf-beta superfamily member body mass index gdf15–gfral signalling axis t-cell senescence contributes open heart 4 tgf-β signaling pathway amp-activated protein kinase insulin/igf-1/mtor signaling superfamily cytokine mic-1/gdf15 diabetes research research conducted medical research cryo-em analyses reveal author correspondence mic-1/gdf15-gfral pathway received consulting/speaking fees diet-induced obese rats growth-differentiation factor 15 growth differentiation factor-15 growth-differentiation factor-15 growth differentiation factor nature+ nature 578 nature 575 nature 550 nature 444 nature 503 nature 558 nature 407 nature genome-wide association studies human mic-1/gdf15 vary exert anti-inflammatory effects tgf-beta superfamily gdf15-targeted pharmaceutical approaches
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