Overview of growth differentiation factor 15 in metabolic syndrome

Abstract

Growth and differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) superfamily. GDF15 has been linked with several metabolic syndrome pathologies such as obesity and cardiovascular diseases. GDF15 is considered to be a metabolic regulator, although its precise mechanisms of action remain to be determined. Glial cell-derived neurotrophic factor family receptor alpha-like (GRAL), located in the hindbrain, has been identified as the receptor for GDF15 and signals through the coreceptor receptor tyrosine kinase (RET). Administration of GDF15 analogues in preclinical studies using various animal models has consistently been shown to induce weight loss through a reduction in food intake. GDF15, therefore, represents an attractive target to combat the current global obesity epidemic. In this article, we review current knowledge on GDF15 and its involvement in metabolic syndrome.

Keywords: growth differentiation factor 15; inflammatory state; metabolic syndrome; obesity.

FIGURE 1

Molecular pathways of GDF15 as cardiometabolic protector. (A) GDF15 expression can be promoted by stress stimuli as well as beneficial stimuli such as exercise or metformin. Those activate downstream signalling pathways converging to phosphorylation of eIF2α, which activates ATF4 to stimulate CHOP and induce GDF15 expression, maturation and secretion. GDF 15 circulates in the blood and target heart and other organs to prevent several metabolic diseases such as obesity, liver steatosis or hypertrophic cardiomyopathy. (B) It binds ALK and EGFR receptor thereby activating several signalling pathways to induce cardiac protection. (C) It also has central effect by binding GFRAL‐RET complex receptor, thereby inhibiting food intake. (D) GDF‐15 also modulates metabolic homeostasis through its action on liver and adipose tissue. ALK, anaplastic lymphoma kinase; ATF4, activating transcription factor 4; CHOP, C/EBP‐homologous protein; eIF2α, eukaryotic initiation factor 2α; GFRAL‐RET, glial cell‐derived neurotrophic factor receptor alpha‐like and the receptor tyrosine kinase RET.

FIGURE 2

Pleiotropic effect of GDF15 on brain, heart, liver, pancreas and adipose tissue. (A) GDF15 reduces macrophages accumulation and ICAM expression which overall improves atherosclerotic plaque stability. (B) Signalling pathways triggered by GDF15 in heart including PI3K, AKT, PERK, FOXO, NF‐kB prevents myocardial hypertrophy and decreases the size of infarcted area during ischemia. (C) In the brain, specifically in the area postrema, when binding to its receptor GFRAL, GDF15 allow RET recruitment and formation of the GDF15‐GFRAL‐RET complex. In turn, it activates intracellular signalling, meanwhile pERK, pAkt and pPLC, hence driving decreased energy intake and obesity seemingly through taste aversion, nausea, food preference and a delay in gastric emptying. (D) The protective effects of GDF15 on liver is likely associated with an increased triglycerides export through VLDL, increased fatty acids oxidation, decreased reactive oxygen species. Altogether these effects reduce inflammation and fibrosis thus preventing steatosis, but the exact mechanism remains unclear since the peripheric receptor has not been identified yet. (E) GDF15 induces weight loss through a direct central effect on the brain, resulting in decreased appetite, food intake and increased lipolysis. (F) GDF15 inhibits macrophage recruiting and inflammatory state in adipose tissue through yet an unknown mechanism. (G) Mitochondria stress and others concomitant stress stimulate GDF15 production, which, in turn, inhibits expression of inflammatory factors and drives an immune‐metabolic homeostasis. AKT, serine/threonine kinase; FOXO, Forkhead box O; NF‐kB, nuclear factor‐kappa B; PERK, protein kinase R‐like ER kinase; PI3K, phosphatidylinositol 3‐kinase; VLDL, very low‐density lipoprotein.