Growth differentiation factor 15 as a potential therapeutic for treating obesity

Abstract

Background Obesity is rapidly becoming one of the world's most critical health care concerns. Comorbidities accompanying excess weight include cardiovascular disease, diabetes, and certain cancers. These comorbidities result in greater hospitalization and other health care-related costs. Economic impacts are likely to be felt more acutely in developing countries, where obesity rates continue to rise and health care resources are already insufficient. Some of the more effective treatments are invasive and expensive surgeries, which some economies in the world cannot afford to offer to a broad population. Pharmacological therapies are needed to supplement treatment options for patients who cannot, or will not, undergo surgical treatment. However, the few drug therapies currently available have either limited efficacy or safety concerns. A possible exception has been glucagon-like peptide-1 analogs, although these have shown a number of adverse events. New drug therapies that are safe and produce robust weight loss are needed. Scope of review Herein, we review the role of growth differentiation factor 15 (GDF15) in feeding behavior and obesity, summarize some of the new and exciting biological discoveries around signaling pathways and tissue sites of action, and highlight initial efforts to develop GDF15-based therapies suitable for inducing weight loss in humans. Major conclusions Within the last several years, great strides have been made in understanding the biology of GDF15. Recent developments include identification of an endogenous receptor, biological localization of the receptor system, impact on energy homeostasis, and identification of molecules suitable for administration to humans as anti-obesity treatments. New and exciting research on GDF15 suggests that it holds promise as a novel obesity treatment as new molecules progress toward clinical development.

Anti-obesity drug discovery: advances and challenges

“…Macrophage inhibitory cytokine 1 (MIC1; also known as GDF15) has gained attention as a target for obesity treatment 267 . GDF15 is a divergent member of the transforming growth factor-β (TGFβ) superfamily 267 .…”

“…Macrophage inhibitory cytokine 1 (MIC1; also known as GDF15) has gained attention as a target for obesity treatment 267 . GDF15 is a divergent member of the transforming growth factor-β (TGFβ) superfamily 267 . Physiologically, GDF15 is expressed in multiple tissues at a low concentration, but increases in response to or association with tissue injury, cancer, metabolic disease, CVD and inflammation 267 , 268 .…”

Dysregulated Inflammation During Obesity: Driving Disease Severity in Influenza Virus and SARS-CoV-2 Infections

“…In brief, long-term treatment with hFGF21 analogues have been shown to reduce dyslipidaemia, enhance insulin sensitivity and reduce body weight in clinical trials (236). In addition, preclinical obesity studies have shown treatment with GDF15 decreases food intake and body weight (283). However, the benefit of augmented FGF21 and GDF15 treatment in reducing risk for severe IAV and SARS-CoV-2 infection in obesity has not yet been explored.…”

The role of pro-domains in human growth factors and cytokines

“…Insulin C-peptide has been widely used as a proxy for secreted insulin due to its higher serum stability, yet it does appear to also have bioactivity of its own [63]. Some of the GFs have been demonstrated, at least in animal models of disease, to have potential for human therapy [64,65]. GDNF and the related family member Neurturin for the treatment of Parkinson's disease [66], Neurturin, as a potential key growth hormone in pancreas development, in diabetes, as well as GDF15 for obesity are particularly notable examples.…”