Nuclear receptors and AMPK: can exercise mimetics cure diabetes?

Abstract

Endurance exercise can lead to systemic improvements in insulin sensitivity and metabolic homeostasis, and is an effective approach to combat metabolic diseases. Pharmacological compounds that recapitulate the beneficial effects of exercise, also known as 'exercise mimetics', have the potential to improve disease symptoms of metabolic syndrome. These drugs, which can increase energy expenditure, suppress hepatic gluconeogenesis, and induce insulin sensitization, have accordingly been highly scrutinized for their utility in treating metabolic diseases including diabetes. Nevertheless, the identity of an efficacious exercise mimetic still remains elusive. In this review, we highlight several nuclear receptors and cofactors that are putative molecular targets for exercise mimetics, and review recent studies that provide advancements in our mechanistic understanding of how exercise mimetics exert their beneficial effects. We also discuss evidence from clinical trials using these compounds in human subjects to evaluate their efficacy in treating diabetes.

Keywords: AMPK; PGC1α; PPARs; diabetes; exercise mimetics; nuclear receptors; sirtuins.

Figure 1. Unified pathways for exercise mimetics

Compounds, either endogenous or synthetic, that can recapitulate the benefits of exercise (red dots) interact with several different parts of a unified nuclear receptor/cofactor transcriptional complex that promotes the expression of genes that maintain metabolic homeostasis. Direct ligands for nuclear receptors (GW501516, fatty acids, and TZDs), activators of the nuclear receptor cofactor PGC1 alpha AMPK and SIRT1 (AICAR and metformin, and nicotinamide riboside, PARP inhibitors, and resveratrol respectively) promote the expression of nuclear receptor target genes (FGF21, adiponectin, FGF1, and irisin) which can be secreted to function as endocrine hormones with peripheral effects. Comprehensively, these exercise mimetics can promote endurance in skeletal muscle, lower blood glucose levels, increase fatty acid metabolism, suppress hepatic gluconeogenesis, and cause browning of white fat into beige fat.