Circulating α-klotho regulates metabolism via distinct central and peripheral mechanisms

Emerging evidence implicates the circulating alpha-klotho protein as a prominent regulator of energy balance and substrate metabolism, with diverse, tissue-specific functions. Despite its well-documented ubiquitous role inhibiting insulin signaling, alpha-klotho elicits potent antidiabetic and anti-obesogenic effects. alpha-Klotho facilitates insulin release and promotes beta cell health in the pancreas, stimulates lipid oxidation in liver and adipose tissue, attenuates hepatic gluconeogenesis, and increases whole-body energy expenditure. The mechanisms underlying alpha-klotho's peripheral functions are multifaceted, including hydrolyzing transient receptor potential channels, stimulating integrin beta 1 -> focal adhesion kinase signaling, and activating PPAR alpha via inhibition of insulin-like growth factor receptor 1. Moreover, until recently, potential metabolic roles of alpha-klotho in the central nervous system remained unexplored; however, a novel alpha-klotho -> fibroblast growth factor receptor -> PI3kinase signaling axis in the arcuate nucleus of the hypothalamus has been identified as a critical regulator of energy balance and glucose metabolism. Overall, the role of circulating alpha-klotho in the regulation of metabolism is a new focus of research, but accumulating evidence identifies this protein as an encouraging therapeutic target for Type 1 and 2 Diabetes and obesity. This review analyzes the new literature investigating alpha-klotho-mediated regulation of metabolism and proposes impactful future directions to progress our understanding of this complex metabolic protein. (C) 2021 Elsevier Inc. All rights reserved.