Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

Abstract

Metabolic diseases, such as diabetes, obesity, and fatty liver disease, have now reached epidemic proportions. Receptor tyrosine kinases (RTKs) are a family of cell surface receptors responding to growth factors, hormones, and cytokines to mediate a diverse set of fundamental cellular and metabolic signaling pathways. These ligands signal by endocrine, paracrine, or autocrine means in peripheral organs and in the central nervous system to control cellular and tissue-specific metabolic processes. Interestingly, the expression of many RTKs and their ligands are controlled by changes in metabolic demand, for example, during starvation, feeding, or obesity. In addition, studies of RTKs and their ligands in regulating energy homeostasis have revealed unexpected diversity in the mechanisms of action and their specific metabolic functions. Our current understanding of the molecular, biochemical and genetic control of energy homeostasis by the endocrine RTK ligands insulin, FGF21 and FGF19 are now relatively well understood. In addition to these classical endocrine signals, non-endocrine ligands can govern local energy regulation, and the intriguing crosstalk between the RTK family and the TGFβ receptor family demonstrates a signaling network that diversifies metabolic process between tissues. Thus, there is a need to increase our molecular and mechanistic understanding of signal diversification of RTK actions in metabolic disease. Here we review the known and emerging molecular mechanisms of RTK signaling that regulate systemic glucose and lipid metabolism, as well as highlighting unexpected roles of non-classical RTK ligands that crosstalk with other receptor pathways.

Keywords: glucose; lipids; metabolism; receptor tyrosine kinases; signaling.

FIGURE 1

Control of glucose and lipid metabolism by RTK ligands. The schematic figure shows the diversity of functions mediated by RTK ligands and their respective receptors and their tissues of action. EGF binds EGFR to induce lipogenesis in the liver, and increase TG secretion (Scheving et al., 2014). NRG1 acts on ErbB3 and/or ErbB4 to inhibit gluconeogenesis in the liver (Ennequin et al., 2015; Zhang et al., 2018), and to increase glucose uptake and oxidative phosphorylation in myotubes (Canto et al., 2004, 2007; Suárez et al., 2001). NRG1 also decrease food intake by acting on ErbB4 in the brain (Ennequin et al., 2015; Zhang et al., 2018). NRG4 acts on ErbB3 and/or ErbB4 to induce β-oxidation and inhibit de novo lipogenesis in liver (Chen et al., 2017). Insulin acts via the insulin receptor to increase glucose uptake in all metabolic tissues while suppressing gluconeogenesis and inducing lipogenesis in the liver (Saltiel and Kahn, 2001; Samuel and Shulman, 2016; Vecchio et al., 2018). PDGF-AA acts through PDGFR-α and/or PDGFR-β to suppress hepatocyte insulin sensitivity (Abderrahmani et al., 2018), while PDGF-BB decreases insulin sensitivity in both the liver and white adipose tissue (Raines et al., 2011; Onogi et al., 2017). SCF promotes Pgc1α transcription and mitochondrial biogenesis in brown fat (Huang et al., 2014). CSF1 acts on CSF1R and induces lipid droplet gene expression, lipid accumulation, and increases hepatic Kupffer cells in the liver (Gow et al., 2014; Pridans et al., 2018). FGF1 acts on FGFR1 in the brain to suppress food intake (Suh et al., 2014; Scarlett et al., 2016). FGF5 acts on FGFR1 to suppress lipid accumulation in the liver (Hanaka et al., 2014). FGF10 acts on FGFR2 to increase adipogenesis in adipocytes (Sakaue et al., 2002; Asaki et al., 2004). FGF19 binds to β-Klotho/FGFR1/4 to induce β-oxidation, increase hepatic glycogen and protein synthesis, reduce lipogenesis in white adipose tissue; suppress food intake and improve glucose tolerance through actions in the brain (Tomlinson et al., 2002; Fu et al., 2004; Marcelin et al., 2014; Perry et al., 2015). FGF21 binds to FGFR1/β-Klotho to induce fatty acid (FA) oxidation, decrease triglycerides and improve insulin sensitivity in liver. FGF21 also increases glucose uptake, energy expenditure and improves insulin sensitivity by acting on muscle and adipose tissue. FGF21 inhibits food intake through central effects (Kharitonenkov et al., 2005; Coskun et al., 2008; Xu et al., 2009; Ge et al., 2011; Fisher et al., 2012; Bookout et al., 2013; Minard et al., 2016; BonDurant et al., 2017). HGF activates MET which induces glucose uptake in both adipocytes and myotubes (Bertola et al., 2007; Perdomo et al., 2008) decreases lipid accumulation in liver (Kosone et al., 2007), and increases glycogen synthesis and glucose uptake in hepatocytes (Fafalios et al., 2011). MSP binds to RON to inhibit lipid accumulation in the liver (Stuart et al., 2015; Chanda et al., 2016). GAS6 activates TAM receptor family members to decrease β-oxidation and increase inflammation in the liver (Fourcot et al., 2011). GDF15 acts on RET/GFRAL to induce mitochondrial respiration, lipolysis, and β-oxidation in both the liver and in adipose tissue (Chung et al., 2017). GDF15 also acts on the brain to suppress appetite (Tsai et al., 2013, 2014; Hsu et al., 2017; Yang et al., 2017; Patel et al., 2019).