Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

Abstract

Integrative Physiology, a section of the journal Frontiers in PhysiologyMetabolic 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.

Single-cell dissection of obesity-exercise axis in adipose-muscle tissues

“…A recent report showed MSC-produced ECM components potentiate MSC response to differentiation stimuli through intracellular signaling pathway activation 71 . We observed the receptor tyrosine kinase (RTK) signaling pathway, a mediator of fundamental cellular and metabolic signaling pathways in response to growth factors, hormones, and cytokines 72 , tracks ECM changes in ASCs and FAPs. Interestingly, both the activity and substrate specificity of RTK signaling can be strongly influenced by ECM interactions, and controlled by ECM biochemistry and stiffness 73 .…”

Impact of obesity on the molecular response to a single bout of exercise in a preliminary human cohort

“…Lean individuals increased receptor tyrosine kinase signaling after exercise, whereas individuals with obesity did not. Interestingly, dysregulated receptor tyrosine kinase signaling has been implicated in obesity and is the focus of ongoing research (30,31). In individuals with obesity, GSEA identified decreased levels of protein translation together with increased proteasomal activity.…”

Soluble LRIG2 is a potential biomarker for type 2 diabetes mellitus

“…EGFR signaling enhances aerobic glycolysis in cancer cells (30,31). Furthermore, inhibition of EGFR signaling was shown to improve insulin sensitivity in several studies (14,32). Reportedly, treatment with the specific EGFR inhibitor, PD153035, reduced fasting glucose and fasting insulin, and improved glucose intolerance and insulin resistance in high-fat diet (HFD)-fed mice (15).…”