Abstract
The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor activates intracellular signaling cascades involving the enzymes extracellular signal-regulated protein kinase-1/2 (ERK1/2), phosphatidylinositol 3-kinase, protein kinase B/Akt, and phospholipase Cγ as signal transducers. Insulin receptor stimulation is correlated with multiple physiological and biochemical functions, including glucose transport, glucose homeostasis, food intake, proliferation, glycolysis, and lipogenesis. This review article focuses on the activation of gene transcription as a result of insulin receptor stimulation. Signal transducers such as protein kinases or the GLUT4-induced influx of glucose connect insulin receptor stimulation with transcription. We discuss insulin-responsive transcription factors that respond to insulin receptor activation and generate a transcriptional network executing the metabolic functions of insulin. Importantly, insulin receptor stimulation induces transcription of genes encoding essential enzymes of glycolysis and lipogenesis and inhibits genes encoding essential enzymes of gluconeogenesis. Overall, the activation or inhibition of insulin-responsive transcription factors is an essential aspect of orchestrating a wide range of insulin-induced changes in the biochemistry and physiology of insulin-responsive tissues.
Highlights
Insulin and the Insulin ReceptorThe hormone insulin was discovered 100 years ago, starting scientific exploration of the regulation of metabolic pathways by hormones
The best example is the regulation of the fatty acid synthase gene by Upstream Stimulatory Factor (USF), SREBP, Liver X receptor, and carbohydrate response element-binding protein (ChREBP)
There is a negative feedback loop involving the inhibition of SREBP-1c expression and transcriptional activity by FoxO1
Summary
The hormone insulin was discovered 100 years ago, starting scientific exploration of the regulation of metabolic pathways by hormones. Insulin, synthesized and secreted by pancreatic β-cells, is the key hormone for regulating glucose homeostasis. It lowers hepatic gluconeogenesis and stimulates glucose uptake into adipocytes and skeletal muscle. The insulin receptor is a receptor tyrosine kinase, which is formed by a tetramer with two α and two β subunits. Insulin binding activates the enzymatic function of the receptor, leading to a transphosphorylation and a further increase in kinase activity, allowing the tyrosine phosphorylation of several insulin receptor substrates that are connected with various signaling cascades within the cell. The article outlines how the activity of several transcription factors executes the function of insulin in regulating many cellular activities, including cell growth, lipogenesis, and homeostasis
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