Hormones coordinate metabolic activity across different tissues, ensuring that energy supply meets demand. The major metabolic hormones act through specific receptors and signaling pathways to regulate enzyme activity, gene expression, and substrate transport in a tissue-specific manner.
Insulin
Insulin is the primary anabolic hormone, secreted by pancreatic beta cells in response to elevated blood glucose and amino acid levels, playing a central role in glucose homeostasis. It promotes the storage of fuels by stimulating glucose uptake in muscle and adipose tissue, glycogen synthesis in liver and muscle, lipogenesis in adipose tissue and liver, and protein synthesis in muscle. Insulin inhibits glycogenolysis, gluconeogenesis, and lipolysis. The insulin receptor is a receptor tyrosine kinase that activates IRS proteins, leading to PI3K-AKT and MAPK signaling cascades. AKT phosphorylates FOXO transcription factors, excluding them from the nucleus and suppressing gluconeogenic gene expression, and also promotes GLUT4 translocation to the plasma membrane.
Glucagon
Glucagon is the primary catabolic hormone, secreted by pancreatic alpha cells when blood glucose falls. It acts mainly on the liver to stimulate glycogenolysis and gluconeogenesis, raising blood glucose. Glucagon also activates lipolysis in adipose tissue and ketogenesis in the liver during prolonged fasting. The glucagon receptor is a G protein-coupled receptor that activates adenylyl cyclase, increasing cAMP and activating protein kinase A. PKA phosphorylates and activates glycogen phosphorylase while inhibiting glycogen synthase, switching the liver from glucose storage to glucose production.
Epinephrine and Norepinephrine
Catecholamines released from the adrenal medulla and sympathetic nerve terminals provide rapid metabolic responses to stress, exercise, and hypoglycemia. Epinephrine acts through beta-adrenergic receptors to increase cAMP, stimulating glycogenolysis in both liver and muscle, mobilizing fatty acids from adipose tissue, and increasing heart rate and metabolic rate. Unlike glucagon, which acts only on the liver, epinephrine mobilizes glucose from both hepatic glycogenolysis and muscle glycogenolysis, with muscle glucose being used locally rather than released into the circulation.
Cortisol
Cortisol is a glucocorticoid hormone released from the adrenal cortex in response to stress and low blood glucose, regulated by the hypothalamic-pituitary-adrenal axis. Cortisol exerts permissive and direct effects on metabolism. It stimulates gluconeogenesis in the liver by inducing the expression of key enzymes such as PEP carboxykinase and glucose-6-phosphatase. It promotes protein catabolism in muscle, providing amino acids for gluconeogenesis, and stimulates lipolysis in adipose tissue. Cortisol also antagonizes insulin action, contributing to insulin resistance when chronically elevated. Its effects develop more slowly than those of insulin and glucagon because they involve changes in gene expression.
Growth Hormone
Growth hormone is secreted by the anterior pituitary and has complex metabolic effects. It stimulates protein synthesis and muscle growth, but during fasting it promotes lipolysis and fatty acid utilization while antagonizing insulin-mediated glucose uptake. Growth hormone stimulates the liver to produce insulin-like growth factor 1, which mediates many of its growth-promoting effects. The metabolic effects of growth hormone are mediated through JAK-STAT signaling, with STAT5 regulating target gene transcription.
Thyroid Hormones
Thyroid hormones, thyroxine and triiodothyronine, regulate basal metabolic rate by controlling the expression of genes involved in energy metabolism. T3 increases oxygen consumption and heat production in most tissues by inducing uncoupling proteins and stimulating Na+/K+-ATPase activity. Thyroid hormones also promote carbohydrate and lipid metabolism, increasing the rate of glucose absorption, glycolysis, gluconeogenesis, and lipolysis. Hyperthyroidism causes weight loss and increased metabolic rate, while hypothyroidism causes weight gain and lethargy.
Leptin and Adipokines
Leptin is secreted by adipose tissue in proportion to fat mass and signals energy sufficiency to the hypothalamus. It suppresses appetite and increases energy expenditure through activation of melanocortin pathways. Leptin also regulates peripheral metabolism by improving insulin sensitivity and promoting fatty acid oxidation. Adiponectin, another adipokine, enhances insulin sensitivity and fatty acid oxidation. Leptin deficiency or resistance contributes to obesity and metabolic syndrome.
