⚗️Biological Chemistry II Unit 7 – Hormonal Regulation of Metabolism

Key Hormones and Their Functions

• Insulin promotes glucose uptake and storage, stimulates lipogenesis, and inhibits lipolysis and gluconeogenesis
• Glucagon stimulates glycogenolysis and gluconeogenesis, increasing blood glucose levels during fasting or hypoglycemia
• Thyroid hormones (T3 and T4) increase basal metabolic rate, stimulate protein synthesis, and enhance lipid and carbohydrate metabolism
  • T3 (triiodothyronine) is the more active form of thyroid hormone
  • T4 (thyroxine) is the prohormone that is converted to T3 in target tissues
• Growth hormone (GH) promotes protein synthesis, lipolysis, and insulin resistance, stimulating growth and development
• Cortisol, a glucocorticoid, enhances gluconeogenesis, promotes protein catabolism, and modulates immune responses
• Epinephrine and norepinephrine, catecholamines, stimulate glycogenolysis, lipolysis, and increase heart rate and blood pressure during stress
• Adiponectin, secreted by adipocytes, enhances insulin sensitivity, stimulates fatty acid oxidation, and has anti-inflammatory properties

Endocrine Glands and Hormone Production

• The hypothalamus releases releasing hormones (e.g., TRH, CRH) that stimulate or inhibit the anterior pituitary gland
• The anterior pituitary gland secretes trophic hormones (e.g., TSH, ACTH, GH) that regulate the function of other endocrine glands
• The thyroid gland produces T3 and T4 in response to TSH stimulation, which are essential for regulating metabolism and development
• The adrenal glands consist of the adrenal cortex and medulla
  • The adrenal cortex secretes glucocorticoids (cortisol), mineralocorticoids (aldosterone), and androgens
  • The adrenal medulla releases catecholamines (epinephrine and norepinephrine) in response to stress
• The pancreas contains islets of Langerhans, which include $\alpha$-cells (secrete glucagon) and $\beta$-cells (secrete insulin)
• Adipose tissue, an endocrine organ, secretes adipokines (e.g., leptin, adiponectin) that regulate energy balance and insulin sensitivity

Hormone Receptors and Signaling Pathways

• Lipid-soluble hormones (e.g., thyroid hormones, steroid hormones) diffuse through the cell membrane and bind to intracellular receptors
  • Hormone-receptor complexes translocate to the nucleus and act as transcription factors, regulating gene expression
• Water-soluble hormones (e.g., insulin, glucagon) bind to cell surface receptors, initiating intracellular signaling cascades
• G protein-coupled receptors (GPCRs) are activated by hormones like glucagon and catecholamines, leading to the production of second messengers (cAMP, IP3, DAG)
  • cAMP activates protein kinase A (PKA), which phosphorylates target proteins and regulates metabolic enzymes
• Receptor tyrosine kinases (RTKs), such as the insulin receptor, undergo autophosphorylation upon ligand binding and activate downstream signaling pathways (PI3K/Akt, MAPK)
• Insulin signaling involves the phosphorylation of insulin receptor substrates (IRS) and activation of PI3K/Akt pathway, leading to glucose uptake and storage
• Glucagon signaling activates adenylate cyclase, increasing cAMP levels and activating PKA, which stimulates glycogenolysis and gluconeogenesis

Metabolic Pathways Affected by Hormones

• Glycolysis is stimulated by insulin, which increases the expression and activity of glycolytic enzymes (e.g., glucokinase, phosphofructokinase)
• Gluconeogenesis is promoted by glucagon and cortisol, which upregulate key enzymes (e.g., PEPCK, glucose-6-phosphatase)
• Glycogenolysis is stimulated by glucagon and catecholamines, activating glycogen phosphorylase and releasing glucose from glycogen stores
• Lipogenesis is enhanced by insulin, which activates acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), promoting the synthesis of fatty acids
• Lipolysis is stimulated by glucagon, catecholamines, and growth hormone, activating hormone-sensitive lipase (HSL) and releasing free fatty acids from triglycerides
• Protein synthesis is promoted by insulin and growth hormone, which activate mTOR signaling and stimulate ribosomal activity
• Protein catabolism is enhanced by cortisol and thyroid hormones, which increase the expression of proteolytic enzymes and amino acid transporters

Glucose Homeostasis and Insulin Action

• Blood glucose levels are tightly regulated within a narrow range (70-110 mg/dL) by the actions of insulin and glucagon
• Insulin is secreted by pancreatic $\beta$-cells in response to elevated blood glucose levels (e.g., after a meal)
  • Insulin stimulates glucose uptake by skeletal muscle and adipose tissue via GLUT4 translocation
  • Insulin promotes glycogenesis in the liver and muscle, storing excess glucose as glycogen
• Insulin resistance occurs when tissues become less responsive to insulin, leading to hyperglycemia and compensatory hyperinsulinemia
• Glucagon is released by pancreatic $\alpha$-cells during fasting or hypoglycemia, stimulating hepatic glucose production
  • Glucagon activates glycogenolysis, releasing glucose from liver glycogen stores
  • Glucagon promotes gluconeogenesis, synthesizing glucose from non-carbohydrate precursors (amino acids, lactate, glycerol)
• The hypothalamus senses changes in blood glucose levels and regulates insulin and glucagon secretion via the autonomic nervous system

Lipid Metabolism Regulation

• Insulin promotes lipogenesis in adipose tissue and the liver, stimulating the synthesis of fatty acids and triglycerides
  • Insulin activates lipoprotein lipase (LPL), which hydrolyzes triglycerides in circulating lipoproteins, releasing fatty acids for uptake by adipocytes
• Glucagon, catecholamines, and growth hormone stimulate lipolysis, releasing free fatty acids from adipose tissue
  • Hormone-sensitive lipase (HSL) is activated by PKA phosphorylation, hydrolyzing triglycerides into fatty acids and glycerol
• Thyroid hormones increase the expression of LDL receptors, enhancing the clearance of LDL cholesterol from the circulation
• Cortisol promotes lipolysis and the redistribution of fat from peripheral to central adipose depots, contributing to insulin resistance
• Adiponectin, an adipokine, stimulates fatty acid oxidation in muscle and liver, reducing triglyceride accumulation and improving insulin sensitivity

Protein Metabolism and Hormonal Control

• Insulin and growth hormone stimulate protein synthesis by activating the mTOR signaling pathway
  • mTOR phosphorylates ribosomal protein S6 kinase (S6K) and eIF4E-binding protein (4E-BP1), enhancing translation initiation
• Insulin inhibits protein catabolism by suppressing the expression of ubiquitin-proteasome system components and autophagy-related genes
• Glucagon and cortisol promote protein catabolism during fasting or stress, providing amino acids for gluconeogenesis
  • Cortisol upregulates the expression of proteolytic enzymes (e.g., cathepsins, calpains) and amino acid transporters
• Thyroid hormones stimulate protein synthesis and increase the basal metabolic rate, enhancing the turnover of proteins in various tissues
• Growth hormone has anabolic effects on protein metabolism, stimulating the synthesis of insulin-like growth factor-1 (IGF-1) in the liver and other tissues
  • IGF-1 mediates many of the growth-promoting effects of growth hormone, stimulating cell proliferation and differentiation

Hormonal Imbalances and Metabolic Disorders

• Diabetes mellitus is characterized by hyperglycemia resulting from insulin deficiency (type 1) or insulin resistance (type 2)
  • Chronic hyperglycemia leads to complications such as neuropathy, nephropathy, and retinopathy
• Metabolic syndrome is a cluster of conditions (abdominal obesity, insulin resistance, dyslipidemia, hypertension) that increase the risk of type 2 diabetes and cardiovascular disease
• Cushing's syndrome, caused by excessive cortisol production, results in central obesity, insulin resistance, and muscle wasting
• Hypothyroidism, a deficiency of thyroid hormones, leads to decreased basal metabolic rate, weight gain, and hypercholesterolemia
• Hyperthyroidism, an excess of thyroid hormones, causes increased basal metabolic rate, weight loss, and tachycardia
• Growth hormone deficiency in children results in short stature and delayed puberty, while adult-onset deficiency leads to increased body fat and decreased muscle mass
• Acromegaly, caused by excessive growth hormone secretion in adults, results in the enlargement of hands, feet, and facial features, as well as insulin resistance and cardiovascular complications