15.2 Hormonal control of metabolism

Pancreatic Hormones

Insulin and Glucagon

Insulin and glucagon are the two primary hormones the pancreas uses to keep blood glucose within a narrow range. They work in opposition: insulin lowers blood glucose, and glucagon raises it.

Insulin is secreted by beta cells of the pancreatic islets when blood glucose rises (typically after a meal). It promotes glucose uptake into cells and drives storage pathways:

• Glycogenesis in liver and muscle (glucose → glycogen)
• Lipogenesis in adipose tissue (glucose → fatty acids → triacylglycerols)
• Increased amino acid uptake and protein synthesis

Mechanistically, insulin binds its receptor tyrosine kinase on the cell surface, triggering autophosphorylation and recruitment of insulin receptor substrates (IRS proteins). This activates the PI3K/Akt pathway, which stimulates translocation of GLUT4 transporters to the plasma membrane in muscle and adipose tissue, allowing glucose entry.

Glucagon is secreted by alpha cells when blood glucose drops (during fasting). It acts primarily on the liver to raise blood glucose through:

• Glycogenolysis (glycogen → glucose)
• Gluconeogenesis (non-carbohydrate precursors → glucose)

Glucagon binds a G protein-coupled receptor (GPCR) on hepatocytes, activating adenylyl cyclase and raising intracellular cAMP. This activates protein kinase A (PKA), which phosphorylates downstream targets to promote glucose release.

Receptor-Mediated Signaling and Hormone-Sensitive Enzymes

Both insulin and glucagon ultimately change the activity of key metabolic enzymes, largely through phosphorylation and dephosphorylation. Understanding which enzymes are active in which phosphorylation state is critical.

Insulin also works at the level of gene expression, upregulating transcription of glucokinase, fatty acid synthase, and other anabolic enzymes through transcription factors like SREBP-1c.

Metabolic Switch

The opposing actions of insulin and glucagon create a "metabolic switch" between two broad states:

• Fed state (high insulin, low glucagon): Anabolic processes dominate. Glucose is taken up by tissues, glycogen is synthesized, lipogenesis proceeds, and catabolic pathways like gluconeogenesis and lipolysis are suppressed.
• Fasting state (low insulin, high glucagon): Catabolic processes dominate. The liver breaks down glycogen and ramps up gluconeogenesis to maintain blood glucose. Adipose tissue releases fatty acids via lipolysis, and the liver produces ketone bodies during prolonged fasting.

The ratio of insulin to glucagon (not the absolute level of either hormone alone) is what determines which metabolic programs are active. A high insulin-to-glucagon ratio favors storage; a low ratio favors mobilization.

Stress and Energy Hormones

Cortisol and Epinephrine

These hormones are released by the adrenal glands during physical or psychological stress and shift metabolism toward energy mobilization.

Cortisol is a glucocorticoid (steroid hormone) released from the adrenal cortex. Because it's lipophilic, it crosses the plasma membrane and binds an intracellular receptor that acts as a transcription factor. Its metabolic effects include:

• Stimulating gluconeogenesis in the liver (upregulates PEPCK and glucose-6-phosphatase)
• Promoting proteolysis in muscle to supply amino acid substrates for gluconeogenesis
• Reducing glucose uptake in peripheral tissues (insulin-antagonistic effect)
• Stimulating lipolysis in adipose tissue

Cortisol acts on a timescale of hours because it works through changes in gene transcription. It also has anti-inflammatory and immunosuppressive effects, which is why synthetic glucocorticoids are used clinically.

Epinephrine (adrenaline) is a catecholamine released from the adrenal medulla. It signals through GPCRs (both $\alpha$ and $\beta$ adrenergic receptors), activating the cAMP/PKA pathway similarly to glucagon. Its metabolic effects are rapid (seconds to minutes):

• Glycogenolysis in liver and skeletal muscle (glucagon only acts on the liver)
• Lipolysis in adipose tissue
• Increased heart rate, blood pressure, and bronchodilation to support the "fight or flight" response

A key distinction: epinephrine activates glycogen phosphorylase in muscle, but the resulting glucose-6-phosphate is used locally for glycolysis (muscle lacks glucose-6-phosphatase and cannot export free glucose). In the liver, glucose-6-phosphate is converted to free glucose and released into the blood.

Thyroid Hormones and Growth Hormone

Thyroid hormones ($T_3$ and $T_4$) are produced by the thyroid gland. $T_4$ is the more abundant circulating form, but $T_3$ is the more biologically active form ($T_4$ is converted to $T_3$ by deiodinases in peripheral tissues). Both are derived from tyrosine and require iodine for synthesis.

Their metabolic effects include:

• Increasing basal metabolic rate by upregulating $Na^+/K^+$-ATPase activity and mitochondrial uncoupling proteins
• Stimulating glucose and fatty acid oxidation, increasing $O_2$ consumption and heat production
• Promoting protein synthesis and normal growth and development (especially brain development in early life)

Thyroid hormones bind intracellular nuclear receptors (thyroid hormone receptors, TRs) that regulate gene transcription, so their effects develop over days to weeks.

Growth hormone (GH) is secreted by the anterior pituitary and has both direct and indirect metabolic effects. Many of its growth-promoting effects are mediated by insulin-like growth factor 1 (IGF-1), produced mainly by the liver.

• Stimulates protein synthesis and tissue growth (muscle, bone)
• Promotes lipolysis and fatty acid oxidation
• Has anti-insulin effects on glucose metabolism: reduces glucose uptake in peripheral tissues and stimulates hepatic gluconeogenesis, raising blood glucose

This anti-insulin action is why excess GH (acromegaly in adults, gigantism in children) can cause insulin resistance and hyperglycemia. GH deficiency in children leads to short stature.

Appetite Regulation Hormones

Leptin and Ghrelin

These two hormones form a feedback system that regulates appetite and long-term energy balance, acting primarily on the hypothalamus (specifically the arcuate nucleus).

Leptin is produced by adipose tissue in proportion to fat mass. It functions as a long-term "fuel gauge":

• Signals to the hypothalamus that energy stores are sufficient
• Suppresses appetite (inhibits NPY/AgRP neurons, activates POMC/CART neurons)
• Increases energy expenditure and sympathetic nervous system activity

In obesity, leptin levels are actually high (because there's more adipose tissue), but the hypothalamus becomes less responsive. This leptin resistance blunts the satiety signal, contributing to continued overeating despite large fat stores. The mechanism involves impaired leptin receptor signaling and reduced transport of leptin across the blood-brain barrier.

Ghrelin is produced primarily by the stomach and acts as a short-term hunger signal:

• Levels rise before meals and drop after eating
• Stimulates appetite by activating NPY/AgRP neurons in the hypothalamus
• Promotes GH secretion from the anterior pituitary (ghrelin was originally identified as the "growth hormone secretagogue")

The balance between leptin and ghrelin helps maintain energy homeostasis. Disruptions in either signal, whether from leptin resistance, bariatric surgery (which alters ghrelin secretion), or genetic mutations in leptin or its receptor, can significantly affect body weight regulation and contribute to obesity or eating disorders.