Major Hormones Regulating Obesity

1. Leptin (THE central regulator)

• Source: Adipose tissue
• Mechanism: Secretion is proportional to fat mass. Binds receptors in the arcuate nucleus of the hypothalamus, decreasing appetite and increasing energy expenditure by:
  • Stimulating POMC/CART neurons (anorexigenic - suppress food intake)
  • Inhibiting NPY/AgRP neurons (orexigenic - stimulate food intake)
• In obesity: Leptin levels are chronically elevated but the brain becomes leptin resistant - the response to rising leptin is blunted, while falling leptin (during weight loss) is a powerful hunger stimulus. This asymmetry explains why diets fail and weight rebounds.
• Key concept: Leptin acts as an adipostat - it regulates both short-term (post-meal satiety lasting hours) and long-term (body fat set-point) food intake.
• • Harrison's Principles of Internal Medicine 22E (2025)

2. Ghrelin ("The Hunger Hormone")

• Source: Stomach (primarily), intestine, hypothalamus, pancreas
• Active form: Acyl-ghrelin (the orexigenic form)
• Mechanism: Acts via G-protein coupled receptors widely distributed in hypothalamus, pituitary, pancreas, and gut. Activates NPY/AgRP neurons to stimulate appetite.
• Pattern:
  • Levels rise with fasting, weight loss, and caloric restriction
  • Levels fall after feeding and in obese subjects
  • IV administration induces hunger and increases oral intake
• Therapeutic relevance: Ghrelin antibodies and receptor antagonists are under investigation as anti-obesity agents.
• • Mulholland & Greenfield's Surgery: Scientific Principles and Practice, 7e

3. Insulin

• Source: Pancreatic β-cells
• Role in obesity: A key afferent signal to the hypothalamus. Acts as both an anorexigenic signal (suppressing appetite at the hypothalamus) and a major driver of fat storage. In obesity, insulin resistance develops, creating a vicious cycle - more insulin is secreted, promoting further fat deposition.
• • Robbins, Cotran & Kumar Pathologic Basis of Disease

4. GLP-1 and GIP (Incretins)

• Source: Enteroendocrine cells of the intestine (L-cells produce GLP-1; K-cells produce GIP)
• Mechanism:
  • Stimulate insulin secretion from pancreatic β-cells (incretin effect)
  • GLP-1 also reduces appetite by acting on hypothalamic receptors and slowing gastric emptying
• Clinical importance: GLP-1 receptor agonists (e.g., semaglutide, liraglutide) and dual GLP-1/GIP agonists (tirzepatide) are among the most effective current anti-obesity drugs, with proven benefits also in heart failure and renal disease.
• • Robbins, Cotran & Kumar Pathologic Basis of Disease

5. Peptide YY (PYY)

• Source: L-cells of the ileum and colon (released post-meal)
• Mechanism: An anorexigenic gut hormone that suppresses appetite by acting on the arcuate nucleus. Levels are lower in obese individuals.

6. Adiponectin

• Source: Adipose tissue
• Role: An anti-obesity adipokine. Increases insulin sensitivity, stimulates fatty acid oxidation, and has anti-inflammatory effects. Levels are paradoxically decreased in obesity despite excess adipose tissue - this contributes to insulin resistance and metabolic syndrome.
• • Mulholland & Greenfield's Surgery; Histology: A Text and Atlas

7. Neuropeptide Y (NPY) and AgRP - Hypothalamic Mediators

• These are not peripheral hormones but are critical central mediators within the arcuate nucleus:
  • NPY/AgRP neurons: Orexigenic - stimulate food intake, reduce energy expenditure
  • POMC/CART neurons: Anorexigenic - suppress food intake, increase energy expenditure
• All peripheral hormones ultimately act through these two neuronal populations.
• • Mulholland & Greenfield's Surgery, 7e

8. Other Adipokines and Gut Peptides

• • Mulholland & Greenfield's Surgery, 7e

Summary: Hormonal Imbalance in Obesity