Pathophysiology of Obesity

Definitions & Classification - Sizing Up the Scale

• BMI Categories (kg/m²): $BMI = weight (kg) / height (m^2)$
  • WHO: Overweight 25-29.9; Obese I 30-34.9; II 35-39.9; III ≥ 40
  • Asian-Indian: Overweight 23-24.9; Obese ≥ 25
• Waist Circumference (Central Obesity Risk):
  • Men: > 102 cm (> 90 cm Asian)
  • Women: > 88 cm (> 80 cm Asian)
• Fat Distribution:
  • Android (apple): Central fat, ↑ metabolic risk.
  • Gynoid (pear): Peripheral fat (hips/thighs).

⭐ WHR (Waist-to-hip ratio) > BMI for CVD risk. Men > 0.90, Women > 0.85.

Etiology of Obesity - The Why & How

• Genetic Predisposition:
  • Polygenic: FTO gene is a significant common variant.
  • Monogenic (rare): e.g., MC4R mutations, leptin/leptin receptor defects.
• Environmental Influences:
  • Obesogenic environment: Pervasive availability of high-calorie, palatable foods.
  • Dietary patterns: High intake of processed foods, sugary drinks, unhealthy fats; low fiber.
  • Lifestyle: Increased sedentary behavior, reduced physical activity.
• Socioeconomic Status: Complex interaction, influences food choices & activity.
• Medications Inducing Weight Gain:
  • E.g., Corticosteroids, antipsychotics (olanzapine), some antidepressants, insulin.

⭐ The FTO gene is the strongest known common genetic susceptibility factor for obesity.

Hormonal Dysregulation - Appetite's Orchestra

Appetite is centrally regulated by the hypothalamus, primarily the arcuate nucleus. It houses:

• Anorexigenic POMC/CART neurons (promote satiety).
• Orexigenic AgRP/NPY neurons (promote hunger). Dysregulation of key peripheral hormones contributes significantly to obesity:

⭐ Leptin resistance, rather than deficiency, is a hallmark of common human obesity.

Adipose Tissue Dysfunction - More Than Storage

• Adipose tissue: an active endocrine organ, not just storage. Secretes adipokines:
  • Adiponectin: ↓ in obesity; anti-inflammatory, insulin-sensitizing.
  • Leptin: ↑ in obesity (leptin resistance); pro-inflammatory at high levels.
  • Resistin: ↑; pro-inflammatory, promotes insulin resistance.
  • TNF-α (Tumor Necrosis Factor-alpha): ↑; pro-inflammatory, contributes to insulin resistance.
  • IL-6 (Interleukin-6): ↑; pro-inflammatory.
• Increased macrophage infiltration (M1 polarization) fuels chronic low-grade inflammation.
• Lipotoxicity (excess free fatty acids) impairs cellular function, leading to insulin resistance.

⭐ Visceral adipose tissue is more metabolically active and pathogenic than subcutaneous adipose tissue.

Systemic Complications - Systemic Strikes

• Metabolic Syndrome: (IDF/AHA/NHLBI) Central obesity + 2 of:
  • ↑Triglycerides: $\ge$ 150 mg/dL
  • ↓HDL-C: < 40 mg/dL (men), < 50 mg/dL (women)
  • ↑BP: $\ge$ 130 / $\ge$ 85 mmHg
  • ↑Fasting Glucose: $\ge$ 100 mg/dL
• Endocrine: Type 2 Diabetes (T2DM), Polycystic Ovary Syndrome (PCOS).
• Cardiovascular: Hypertension, Coronary Artery Disease (CAD), Stroke.
• Hepatic: Non-alcoholic fatty liver disease (NAFLD/NASH).
• Respiratory: Obstructive Sleep Apnea (OSA).
• Musculoskeletal: Osteoarthritis.
• Oncologic: ↑Risk: colorectal, breast (post-menopause), endometrial cancers.
• Lipids: Dyslipidemia (↑TG, ↓HDL, ↑small dense LDL).

⭐ Obesity is a leading cause of preventable non-communicable diseases worldwide.

High-Yield Points - ⚡ Biggest Takeaways

• Obesity: chronic, relapsing disease; multifactorial etiology (genetic, environmental, hormonal).
• Adipose tissue: an active endocrine organ secreting adipokines (leptin, adiponectin).
• Leptin resistance (not deficiency) is common, causing failed satiety signals.
• Ghrelin (stomach): primary orexigenic hormone, stimulates appetite.
• Insulin resistance: key metabolic derangement linking obesity to T2DM.
• Chronic low-grade inflammation (macrophage infiltration in adipose tissue) drives complications.
• Gut microbiome alterations (dysbiosis) implicated in energy homeostasis and obesity development.