Pathophysiology of Obesity

Pathophysiology of Obesity

Pathophysiology of Obesity

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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).

Android and Gynoid Body Fat Distribution

⭐ 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:
HormoneSourcePrimary ActionLevel/Effect in Obesity
LeptinAdipose tissueSatiety↑, Resistance (key feature)
GhrelinStomachHungerOften not suppressed post-meal
InsulinPancreasGlucose uptake, fat storage↑, Resistance
GLP-1GutSatiety, ↑ insulin secretionPotentially ↓
PYYGutSatietyPotentially ↓
CCKGutSatiety, ↓ gastric emptyingPotentially altered

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

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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.

Adipokines and their effects on various organs

⭐ 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 Pathophysiology & Bioactive Food Components

⭐ 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.

Practice Questions: Pathophysiology of Obesity

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Flashcards: Pathophysiology of Obesity

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