Pathophysiology

Pathophysiology

I-6. Adipose tissue function and dysfunction

脂肪組織の機能と機能障害

Types of Adipose Tissue

  • Brown (BAT): thermogenesis via fatty-acid oxidation; newborns and upper body in adults.
  • White (WAT): insulation, energy storage as TAG, energy release in starvation/activity.
    • Subcutaneous (sWAT): upper body (abdominal, limb, breast) + lower (gluteofemoral).
    • Visceral (vWAT): around internal organs.
  • Beige (BeAT): BAT+WAT features; reversibly produced from WAT on cold exposure.

Physiology of White Adipose Tissue

Components: adipocytes, pre-adipocytes, endothelial cells, fibroblasts, macrophages, immune cells.

  • Lipolysis–lipogenesis homeostasis: circulating glucose/FFA → adipocyte uptake → TAG synthesis (lipid droplets); when energy is needed, TAG → FFA + glycerol → circulation (liver, muscle).
  • Insulin sensitivity: insulin promotes lipogenesis, inhibits lipolysis (inhibits PKA → blocks FFA release). If insulin fails to act, lipolysis dominates → continuous FFA release.
  • Secretory functions: endocrine/auto-/paracrine hormones, miRNAs, exosomes, complement factors.

Adipocytokines

  • Adiponectin (“good guy”): very high plasma levels, mainly sWAT (lower body), higher in women.
    • Endocrine: insulin sensitizer in liver (↓gluconeogenesis, ↓fibrosis) and muscle (↑glucose uptake, ↑FA oxidation); cardioprotection (eNOS); anti-inflammatory.
    • Auto/paracrine: lipogenic, promotes adipogenesis, anti-inflammatory.
  • Leptin: mainly sWAT, higher in women; correlates with fat mass (energy sensor).
    • CNS: inhibits food intake, ↑energy expenditure; acts on thyroid, SYM NS, BAT.
    • CNS-independent: insulin sensitizer (muscle, liver, fat), inhibits β-cell insulin production.
    • Immune: pro-inflammatory; implicated in tumorigenesis.
  • Resistin (“bad guy”): mainly from macrophages; induces insulin resistance; pro-inflammatory.

Adipose Tissue Expansion: Hyperplasia vs Hypertrophy

When overeating exceeds the adipocyte TAG storage limit:

  • Successful adipogenesis → hyperplasia (new cells).
  • Unsuccessful adipogenesis → hypertrophy (existing cells enlarge).

Hyperplasia (healthy expansion)

  • Pre-adipocytes differentiate → ↑cell number → extra storage capacity (sWAT has higher adipogenic capacity).
  • Key factors: PPARγ (↑/normal adiponectin — pharmacological target), SREBP1c (↑lipogenic enzymes).
  • Metabolic/secretory function normal: normal adiponectin, normal insulin sensitivity.
  • Supportive cells: angiogenesis coupled to adipogenesis (avoids hypoxia), ECM remodeling (avoids fibrosis), favorable immune profile (M2 macrophages, eosinophils, Th2, anti-inflammatory cytokines).

Hypertrophy (unhealthy expansion)

  • ↑Cell size → ↑membrane rigidity (rupture), disrupted signaling.
  • Deteriorating function: ↓adiponectin, ↑leptin/TNF-α, ↓insulin sensitivity → ↑lipolysis → FFA leakage.
  • Necrosis-like death → macrophage infiltration, crown-like structures.
  • Supportive cells fail: insufficient angiogenesis → hypoxia; insufficient ECM remodeling → fibrosis; unfavorable immune profile (M1 macrophages, neutrophils, Th1, pro-inflammatory IL-6/TNF-α/resistin).

💡 The core problem is not the amount of fat (initially) but the metabolic health of the adipose tissue — raising the idea of “metabolically healthy obesity,” which holds for a time but can later progress to an unhealthy state.

一問一答

▶What are the three types of adipose tissue and their functions?

Brown (BAT): thermogenesis via FA oxidation; White (WAT): insulation/energy storage as TAG; Beige (BeAT): reversibly produced from WAT on cold exposure with BAT+WAT features.

▶What distinguishes subcutaneous from visceral white adipose tissue?

Subcutaneous (sWAT): upper body + gluteofemoral, higher adipogenic capacity (healthier); visceral (vWAT): around internal organs, higher metabolic risk.

▶How does insulin regulate lipolysis and lipogenesis in adipocytes?

Insulin promotes lipogenesis and inhibits lipolysis (inhibits PKA → blocks FFA release); if insulin fails to act, lipolysis dominates → continuous FFA release.

▶What are the functions of adiponectin (the "good guy")?

Insulin sensitizer (↓hepatic gluconeogenesis, ↑muscle glucose uptake/FA oxidation), cardioprotective (eNOS), anti-inflammatory, and promotes adipogenesis; highest in lower-body sWAT and in women.

▶What are the functions of leptin?

Energy sensor correlating with fat mass: CNS effects (inhibits food intake, ↑energy expenditure), insulin sensitizer (CNS-independent), and pro-inflammatory/immune actions.

▶What is resistin and its effect?

An adipocytokine mainly from macrophages (the "bad guy") that induces insulin resistance and is pro-inflammatory.

▶What is the difference between hyperplasia and hypertrophy in adipose expansion?

Hyperplasia = successful adipogenesis forming new cells (healthy); hypertrophy = unsuccessful adipogenesis with existing cells enlarging (unhealthy).

▶Why is hyperplastic (healthy) adipose expansion metabolically favorable?

Pre-adipocytes differentiate to add storage capacity with normal adiponectin and insulin sensitivity, coupled angiogenesis (no hypoxia), ECM remodeling (no fibrosis), and an M2/Th2 anti-inflammatory profile.

▶What key transcription factors drive healthy adipogenesis?

PPARγ (maintains adiponectin — a pharmacological target) and SREBP1c (↑lipogenic enzymes).

▶What characterizes hypertrophic (unhealthy) adipose expansion?

Enlarged cells with rigid membranes (rupture), ↓adiponectin, ↑leptin/TNF-α, ↓insulin sensitivity → FFA leakage, plus hypoxia, fibrosis, and an M1/Th1 pro-inflammatory profile with crown-like structures.

▶What are "crown-like structures" in adipose tissue?

Macrophages infiltrating around necrosis-like dying hypertrophic adipocytes, a hallmark of inflamed adipose tissue.

▶What is the concept of "metabolically healthy obesity"?

The core problem is initially the metabolic health of the adipose tissue rather than the amount of fat; healthy (hyperplastic) expansion can be metabolically healthy for a time but may later progress to an unhealthy state.

▶What are the secretory functions of white adipose tissue?

It is an endocrine organ secreting hormones (adipocytokines), miRNAs, exosomes, and complement factors with endocrine, autocrine, and paracrine actions.

▶Describe the lipolysis–lipogenesis homeostasis of WAT.

Adipocytes take up circulating glucose/FFA to synthesize TAG (lipid droplets); when energy is needed, TAG breaks down to FFA + glycerol released to the circulation for liver and muscle.

▶Where is brown adipose tissue found, and what is its main mechanism?

In newborns and the upper body of adults; it generates heat via fatty-acid oxidation (thermogenesis).

▶Why does hypertrophic adipose tissue become hypoxic and fibrotic?

Cell enlargement outpaces insufficient angiogenesis (→ hypoxia) and insufficient ECM remodeling (→ fibrosis).

▶What cell types make up white adipose tissue besides adipocytes?

Pre-adipocytes, endothelial cells, fibroblasts, macrophages, and immune cells.

▶What triggers FFA leakage from hypertrophic adipose tissue?

Reduced insulin sensitivity means lipolysis is no longer suppressed → continuous FFA release into the circulation.

▶How does the immune profile differ between healthy and unhealthy adipose tissue?

Healthy: M2 macrophages, eosinophils, Th2, anti-inflammatory cytokines. Unhealthy: M1 macrophages, neutrophils, Th1, pro-inflammatory IL-6/TNF-α/resistin.

▶Why does adiponectin decrease and leptin increase in obesity?

Hypertrophic, dysfunctional adipocytes downregulate protective adiponectin while overproducing leptin (and TNF-α), contributing to insulin resistance and inflammation.