Normal Insulin Signaling in Adipose Tissue
Insulin normally keeps stored fat locked inside fat cells.
- 5–10: Fasting insulin (healthy) (µIU/mL)
- ~95%: Lipolysis suppression (by postprandial insulin)
- ~200k: Adipocyte insulin receptors (per cell)
- Low: HSL activity (fed state) (hormone-sensitive lipase)
Insulin binds the adipocyte receptor
Insulin locks onto its receptor on fat cells.
Signaling shuts down lipolysis
PI3K-Akt signaling inhibits hormone-sensitive lipase.
Healthy insulin action keeps 95% of stored fat locked away.
Fat storage stays balanced
Fat is stored and released only when truly needed.
Adipose Tissue Becomes Insulin Resistant
Fat cells stop hearing insulin's signal clearly.
- 40–70%: Receptor signaling loss (in resistant adipocytes)
- Obesity: Common driver (visceral fat expansion)
- TNF-α, IL-6: Inflammatory cytokines (impair signaling)
- Months–yrs: Onset timescale (gradual progression)
Receptor signaling weakens
Chronic inflammation blunts the insulin receptor cascade.
Inflammation drives dysfunction
Enlarged fat cells release inflammatory signals locally.
Visceral fat expansion is a major trigger of resistance.
Suppression of lipolysis fails
Insulin can no longer hold hormone-sensitive lipase back.
Unrestrained Adipose Lipolysis
Fat cells begin releasing fatty acids continuously.
- High: HSL activity (unchecked by insulin)
- 2–3×: FFA release rate (above normal)
- Elevated: Glycerol co-release (lipolysis byproduct)
- >600: Circulating FFA (µmol/L (elevated))
Hormone-sensitive lipase runs free
Triglycerides inside adipocytes are broken apart rapidly.
Fatty acids spill into blood
Free fatty acids exit fat cells faster than they're cleared.
Unchecked lipolysis can double or triple normal FFA output.
A vicious cycle begins
Rising FFAs further worsen insulin resistance elsewhere.
Free Fatty Acid Flux into the Liver
Fatty acids travel via the bloodstream straight to the liver.
- ↑↑: Portal FFA delivery (direct venous route)
- ~80%: Hepatic FFA uptake (of circulating FFA extracted)
- FATP, CD36: Uptake transporters (fatty acid carriers)
- ~60%: Source of liver fat (from adipose lipolysis)
Portal blood carries the surge
Visceral fat drains fatty acids directly into the portal vein.
Hepatocytes absorb the excess
Liver cells take up fatty acids via CD36 and FATP transporters.
Most fat found in a fatty liver comes from adipose lipolysis.
Liver capacity is overwhelmed
Incoming fatty acids exceed the liver's oxidation capacity.
De Novo Lipogenesis and Triglyceride Storage
The liver converts surplus fatty acids into stored fat droplets.
- >5%: Hepatic TG content (defines fatty liver)
- ~26%: De novo lipogenesis share (of liver fat in NAFLD)
- SREBP-1c: Key lipogenic enzyme (drives fat synthesis)
- ~30%: Global NAFLD prevalence (of adults)
Excess FFAs are re-esterified
Hepatocytes package fatty acids into triglycerides for storage.
Lipogenic genes switch on
SREBP-1c drives new fat synthesis from excess substrate.
Hepatic steatosis begins once liver fat exceeds 5% by weight.
Fat droplets accumulate visibly
Triglyceride droplets build up inside liver cells over time.