Leptin is produced by adipocytes and acts on the hypothalamus. In diet-induced obesity, a state of leptin resistance occurs. The PRIMARY intracellular mechanism of leptin resistance involves:

• A Upregulation of SOCS3 (suppressor of cytokine signalling 3) which inhibits JAK2/STAT3 leptin signalling ✓
• B Downregulation of ObR (leptin receptor) due to receptor internalisation
• C Reduction in adiponectin levels, competitively blocking the leptin receptor
• D Excessive phosphorylation of AMPK inhibiting hypothalamic leptin signalling

Explanation

Leptin signals through its receptor (ObRb) via JAK2–STAT3 pathway in the hypothalamus. STAT3 activation induces SOCS3 expression as a negative feedback loop; in chronic obesity with sustained hyperleptinemia, SOCS3 is persistently upregulated and inhibits JAK2 activation, creating a state of leptin resistance where the brain fails to respond despite elevated serum leptin. Protein tyrosine phosphatase 1B (PTP1B) also contributes to leptin resistance.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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