Leptin is secreted by adipocytes in proportion to fat mass. In diet-induced obesity, leptin resistance develops. The PRIMARY intracellular mechanism of leptin resistance involves:

• A Downregulation of leptin receptor (LepR) expression in the arcuate nucleus due to chronic receptor occupancy
• B Induction of SOCS3 (suppressor of cytokine signalling 3) by leptin itself, which inhibits JAK2 phosphorylation of STAT3 ✓
• C Increased expression of protein tyrosine phosphatase 1B (PTP1B) in hypothalamic neurons dephosphorylating JAK2
• D Reduced adiponectin competing with leptin for hypothalamic LepRb binding

Explanation

Leptin signals via LepRb, activating JAK2 which phosphorylates STAT3, inducing POMC and suppressing AgRP in the arcuate nucleus. Leptin itself induces SOCS3 as a negative feedback mechanism; in chronic hyperleptinemia of obesity, SOCS3 is chronically upregulated and persistently suppresses JAK2 activity, creating a state of functional leptin resistance despite high circulating leptin. PTP1B also contributes (option C is partly true), but SOCS3 induction is the primary, leptin-driven mechanism of feedback resistance. Adiponectin uses a different receptor (AdipoR1/R2).

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

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