leptin resistance

Leptin resistance is a puzzling situation where the body has plenty of the “fullness” hormone leptin, yet the brain acts as if it has too little. It is like a smoke alarm with dead batteries: the smoke (lots of fat and lots of leptin) is there, but the warning never gets through, so appetite is not properly suppressed.

In most obesity, leptin levels are high because there is a lot of fat tissue making it. Logically that should curb appetite, but in practice the hypothalamic neurons respond poorly. Proposed mechanisms include reduced transport of leptin across the blood–brain barrier, inflammation and cellular stress in hypothalamic neurons, and intracellular brakes on leptin's signaling pathway. The result is a brain that perceives a relative energy deficit even amid surplus, driving continued eating and a defended higher weight.

Leptin resistance is a major reason why giving extra leptin does not treat common obesity — the system is already saturated and unresponsive. It also helps explain why weight loss is so hard to maintain: as fat shrinks and leptin falls, the still-resistant brain reads the drop as starvation and ramps up hunger.