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In this Metabolic Classroom lecture, Dr. Bikman explains how rare genetic forms of obesity—known as monogenic obesity—reveal deep insights into how the body stores fat and why the “calories in, calories out” model falls short.

He introduces three genetic conditions—leptin deficiency, POMC deficiency, and MC4R mutations—that disrupt appetite control and fat storage, all while keeping calorie intake the same. These disorders highlight how hormonal imbalances, especially chronically elevated insulin, play the decisive role in whether energy is stored or burned.

Ben walks through the hypothalamic POMC pathway, a brain circuit central to hunger and metabolism. Disruptions in this pathway don’t just make people feel constantly hungry; they reprogram the entire body to hoard calories as fat, even when calorie intake is strictly controlled. Animal and human studies consistently show that these conditions drive dramatic fat gain without an increase in food consumption, clearly separating energy intake from energy storage.

In all three conditions, the common endpoint is hyperinsulinemia—chronically elevated insulin levels—which drives fat storage and insulin resistance. Whether leptin is missing, POMC signals are silenced, or MC4R is defective, insulin surges as the body shifts into extreme conservation mode. This reinforces the idea that obesity is often less about willpower and more about hormonal signaling. Understanding these rare conditions sheds light on more common forms of obesity and reveals that insulin—not just calories—is the gatekeeper of fat storage.

Show Notes/References:

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