The Metabolic Classroom with Dr. Ben Bikman

The Real Cause of Fat Gain: Genetics, Hormones, and Insulin

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Aug 18, 2025

Delving into the intriguing world of obesity, experts reveal how genetics and hormones play pivotal roles in fat storage, challenging the conventional 'calories in, calories out' view. Learn about monogenic obesity and specific genetic conditions that disrupt appetite control. The hypothalamic POMC pathway is highlighted, showcasing how it regulates hunger and metabolism. Crucially, chronically elevated insulin levels are identified as major players in energy storage, further illuminating the complex relationship between our biology and weight management.

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INSIGHT

Insulin As The Gatekeeper Of Fat

Insulin is the primary hormonal signal that determines whether calories get stored as fat or burned.
Elevated insulin drives adipocytes to take up and lock away triglycerides while blocking lipolysis.

INSIGHT

POMC Pathway Controls Appetite And Energy

The hypothalamic POMC pathway balances hunger and energy expenditure via two opposing neuron sets.
POMC neurons produce alpha-MSH which activates MC4R to suppress appetite and increase energy use.

ANECDOTE

Leptin Mutations Mimic Starvation

Leptin or leptin receptor mutations make the brain think the body is starving, driving extreme hunger.
This genetic defect appears in infancy and causes profound, early-onset obesity.

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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.

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