The Metabolic Classroom with Dr. Ben Bikman

GLP-1 Isn’t Enough: Why Glucagon is the Key to Lasting Weight Loss

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Dec 22, 2025

Discover the often-overlooked role of glucagon, insulin's counterbalance, in weight loss. Learn how glucagon promotes fat burning primarily in the liver, enhancing ketone production and energy expenditure. Ben Bikman challenges the myth that glucagon directly releases fat from adipose tissue. Recent studies reveal that combining GLP-1 with glucagon can lead to superior weight loss results, suppressing appetite while boosting metabolism. Practical tips include lowering carbs and fasting to naturally enhance glucagon's benefits.

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INSIGHT

Pancreatic Tug Of War Determines Metabolism

Insulin and glucagon are neighboring pancreatic hormones that act in constant opposition to determine storage versus release of energy.
The insulin-to-glucagon ratio is the metabolic fulcrum dictating whether your body stores fat or burns it.

INSIGHT

Glucagon Doesn't Pull Fat From Human Fat

The long-held idea that glucagon directly triggers fat release from human adipose tissue is a rodent-derived misconception.
Human white fat has very low glucagon receptor expression, so physiological glucagon does not meaningfully increase lipolysis.

INSIGHT

Liver Is Glucagon's Fat-Burning Hub

Glucagon's primary fat-burning action in humans occurs in the liver, not adipose tissue.
It activates cAMP/PKA signaling to inhibit fat synthesis and remove inhibition of CPT1, enabling mitochondrial fat oxidation.

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In this lecture, Dr. Ben Bikman explores the misunderstood role of glucagon, insulin’s often-overlooked metabolic counterpart.

While insulin encourages fat storage and glucose uptake, glucagon signals the body to mobilize and burn stored energy. Contrary to popular belief, glucagon does not stimulate fat release from adipose tissue in humans. Instead, its fat-burning effects occur primarily in the liver, where it enhances fatty acid oxidation, ketone production, and energy expenditure.

Glucagon’s power lies in shifting the metabolic balance through the insulin-to-glucagon ratio—a key determinant of whether the body stores or burns fat. Ben also unpacks the liver's molecular response to glucagon, including activation of mitochondrial fat-burning enzymes and ketone formation. Human studies now confirm that glucagon increases liver fat oxidation, making it a valuable target in new weight-loss drugs.

New dual and triple agonist drugs that combine GLP-1 with glucagon receptors show superior weight loss outcomes compared to GLP-1 alone. They not only suppress appetite but also increase metabolic rate, making them potent tools in fighting obesity and fatty liver disease. However, lifestyle strategies like fasting and low-carb diets remain powerful ways to naturally leverage glucagon’s benefits without pharmaceutical intervention.

Show Notes/References:

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NOTE: The information presented is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Dr. Bikman is not a clinician—and, he is not your doctor. Always seek the advice of your own qualified health providers with questions you may have regarding medical conditions.

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