When most people think about fat loss, one hormone dominates the conversation: insulin. And for good reason. Insulin is a powerful anabolic hormone that drives glucose uptake, promotes fat storage, and suppresses fat breakdown.
But insulin does not act alone.
There is another hormone—produced in the same pancreas, right next door to insulin—that works in direct opposition. That hormone is glucagon, and it plays a critical, often misunderstood role in fat burning and metabolic health.
In this Metabolic Classroom, I explore how glucagon works, clear up common misconceptions, and explain why modern metabolic therapies are increasingly leveraging glucagon to enhance fat loss and improve liver health.
Prefer to listen without the ads? Become a Ben Bikman Insider.
Insulin and Glucagon: A Metabolic Balancing Act
Insulin and glucagon are produced by neighboring cells within the pancreatic islets of Langerhans. Insulin is secreted by beta cells, while glucagon comes from alpha cells. Despite their proximity, these hormones have opposing roles.
- Insulin signals abundance. It promotes energy storage by driving glucose into cells, converting excess energy into fat, and suppressing fat breakdown.
- Glucagon signals scarcity. It tells the body to release stored energy by increasing glucose availability, promoting fat oxidation, and supporting ketone production.
Rather than focusing on insulin or glucagon in isolation, metabolic health is best understood through the insulin-to-glucagon ratio. This ratio determines whether the body is in storage mode or release mode.
After a carbohydrate-heavy meal, insulin rises and glucagon is suppressed—shifting metabolism toward storage. During fasting or carbohydrate restriction, insulin falls and glucagon rises—shifting metabolism toward fuel liberation and fat burning.
A Common Myth: Does Glucagon Burn Fat in Fat Cells?
For decades, textbooks and lectures taught that glucagon directly stimulates fat breakdown in adipose tissue. This idea largely came from early rodent studies showing that glucagon activates hormone-sensitive lipase in rat fat cells.
However, this mechanism does not translate well to humans.
Human adipose tissue expresses very low levels of glucagon receptors—often nearly undetectable in mature fat cells. Functional studies confirm this:
- When glucagon is infused into human subjects, even at levels several times higher than normal fasting concentrations, it does not meaningfully increase lipolysis in adipose tissue.
- Any lipolytic effect appears only at supraphysiological doses that the human body would never naturally produce.
The takeaway is simple: in humans, glucagon is not a primary driver of fat release from fat cells. That role is largely handled by low insulin levels and catecholamines like epinephrine.
So if glucagon isn’t burning fat in adipose tissue, where does it do its work?
The Liver: Where Glucagon Drives Fat Burning
The liver is the primary target organ for glucagon—and this is where its fat-burning effects become clear.
Hepatocytes are rich in glucagon receptors. When glucagon binds, it triggers signaling pathways that fundamentally shift liver metabolism:
- Fat synthesis is suppressed by inactivating acetyl-CoA carboxylase, reducing malonyl-CoA production.
- Fat oxidation is increased by removing inhibition on CPT-1, the enzyme that shuttles fatty acids into mitochondria.
- Mitochondrial capacity for fat burning increases, allowing incoming fatty acids to be oxidized rather than stored or exported.
Recent research has also shown that glucagon stimulates intrahepatic lipolysis, breaking down fat stored within the liver itself. Human studies demonstrate that glucagon infusion increases hepatic mitochondrial oxidation and improves markers of fatty liver disease.
In short, glucagon creates a metabolic environment in the liver that favors fat burning over fat storage.
Glucagon, Ketones, and the Role of Low Insulin
As liver fat oxidation increases, acetyl-CoA production rises. In the fed state, acetyl-CoA enters the TCA cycle. But during fasting or carbohydrate restriction, oxaloacetate is diverted toward glucose production.
The result? Ketone body formation.
Glucagon supports this process by increasing fatty acid oxidation and shifting hepatic metabolism toward ketogenesis. That said, research suggests that low insulin may be the permissive factor, with glucagon acting as an amplifier rather than the sole driver.
Once again, the insulin-to-glucagon ratio—not glucagon alone—determines metabolic outcomes.
Why New Weight-Loss Drugs Include Glucagon
This biology helps explain a major shift in metabolic medicine.
GLP-1 drugs like semaglutide are effective at reducing appetite and improving blood sugar control, but they don’t significantly increase energy expenditure. As weight is lost, metabolism often slows—a phenomenon known as metabolic adaptation.
Newer therapies are addressing this limitation by combining GLP-1 receptor activation with glucagon receptor agonism.
- GLP-1 reduces calorie intake.
- Glucagon helps maintain fat oxidation and energy expenditure—especially in the liver.
Clinical trials of dual and triple agonist drugs show greater weight loss, improved liver health, and better metabolic outcomes compared to GLP-1 alone. This combination directly leverages glucagon’s ability to keep fat-burning machinery active even as body weight drops.
The Practical Takeaway
Glucagon has lived in insulin’s shadow for far too long.
While insulin drives energy storage, glucagon enables energy release—especially through hepatic fat oxidation. In humans, glucagon’s primary role in fat burning occurs in the liver, not in fat cells, and its effectiveness depends heavily on keeping insulin low.
Strategies that naturally support healthy glucagon signaling include:
- Reducing refined carbohydrate intake
- Practicing time-restricted eating or intermittent fasting
- Maintaining insulin sensitivity through movement and resistance training
Fat loss isn’t about eliminating insulin—it’s about restoring balance.
Lower insulin.
Let glucagon do its job.