Lauren Gatta

One of the underlying principles of the ketogenic diet — similar to the popular paleo diet — is that the body can shift from burning carbohydrates to burning fat while in starvation mode. People on the keto diet stop eating carbs, thereby forcing their bodies to burn fat instead.

Yale researchers have uncovered new information about how this shift in metabolism occurs in the body.

The transition from carbohydrate to fat metabolism has long been attributed solely to drops in insulin. Researchers discovered that, on the contrary, reductions in both leptin — a hormone made by fat cells that inhibits hunger — and insulin are necessary to produce enough glucose for the body to survive during starvation. The results were published in the journal Cell on Jan. 11.

“The question of how humans and animals maintain sufficient plasma glucose concentrations during starvation has been the subject of active debate for decades,” said Rachel Perry, scientist at the School of Medicine and first author of the study.

To survive the feast-famine cycles that have occurred throughout history, humans and animals evolved mechanisms to maintain adequate glucose supply to critical organs when food is scarce, Perry said. The researchers found that leptin, as well as insulin and glucagon, are involved in this physiological process.

The decrease of leptin levels stimulates hormones that promote fat breakdown during prolonged starvation, according to the paper. By doing so, the body shifts from glucose to fat metabolism, generating enough glucose in the liver to supply to the brain and heart during this starvation period.

“We identified a novel leptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, white adipose tissue and liver,” said Gerald Shulman, professor at the School of Medicine and senior author of the study.

When a human or animal enters starvation, liver glycogen, which is how the body stores glucose in the short-term, becomes depleted. The researchers found that lower levels of liver glycogen result in reduced plasma glucose, insulin and leptin concentrations.

The decreased level of plasma glucose then lowers muscle glucose-alanine cycling — a cycle in which the liver uses skeletal muscle to produce glucose — leading to lower rates of gluconeogenesis, or glucose synthesis, Perry explained. The body avoids the breakdown of muscle, which is needed for survival and mobility, to obtain energy, turning instead to its fat stores for fuel.

Additionally, the researchers identified leptin as the mediator of the pathway that increases the rate of fat lipolysis, helping to maintain glucose synthesis. These findings suggest that leptin functions during starvation to provide enough glucose to the body and permit survival even when glucose generation is lowered, according to Shulman.

The study revealed new insights about the shift to fat metabolism by measuring the impact of reductions in plasma leptin in rats at realistic concentrations, Perry said.

“Importantly, we performed what we believe to be the first physiologic leptin replacement studies in fasted rodents,” she said.

Previous studies had administered 10 to 100 times the amount of leptin normally produced, making it impossible to understand the role of variations in leptin within the normal range between fed and fasted conditions, she noted.

In contrast, this study administered leptin continuously to raise plasma leptin concentrations, enabling the researchers to accurately analyze its role in promoting glucose synthesis during starvation.

“Our findings identify a novel mechanism by which rodents maintain adequate substrate supply to permit survival in the fasted state,” Perry said. “We are, of course, very curious to know whether these results translate to humans.”

She added that the researchers are now studying whether reductions in plasma leptin are required to maintain plasma glucose concentrations in humans during the fasted state.

Fatty-acid metabolism disorders, which result in an inability to produce energy within the liver and muscles from fatty acid sources, are found in one in 10,000 births, according to the American Academy of Family Physicians.

Amy Xiong | amy.xiong@yale.edu

Correction, Jan. 16: An earlier version of the article incorrectly stated medical school professor Gerald Shulman’s authorship. He is senior author, not lead author.