Eat Fat But Stay Thin: Mice Can Do It, Maybe Someday We Can Too

The journal Nature reports that some lab mice have lived out my food fantasy: Even though they ate a heavy, high-fat diet — my particular dream is unlimited Ben & Jerry's — they did not become obese, because researchers found a novel way to tweak their metabolism.

Sigh. The caveats first: What works in mice might not in humans. It might not be safe. Clinical trials are not on the immediate horizon. This is no reason to stop eating healthy food and exercising.

But we can dream, right? And we can savor the explanations from Dr. Barbara Kahn of Beth Israel Deaconess Medical Center and Harvard Medical School, senior author on the Nature paper. She sums up: "We found an enzyme in fat that appears to be elevated in people with obesity and diabetes. And if we inhibit it in mice, we can increase the amount of energy that the animal burns, and thereby decrease the amount of calories that are stored as fat."

It's something like the extra energy you burn when you exercise, she said — except without the exercise.

Dr. Kahn's team found a gene that, when suppressed, makes metabolism less efficient — which is actually a good thing if you're trying to avoid obesity.

"Generally, in our lives, we think it's good to be efficient — and it certainly is good to be efficient in time management," she said. "But if your metabolism is efficient, it means you need fewer calories to generate the energy that cells need for their basic metabolism, and therefore, if you eat too many calories, you will put on weight. But if the cells are inefficient, they'll burn up those extra calories and you won't put on weight."

So do these findings --- centering on an enzyme known as nicotinamide N-methyltransferase or NNMT — indeed hold the promise of some sort of drug to prevent or treat obesity?

"The approach we used in the mice was mainly prevention," Dr. Kahn said, "but the same idea should work for treatment of obesity. I have to caution, of course: one has to look into all the safety aspects if one considers such a treatment in humans. But all the cellular machinery is there, so it should work."

One exciting aspect of the study, she added, is that the “drug delivery” technique her team used to suppress the gene is already being used in humans to target other genes for several diseases. So the technology would be readily available if the suppression of the NNMT gene in fat and liver proves safe.

If the idea of altering your metabolism to stay thin sounds familiar, you may have heard about recent findings on "brown fat," what some call "a fat that helps you lose weight."

Weight-loss drugs long focused mainly on aiming to curb appetite, but they can pose a risk of serious side effects. So interest has risen in how to help people lose weight by increasing the amount of calories they burn instead. Work on brown fat and these latest findings in Nature share that concept, Dr. Kahn said, “but the cellular machinery to burn the extra energy is completely different.”

The work leading up to today’s paper began 20 years ago, she said, with the discovery that, in their fat cells, people with obesity and diabetes had low levels of a gene that encodes a protein that transports sugar into the cell. Low levels of that sugar transporter put people at high risk for developing type 2 diabetes, and when mice were genetically engineered to have similar low levels of this sugar transporter, they turned out to be prone to diabetes.

The Nature findings resulted from a systematic search for a gene that could have the opposite effect.

Ultimately, Dr. Kahn said, there's no stay-thin magic around the corner, but the NNMT findings on how to tweak the metabolism could eventually help fight fat. "It doesn't supplant diet and exercise," she said, "but it could provide a major augmentation of those effects, a major adjunct to those approaches."

For readers of a biochemical bent, here's more from the Beth Israel Deaconess press release:

NNMT is an enzyme that processes vitamin B3 and has been linked to certain types of cancer, as well as Alzheimer’s disease, explains co-corresponding author Qin Yang, MD, PhD, a Klarman Scholar in the Kahn laboratory at BIDMC and Assistant Professor of Medicine at Harvard Medical School. “Now we have identified an entirely new role for this enzyme in fat tissue, and that is to regulate energy metabolism,” he adds.

The new findings hinge on a biochemical mechanism known as a futile cycle, in which cellular reactions are sped up, thereby generating more energy. “We all know people who can seemingly eat whatever they want and not gain weight,” explains Kahn, who holds the George R. Minot Endowed Chair as Professor of Medicine at Harvard Medical School and is Vice-Chair of the Department of Medicine at BIDMC. “Part of the reason for this natural weight control owes to basal cellular metabolism – the body’s inherent rate of burning energy. A futile cycle is one way to speed up energy utilization in cells.”

The investigators first confirmed that levels of NNMT were increased in obese and diabetic mice.
“In a comparison of genetic profiles of fat from mice that were either prone to or protected from developing diabetes, we discovered that the animals that were prone to develop diabetes had a lot of NNMT in the fat and liver,” explains Yang. Together with co-first author Daniel Kraus, MD, Kahn and Yang hypothesized that reducing NNMT levels in these tissues would  accelerate a series of metabolic reactions involving molecules called polyamines, thereby leading to increased energy expenditure, increased leanness and reduced risk of diabetes and its complications.

“Polyamines are a group of biological molecules that are found throughout the body, which have fundamental functions, including regulating cell growth,” explains Kraus. “What’s interesting about the polyamines is that the process of building and degrading them creates a biochemical cycle in which energy is used up. This is a futile cycle.” The team discovered that NNMT inhibition speeds up this futile cycle, resulting in more dietary calories being burned for energy and fewer calories being incorporated into fat.

Importantly, notes Kahn, the team used antisense oligonucleotide (ASO) technology to knock down the NNMT gene. ASOs are short molecular strings of DNA, which can be designed to prevent the synthesis of specific proteins.

“When an ASO is transferred into a cell, it can target a specific gene and suppress it, as was the case with NNMT,” explains Kahn. “Because ASOs have already been approved by the U.S. Food and Drug Administration [FDA] for the treatment of genetic causes of elevated cholesterol or hyperlipidemia, as well as the treatment of a viral eye infection, it’s possible that clinical trials to test an ASO anti-obesity therapy in humans could readily move forward.