A new way cells generate heat

November 19, 2025

A new way cells generate heat

At a Glance

  • Researchers identified a previously unrecognized way the body uses energy to produce heat.
  • The findings suggest a way to promote weight loss by increasing heat generation in brown fat cells.
Infrared images show less heat in the brown fat of a mouse without ACOX2.
Infrared images of heat production from brown fat in a control mouse (left) and a mouse that lacks a protein called ACOX2 (right).
Weisensee Lab

More than 40% of Americans live with obesity. That increases their risk for health problems like type 2 diabetes and heart disease. For that reason, scientists are investigating ways to help people lose weight by increasing how much energy their bodies use.

One intriguing target for such therapies is a type of fat cell called brown fat cells. Brown fat cells use energy to produce heat via a protein called uncoupling protein 1 (UCP1). But mice without UCP1 do not become obese, so their brown fat cells must have other ways to use energy for creating heat.

An NIH-funded research team, led by Dr. Irfan J. Lodhi of Washington University School of Medicine in St. Louis, identified a separate heat-production pathway in brown fat. Their results were published in Nature on September 17, 2025.

The researchers focused on cellular compartments called peroxisomes. These are involved in various aspects of metabolism, including breaking down a major fat component called fatty acids. Peroxisomes are abundant in brown fat cells, and their numbers increase with exposure to cold. The team first looked at how gene activity in brown fat changed when mice with and without UCP1 were exposed to cold.

Cold exposure increased the activity of several genes involved in the creation and function of peroxisomes. One of those genes, ACOX2, codes for a protein that helps cells turn certain fatty acid molecules into energy. Exposure to cold particularly boosted ACOX2 activity in mice without UCP1. Treating brown fat cells lacking UCP1 with norepinephrine, which spurs cells to use more energy, also raised ACOX2 activity.

Next, the researchers deleted ACOX2 from brown fat cells. This increased the amount of fatty acid molecules called monomethyl branched-chain fatty acids (mmBCFA) in the cells, suggesting that the ACOX2 protein helps break down those molecules. Accordingly, the team found that increasing ACOX2 activity reduced the amount of mmBCFA in cells but did not affect other fatty acids. Increasing ACOX2 activity in fat cells also made mice more cold-tolerant, including mice lacking UCP1. That suggests the ACOX2 protein helps cells generate heat through a process that doesn’t require UCP1.

Further experiments confirmed that the ACOX2 protein is located inside brown fat cells’ peroxisomes. Supplying brown fat cells with mmBCFA increased the temperature inside their peroxisomes.

When the researchers fed mice a high-fat diet to promote weight gain, ACOX2 activity increased in the animals’ brown fat cells. Mice without ACOX2 gained more weight than control mice when fed a high-fat diet, even though they didn’t consume more calories or move around less. They also showed signs of insulin resistance, a hallmark of type 2 diabetes in which the hormone insulin is less effective at regulating blood sugar. In contrast, increasing ACOX2 activity reduced weight gain and insulin resistance in mice fed a high-fat diet.

The findings suggest that ACOX2 generates heat by breaking down mmBCFA inside peroxisomes. This process can reduce weight gain by increasing energy use to compensate for increased calorie intake. Increasing the amount of mmBCFA that brown fat burns for heat might thus increase the body’s energy use and aid weight loss in people with obesity.

“Boosting this kind of metabolic process could support weight loss or weight control in a way that is perhaps easier to maintain over time than traditional dieting and exercise,” Lodhi says.

The team plans to test methods for boosting this heat production pathway in people to see if doing so can help people to lose weight.

—by Brandon Levy

Related Links

References

Peroxisomal metabolism of branched fatty acids regulates energy homeostasis. Liu X, He A, Lu D, Hu D, Tan M, Abere A, Goodarzi P, Ahmad B, Kleiboeker B, Finck BN, Zayed M, Funai K, Brestoff JR, Javaheri A, Weisensee P, Mittendorfer B, Hsu FF, Van Veldhoven PP, Razani B, Semenkovich CF, Lodhi IJ. Nature. 2025 Sep 17. doi: 10.1038/s41586-025-09517-7. Epub ahead of print. PMID: 40963015.

Funding

NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of General Medical Sciences (NIGMS).