BYLINE: Written by Jaqueline Mitchell
BOSTON — Most fat stores energy; the body’s brown fat does the opposite. Unlike the white fat that accumulates just under our skin, brown fat burns calories and glucose to generate heat. Formally known as brown adipose tissue, it is a specialized metabolic tissue whose importance in adults has only come into focus in recent years. Brown fat—stored in small, distinct pockets deep within the body—plays an outsized role in body‑weight regulation and blood‑sugar control, making it an attractive target for metabolic therapies.
Now, researchers at Joslin Diabetes Center have identified a molecular switch that controls whether brown fat can turn on its calorie-burning properties, and they have also shown that the same mechanism operates in human tissue. The findings, published in Nature Metabolism, open a new avenue for drug development targeting one of the body’s most powerful natural defenses against obesity and type 2 diabetes.
“Brown fat has enormous potential as a therapeutic target but realizing that potential requires understanding exactly how it is regulated at the molecular level,” said Yu-Hua Tseng, PhD, senior investigator at Joslin Diabetes Center and professor of medicine at Harvard Medical School. “We discovered that hormonal signals can very quickly reorganize the 3D structure of DNA in brown fat cells, acting like a switch that turns its calorie‑burning machinery on or off.”
In nature, brown fat is activated when the body detects cold; the nervous system releases a hormone that instructs brown fat cells to start burning fuel and generating heat. Scientists have known for decades that this signal switches on hundreds of genes. What has been much less clear is how an acute hormonal signal can trigger such a rapid change in gene activity. The link appears to involve changes in DNA structure. Although DNA is often pictured as a long, straight string of letters inside each cell; it is folded and looped in three dimensions.
New genome-mapping methods reveal that this 3D folding pattern is flexible, shifting over time and crucial for gene regulation during long-term processes like development and cell differentiation. However, it was unknown whether quick hormonal signals could also reshape this 3D DNA structure to drive thermogenic gene expression—enabling brown fat cells to swiftly adjust their metabolism to sudden environmental changes, such as cold. That unanswered question is the gap the new study set out to fill.
To tackle this question, the Joslin team used high‑resolution genome mapping methods that reveal how DNA is folded and arranged inside the cell. Working with Dr. Kaifu Chen’s lab at Boston Children’s Hospital and other collaborators, they were able to map how brown fat cells change their 3D genome structure in response to a cold‑triggered hormonal signal.
Tseng and colleagues observed that activation of brown fat is accompanied by rapid changes in 3D DNA organization inside the cell. “These changes bring distant stretches of DNA into contact, forming ‘loops’ that enable key metabolic genes to switch on,” said Yang Zhang, PhD, leading author of the paper and postdoctoral fellow at Joslin Diabetes Center and Harvard Medical School.
At the center of this process, the team discovered, is a protein called H2A.Z—a histone variant that helps open up tightly packed DNA, making regulatory regions of key metabolic genes accessible. Without H2A.Z, this large-scale DNA reorganization cannot occur, and brown fat’s calorie‑burning program stalls.
To test whether this mechanism is essential for brown fat function in living animals, the Joslin scientists disrupted H2A.Z specifically in brown fat cells in mice and examined the physiological consequences. They found that when H2A.Z was ablated, brown fat could no longer mount a normal response to cold: energy expenditure dropped, body‑temperature regulation was impaired, and markers of glucose metabolism worsened — all hallmarks of dysfunctional brown fat. The results showed that H2A.Z is not incidental to brown fat activity; it is required for its metabolic function.
Importantly, the same mechanism operates in human cells. Using primary brown fat cells obtained directly from human donors — a rare and technically demanding resource— the Joslin research team demonstrated that H2A.Z plays a similarly essential role in human brown fat. When the team compared their findings with large‑scale human genetic data, they saw a clear pattern: the DNA regions regulated by H2A.Z are the same regions previous studies have linked with genetic risk for obesity and metabolic disease.
“Our findings help explain how genetic risk for obesity and metabolic disease may actually play out at the molecular level,” said Tseng. “We show that H2A.Z helps shape the DNA interactions that regulate brown fat’s metabolic genes—and those same regions harbor many obesity-related genetic variants. Understanding that connection gives us a more tangible target for translating genetic insights from the lab into real metabolic interventions in the clinic.”
Co-authors from Joslin Diabetes Center and Harvard Medical School included Yang Zhang, Tadataka Tsuji, Chih-Hao Wang, Xiang-Yu Liu, Justin Darcy, Matthew D. Lynes, Morten Lundh, and C. Ronald Kahn. Rongbin Zheng and Kaifu Chen of Boston Children’s Hospital and Harvard Medical School also contributed, as did Yu-Hang Xing, Rui Dong, Sarah E. Johnstone, and Miguel N. Rivera of Massachusetts General Hospital; Brice Emanuelli of the University of Copenhagen; and Rini Arianti, Ferenc Győry, and Endre Kristóf of the University of Debrecen, Hungary.
This work was supported by National Institutes of Health grants R01DK132469, R01DK102898, and R01DK133528 (to Y.-H.T.), R01GM125632, R01GM138407, R01HL148338, R01HL133254, and R01CA278832 (to K.C.), K99HG013662 (to R.Z.), P30DK036836 and S10OD028568 (to Joslin Diabetes Center’s Diabetes Research Center); National Research, Development and Innovation Office of Hungary grants PD146202 and FK145866; the János Bolyai Fellowship of the Hungarian Academy of Sciences; and the Charles A. King Trust Postdoctoral Research Fellowship from the Health Resource in Action.
About Joslin Diabetes Center
Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Part of Beth Israel Lahey Health, Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives. We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is affiliated with Harvard Medical School and one of only 18 NIH-designated Diabetes Research Centers in the United States.
