BOSTON – More than 40 percent of American adults have obesity, a complex condition that can increase the risk of diabetes, cardiovascular disease and certain cancers. One mechanism by which obesity can lead to other health problems is by causing low-grade chronic inflammation, the accumulation of immune cells in insulin-sensitive tissues. Scientists hypothesize that reversing – known as resolving – this chronic inflammation could prevent the onset of obesity-related diseases including diabetes and possibly facilitate weight loss.
In a new paper published in Nature Metabolism, researchers at Joslin Diabetes Center and Brigham and Women’s Hospital found that exposure to cold temperatures resolved obesity-induced inflammation while improving insulin sensitivity and glucose tolerance in diet-induced obese mice. The team further revealed that the process depended on brown adipose (fat) tissue – sometimes considered “good fat” – producing a naturally occurring molecule called Maresin 2 when stimulated by cold. Recognized as an active endocrine organ because it secretes molecules that communicate with other tissues and regulate metabolism, brown adipose tissue helps dissipate stored energy and may potentially promote weight loss and metabolic health.
“Extensive evidence indicates that obesity and metabolic syndrome are linked with chronic inflammation that leads to systemic insulin resistance, so interrupting inflammation in obesity could offer promising therapies for obesity-related disease,” said co-corresponding author Yu-Hua Tseng, PhD, a senior investigator in the Section on Integrative Physiology and Metabolism at Joslin Diabetes Center and professor of medicine at Harvard Medical School. “We discovered that cold exposure reduced inflammation and improved metabolism in obesity, mediated at least in part by the activation of brown adipose tissue. These results reveal a novel function of activated brown in resolving obesity-induced inflammation.”
In two previous studies, Tseng and colleagues discovered that cold exposure could activate brown fat to produce specific lipid mediators that regulate nutrient metabolism. In the current study, the researchers identified a novel role for a lipid mediator produced from brown fat to resolve inflammation.
In the present study, the scientists created a mouse model that becomes obese when fed a typical high-fat, Western diet. When the animals were exposed to a cold environment (around 40 degrees Fahrenheit), the researchers observed that the animals’ insulin sensitivity and glucose metabolism improved and their body weight decreased, compared to control animals maintained at a thermoneutral zone – the environmental temperature where the body does not need to produce heat for maintaining its core body temperature. What’s more, the scientists also noticed a profound improvement in inflammation, as measured by reduced levels of a major inflammatory marker.
“We found that brown fat produces Maresin 2, which resolves inflammation systemically and in the liver,” said co-corresponding author Matthew Spite, PhD, a lead investigator at Brigham and Women’s Hospital and Associate Professor of Anesthesia at Harvard Medical School. “These findings suggest a previously unrecognized function of brown adipose tissue in promoting the resolution of inflammation in obesity via the production of this important lipid mediator.”
Moreover, these findings also suggest that Maresin 2 could have clinical applications as a therapy for patients with obesity, metabolic disease, or other diseases linked to chronic inflammation; however, the molecule itself breaks down quickly in the body. Tseng and colleagues seek a more stable chemical analog for clinical use.
The team notes a shortcut to improved metabolic health may already exist. Multiple human studies conducted at Joslin and elsewhere show that exposure to mild cold temperatures (50 to 55 degrees Fahrenheit) have been shown to be sufficient to activate brown adipose tissue and improve metabolism, though the mechanisms are not well understood.
Co-authors included Satoru Sugimoto, Shio Kobayashi, Tadataka Tsuji, Chih-Hao Wang, Tian Lian Huang, Joji Kusuyama, Sean D. Kodani, Justin Darcy, Gerson Profeta, Thomas Serwold, and Laurie J. Goodyear of Joslin Diabetes Center; Efi Kokkotou of Beth Israel Deaconess Medical Center; Hebe Agustina Mena, Brian E. Sansbury, and Xuanzhi Yin of Brigham and Women’s Hospital; Luiz Osório Leiria and Nayara Pereira of Ribeirão Preto Medical School, University of São Paulo; Rudolph E. Tanzi, Can Zhang of Massachusetts General Hospital; and Aaron M. Cypess of National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health.
This work was supported in part by US National Institutes of Health (NIH) grants (R01DK122808, R01DK077097, R01DK102898, R01HL106173, R01DK099511, R01DK112283, P30DK0368360) and by US Army Medical Research grant W81XWH-17-1-0428; the Manpei Suzuki Diabetes Foundation in Japan; grant 2019/20554-7 from The São Paulo Research Foundation, FAPESP; an American Diabetes Association post-doctoral fellowship (1-16-PDF-063); the Sao Paulo Research Foundation (FAPESP) grants 2017/02684 and 2019/26008-4.
Spite and Tseng are inventors of a pending provisional patent application related to Maresin 2 and metabolic therapeutics.
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 U.S. For more information, visit www.joslin.org.
