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Harvard Doctors Reverse Long-Held Ideas About Fat, Diabetes, and Heart Disease

The researchers discovered a new pathway in which endothelial cells drive the body’s metabolism.

According to the researchers, blood vessel cells are a key regulator of brown fat and energy metabolism.

Insulin resistance, a significant risk factor for diabetes, develops when the body’s cells do not react to insulin and are unable to use the glucose (sugar) in the bloodstream. The condition has been linked to an increased risk of cardiovascular disease and atherosclerosis, which is an accumulation of fats within blood arteries that can restrict blood flow to the body’s tissues. However, the precise mechanism through which insulin and the cells lining vascular walls interact is unclear.

Joslin Diabetes Center scientists describe a series of studies designed to investigate the link between insulin, fats, and the vascular system in a paper published in Circulation Research. The group, led by Dr. George King, chief scientific officer and director of research at Joslin, discovered a brand-new method by which the body’s metabolism is controlled by endothelial cells, which line blood vessels. The results challenge scientific dogma by suggesting that, contrary to what was previously believed, vascular dysfunction may really be the root cause of the undesirable metabolic changes that can result in diabetes.

“In people with diabetes and insulin resistance, the idea has always been that white fat and inflammation causes dysfunction in the blood vessels, leading to the prevalence of heart disease, eye disease, and kidney disease in this patient population,” said King, the Thomas J. Beatson, Jr. Professor of Medicine in the Field of Diabetes at Harvard Medical School. “But we found that blood vessels can have a major controlling effect here, and that was not known before.”

Diabetes is connected with an undesirable reduction in the body’s storage of brown fat, also known as brown adipose tissue, in addition to blood vessel problems. Brown fat, as opposed to white fat, burns energy, regulates body weight and metabolism, and maintains body temperature. King and colleagues discovered that mice engineered with heightened insulin sensitivity only in the blood vessels weighed less than control animals, even when given a high-fat diet, in a series of tests using a mouse model of diabetes. The extra insulin-sensitive mice were found to have more brown fat than control animals, as well as reduced blood vessel damage.

The team’s further investigation revealed that insulin signals endothelial cells in the blood vessels to produce nitrous oxide, which in turn triggers the production of brown fat cells. In the context of insulin resistance, endothelial cells produced less nitrous oxide – a decrease known to raise cardiovascular risk – leading to a drop in brown fat production. Because brown fat plays such an integral role in regulating the body’s weight and metabolism, smaller brown fat stores could be a risk factor for, not a symptom of, diabetes.

“What we found here is that the endothelial cells lining the blood vessels can have a major controlling effect on how much brown fat you develop,” said King. “Nitrous oxide comes from endothelial cells to regulate how much brown fat you make, and that finding is very exciting because in the past we thought diabetes causes cardiovascular problems, but that relationship appears to be reversed in this scenario.”

The study’s findings set the stage to use brown fat and the suite of hormones and inflammatory proteins it controls as biomarkers, or signs physicians can test for, for atherosclerosis or cardiovascular disease. Down the road, with future animal and clinical studies, this new information could open the door to an entirely new method of weight control by increasing brown fat tissues through improving endothelial nitrous oxide production.

“Everything is connected,” said King. “We think blood vessels and endothelial cells play an important role not just in regulating brown fat, but also in regulating whole body’s metabolism. Thus, these endothelial cells are a key factor in regulating weight and developing diabetes and, as other labs have shown, blood vessels appear to be a major regulator of brain function as well. Intervening at the level of endothelial cells could have a major impact on many diseases.”

Reference: “Endothelial Cells Induced Progenitors Into Brown Fat to Reduce Atherosclerosis” by Kyoungmin Park, Qian Li, Matthew D. Lynes, Hisashi Yokomizo, Ernesto Maddaloni, Takanori Shinjo, Ronald St-Louis, Qin Li, Sayaka Katagiri, Jialin Fu, Allen Clermont, Hyunseok Park, I-Hsien Wu, Marc Gregory Yu, Hetal Shah, Yu-Hua Tseng and George L. King, 1 June 2022, Circulation Research. 
DOI: 10.1161/CIRCRESAHA.121.319582

The study was funded by the National Institutes of Health and the NIDDK Diabetes Research Center. The authors report no disclosures.

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