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DRC Director's Report - September 2020

Renata Pereira, PhD, Research Assistant Professor of Internal Medicine, Endocrinology and Metabolism, and member of the FOEDRC, is the recipient of a new NIH R01 grant for $1.9M to support her work entitled The role of the integrated stress response in brown adipose tissue-mediated metabolic adaptations. 

“Obesity and related conditions, such as diabetes and heart disease, are some of the greatest health problems affecting today’s society. In an effort to better understand ways in which the body can increase its metabolism to burn fat and prevent the effects of those diseases, Dr. Pereira has focused her studies on special fat cells called brown (or beige) fat cells.

When exposed to cold temperatures, brown fat cells can burn calories to produce heat and warm up the body. Findings from Dr. Pereira’s laboratory demonstrated that, when mice are exposed to cold temperatures for a brief period of time, a series of reactions in their brown fat cells are triggered, which includes the activation of a stress response called the integrated stress response (ISR). 

The ISR seems to induce the release of hormones that improve the body’s metabolism, helping the mice burn calories more efficiently. One of these hormones is called growth and differentiation factor 15 (GDF15), which promotes leanness in mice. To investigate this further, she conducted experiments using genetically-engineered mice that lacked a critical protein called optic atrophy 1 (OPA1) in their brown fat cells. In the absence of the OPA1 protein, activation of the ISR and secretion of GDF15 from brown fat cells occurred even at room temperature. 

As a result, these mice had faster metabolism and were resistant to obesity and diabetes, even when consuming a diet very high in fat. These findings indicate that the processes that activate the ISR in fat cells either by cold temperatures or OPA1 deletion are likely to be the same. Dr. Pereira’s work seeks to identify the specifics of these processes and harness them into new treatments for diabetes and obesity. 

Activating the ISR in these cells improves the body’s metabolic health in two ways: it increases the fat-burning properties of the cells, and produces leanness due to the secretion of GDF15 and potentially other anti-obesity hormones. Completion of this project will reveal the mechanisms underlying ISR activation and the role of the ISR and GDF15 in brown fat cells, potentially leading to new ways to combat obesity and associated disorders in humans.

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