News Release
February 16, 2016

"Beiging" White Fat Cells to Fight Diabetes

Penn Study reveals a signaling pathway required for beige fat formation

PHILADELPHIA - Researchers are getting closer to learning how to turn white fat cells into brown fat cells, in a process called “beiging,” to bring down blood sugar levels and fight diabetes. The team, led by Joseph Baur, PhD, an assistant professor of Physiology in the Perelman School of Medicine at the University of Pennsylvania published their findings this month in the journal Diabetes.

“Beiging of white fat could be harnessed to fight diabetes by burning excess calories to cause a decrease in blood sugar,” Baur said. “Our work suggests that activation of the mTOR pathway plays a critical role in this process.” Induction of beige fat cells is considered a promising strategy to combat obesity because of this cell type’s ability to metabolize glucose and lipids, dissipating the resulting energy as heat.

Brown and white fat cells, or adipocytes, play different roles in the body. While white adipocytes store energy as large fat droplets, brown adipocytes contain smaller fat droplets and are specialized to burn fat to produce heat. To do this brown adipocytes are packed with the powerhouses called mitochondria that contain iron, which gives them their brown color. In fact, babies are born with brown fat along the upper back and shoulders to keep warm.

In adult humans, the recent discovery of brown fat “depots” is also associated with lower body weight. Brown-like fat cells, called beige adipocytes, also appear within white fat deposits in response to cold and other signals. The energy balance within the body is influenced by brown and beige adipocytes, which are stimulated into action by cold temperatures and other signals to burn fat and carbohydrates.

The primary tool used in these studies was rapamycin, a drug that inhibits the protein mTOR (mechanistic target of rapamycin), which can be found in two distinct protein complexes. It was first discovered as a byproduct of Streptomyces hygroscopicus, a bacterium found in a soil sample from Easter Island, an island also known as Rapa Nui, hence the name. Rapamycin is currently used as an immunosuppressant in organ transplant, but has recently attracted attention when it was discovered to extend lifespan in mice.  

Interestingly, in 2012, Baur’s lab discovered that rapamycin also causes insulin resistance due to its ability to inhibit both arms of the mTOR signaling pathway controlled by the protein complexes mTORC1 and mTORC2. They showed in an animal model that these two arms could, in principle, be separated to dissect which pathway controls longevity versus endocrine effects.

In terms of physiology, mTOR signaling is involved in the control of blood sugar and cholesterol levels, and its inhibition increases the risk of diabetes. While previous studies suggested that mTORC1 inhibition would promote beiging of white fat cells, Baur’s present work supports the notion that mTORC1 activity is actually required for cold-induced beiging of white fat cells. If activating mTORC1 directly can bring about the same result, then this approach could potentially be applied to combat diabetes.  

In the Diabetes study, the team shows that rapamycin blocks the ability of cold or drugs that activate a specific neurotransmitter pathway to induce the appearance of beige fat cells. Accordingly, rapamycin-treated mice are cold-intolerant and fail to maintain body temperature and weight when moved to a colder environment.

The findings demonstrate a positive role for mTORC1 in the recruitment of beige fat cells to white fat depots, which could explain some of the negative metabolic effects of mTOR inhibition.

“Our study highlights the complex interconnection between mTOR signaling and metabolism,” said first author Cassie Tran, PhD, a postdoctoral fellow in the Baur lab. “It will be critical in moving forward to determine the specific targets downstream of mTOR that are causing the negative metabolic effects in order to create better drugs and one day drugs that might also extend heathspan. The discovery of a critical signaling pathway for beige-fat formation also suggests the opportunity to target this pathway to therapeutically increase the number of heat-producing cells in obese or diabetic patients.”

Other co-authors include Sarmistha Mukherjee, David W. Frederick, Megan Kissig, James G. Davis, and Patrick Seale, all from Penn.

This work was supported by grants from the National Institutes of Health (R01 AG043483, R01 DK098656, T32 DK07314, K99/R00, AG041765).

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.

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