Increasing a protein concentrated in brown fat appears to lower blood sugar, promote insulin sensitivity, and protect against fatty liver disease by remodeling white fat to a healthier state, a new study led by UT Southwestern scientists suggests. The finding, published online in Nature Communications, could eventually lead to new solutions for patients with diabetes and related conditions.
“By taking advantage of this natural system, we may be able to help make fat depots more metabolically healthy and potentially prevent or treat obesity-associated diabetes,” says study leader Perry E. Bickel, M.D., associate professor of internal medicine at UTSW.
Perry E. Bickel, M.D.
Tens of millions of Americans have Type 2 diabetes, a disease characterized by elevated blood sugar and resistance to insulin, the hormone that allows cells to use blood sugar for energy. This disease has been linked to obesity, with excess white adipose tissue (WAT) – fat tissue that holds the majority of the body’s stored energy – associated with elevated blood sugar and insulin resistance in susceptible people. Humans and other mammals also have a second type of fat, known as brown adipose tissue (BAT), which is able to burn fat as a way to increase body heat in cold temperatures. BAT has been investigated as a potential target for weight loss, says Bickel, but may also have a role in improving blood sugar independent of weight loss.
In the study, Bickel and his colleagues, including co-leader Violeta I. Gallardo-Montejano, M.D., an instructor at UTSW, found that brown fat could play an important protective role against diabetes. The researchers made this discovery while studying perilipin 5 (PLIN5), a protein that coats lipid droplets inside cells, particularly in BAT.
With extra PLIN5, mitochondria in brown fat cells boost their capacity to burn fat even at room temperature. Images by Drs. Violeta I. Gallardo-Montejano and Perry E. Bickel.
When the team genetically engineered mice that made extra PLIN5 in BAT, the animals maintained significantly lower blood sugar concentrations and higher insulin sensitivity during glucose tolerance tests, compared with mice with normal PLIN5 levels. They also had less fatty livers, a condition associated with Type 2 diabetes.
Searching for the mechanism behind these positive changes, the scientists found that the BAT’s mitochondria in the genetically engineered mice had adapted to burn even more fat, similar to what’s seen in animals placed in cold temperatures. However, the adaptation wasn’t enough to explain the blood sugar-lowering effect. Looking closer, the researchers found that the white adipocytes of animals that had extra PLIN5 in their brown adipocytes were smaller and had reductions in some markers of inflammation – changes that are associated with improved sensitivity to insulin and metabolism of sugar.
Bickel notes that BAT appears to communicate with WAT in some unknown way, potentially sending a molecular factor through the bloodstream when PLIN5 levels increase inside brown adipocytes.
“The next question we want to address,” says Bickel, “is what that factor is and whether we can harness it for therapeutic benefit.”
The study was funded by grants from the National Institutes of Health (R01DK115875, R01DK112826, and R01DK108833) and Wayne State University Startup funds.
Other researchers who contributed to this study include Chaofeng Yang and the late Lisa Hahner of UTSW, Joshua A. Johnson, John L. McAfee of Cleveland Clinic, William L. Holland of the University of Utah, and Rodrigo Fernandez-Valdivia of Wayne State University School of Medicine.
Bickel holds the Daniel W. Foster, M.D., Distinguished Chair in Internal Medicine.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 25 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.