Research by Kern Featured in NIDDK Recent Advances and Emerging Opportunities
LEXINGTON, Ky. (May 4, 2021) — Research by UK CCTS Director Philip A. Kern, MD, was recently featured in the 2021 NIDDK Recent Advances & Emerging Opportunities, a compendium published by the National Institute of Diabetes and Digestive and Kidney Diseases to highlight examples of the many research advances published by NIDDK-funded scientists and their colleagues in the most recent fiscal year, along with the technologies that made these achievements possible.
The findings in Kern's paper, Beige Is All the Rage: Drug Treatment Stimulates Beige Fat Formation Resulting in Metabolic Health Benefits in People with Obesity [summarized below] were made possible by funding from the NIDDK and support of the CCTS Clinical Research Unit and Participant Recruitment Services.
STIMULATING BEIGE FAT FORMATION
Beige Is All the Rage: Drug Treatment Stimulates Beige Fat Formation Resulting in Metabolic Health Benefits in People with Obesity
Researchers have shown that treatment with the drug mirabegron, which is approved to treat overactive bladder, stimulates the formation of beige fat tissue in people with insulin resistance and overweight/obesity resulting in several metabolic health benefits, including improved blood glucose (sugar) metabolism. Among different types of fat tissue, brown fat is a form of fat that burns calories (energy) to generate heat, unlike white fat, which is more abundant in the body and stores energy. Beige fat cells, which have similar energy-burning properties to brown fat, can be formed in white fat by cold exposure or through activation of the protein β (beta)3 adrenergic receptor (β3AR), which is present in fat cells and some bladder cells and can be stimulated by mirabegron. Recent studies in mice have demonstrated that beige fat cells can improve glucose metabolism. However, no study had demonstrated a link between beige fat and glucose metabolism in humans.
Investigators recruited 13 women and men, who had overweight/obesity along with either prediabetes or metabolic syndrome, and treated them with mirabegron at the maximal dose approved (50 mg/day) for 12 weeks. Following mirabegron treatment, more than half of the participants who had prediabetes prior to treatment no longer met criteria for that condition. This finding was consistent with overall improvement of glucose tolerance, a marker of how well the body handles blood glucose. Researchers then further examined the participants to measure the function of β cells, which produce the insulin necessary for processing glucose, and how well other tissues respond to insulin (insulin sensitivity). The results indicated that an improvement in both measures led to the improved glucose tolerance. Typically, improved glucose tolerance in people with prediabetes or type 2 diabetes is associated with weight loss. However, interestingly, the participants in this study did not experience weight loss. When the researchers examined how mirabegron treatment affected certain molecular markers known to be present in beige fat, they saw an increase in several of these markers in white adipose tissue, indicating the formation of beige fat cells in response to the drug. These changes correlated with the improved glucose metabolism. The scientists then examined effects on skeletal muscle, and they found that mirabegron treatment induced a beneficial switch in the type of muscle fibers in this tissue, which could account for improvements in insulin sensitivity in muscle. Remarkably, neither β cells nor skeletal muscle cells have the β3AR protein—and thus the beneficial effects of the drug must have been indirect, likely via mirabegron-induced changes in fat tissue. In further experiments, using muscle cells in laboratory culture dishes, the researchers deduced that the effects on fiber type were a result of white adipose tissue “beiging” and sending out a signal to the skeletal muscle cells.
This study demonstrated for the first time in people with overweight/obesity and insulin resistance that mirabegron treatment improves multiple measures of glucose metabolism by inducing beige fat formation in white adipose tissue. In contrast to the increase in beige fat, an increase in brown fat was not observed in this study, but another recent study conducted by intramural NIDDK researchers demonstrated that brown fat is activated by mirabegron in a group of healthy women. While more research is needed to determine the long-term effects of mirabegron treatment on metabolism and if mirabegron can delay the onset of or even reverse type 2 diabetes, the present study brings scientists closer to identifying a safe, effective way to induce beige fat formation and potentially treat metabolic disease.
Finlin BS, Memetimin H, Zhu B,…Kern PA. The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans. J Clin Invest 130: 2319-2331, 2020.