Stimulating Brown Fat Volume Has Potential to Improve Metabolic Outcomes

Introducing a beta3-AR agonist, mirabegron, shows increases in energy expenditure, insulin sensitivity, and improved levels of circulating fats, according to ongoing research at the NIH.

by Aaron Cypess, MD, PhD, and Caroline Apovian, MD

“Almost 15 years ago, it was serendipitously reported that there is functional brown adipose tissue, not only in rodents, but also in adult humans,”1 said Aaron Cypess, MD, PhD, MMSc, acting Section Chief of the Translational Physiology Section, Diabetes, Endocrinology, and Obesity Branch of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, in Bethesda, Maryland.

Dr. Cypess shared this insight in explaining to EndocrineWeb that this finding has led to growing evidence of the important function of so-called brown fat in humans.2,3 This work has also led to an understanding of the role that brown fat may play in metabolic outcomes, which has been noninvasively quantified using 18 F-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), in adult human metabolism,3 he said.  

New class of drugs shows promise as therapy for obesity and diabetes.

This finding has potentially great relevance given the obesity epidemic, and the many comorbidities associated with obesity – namely, impaired glucose tolerance, dyslipidemia, hypertension, and a proinflammatory state.3

Pharmacotherapy Acts on Brown Fat to Good Effect

Historically, clinicians have attempted to manage metabolic disorders and obesity by relying on lifestyle interventions, such as diet and physical activity; however, these efforts have not demonstrated substantial effectiveness and durability.4,5 Consequently, investigators have longed to identify a pharmacologic agent that will induce an increase in fatty acid and glucose oxidation.

Initial research in rodent models demonstrated that activation of the beta-3 adrenergic receptor (β3-AR) leads to increased energy expenditure and improved glucose tolerance. Further efforts have achieved similar benefits in early phase clinical trials in humans. The transition from preclinical to human studies has not been smooth, according to Dr. Cypess, owing to important species differences.

However, when investigators began using the β3-AR agonist, mirabegron, which has Food and Drug Administration-approval for the management of overactive bladder (OAB), they were able to demonstrate that one dose (200 mg) in healthy lean men stimulated glucose uptake in brown fat, white adipose tissue, enhanced lipolysis, and altered bile acid metabolism.2

Testing Effects of Mirabegron on Metabolism in Women

Nevertheless, said Dr. Cypess, “in this current study,3 we wanted to see if mirabegron would activate brown fat in healthy women acutely—IT DOES— and/or chronically—IT DOES— and if so, what other metabolic benefits might it have?”

“To be clear, this was not a study to determine if mirabegron might also become a treatment for obesity or other metabolic disorders, in the near future, in addition to its efficacy in managing OAB,” he said. It should be noted that mirabegron has not been linked with weight loss in men or women.

Rather, this latest work was essentially a “proof of concept study to obtain greater understanding of the role of β3-AR agonism on a wide range of metabolic parameters.” The study focus was aimed not at potential effects of β3-AR agonism on body weight, but rather on increasing the volume of human brown fat and improving HDL-cholesterol and insulin sensitivity.3

Stimulating Brown Fat Mimicks Effects of Mild Exercise

Caroline M. Apovian, MD, FACP, FTOS, DABOM, professor of medicine and pediatrics in the Section of Endocrinology, Diabetes, Nutrition and Weight Management at Boston University School of Medicine, and director of the Nutrition and Weight Management Center at Boston Medical Center, in Massachusetts readily agreed that “this was an interesting proof of concept study.”

This small trial would not yet support clinical changes on its own, as it only included 14 younger (mean age 27.5 years) healthy women (mean body mass index of 25.4 kg/m2) who received double the recommended dose of mirabegron (100 mg daily) for a total of four weeks; there was no control group.3 “Typically, we would need a much larger, longer study with a placebo group to inform any clinical changes in practice,” Dr. Apovian said.

“However,” she told EndocrineWeb, “the numerous metabolic effects of mirabegron that they identified in this trial are exciting and really warrant more study.” Dr. Apovian noted, in particular, they've made a significant discovery of an increased glucose uptake without a change in weight, fat mass, or lean body mass.3

Putting these initial findings into context regarding obesity management, she highlighted the observation that “the metabolic benefits reported in this trial that were attributed to mirabegron were comparable to about six weeks of mild exercise training in healthy women.”

“Of note, too, there was some evidence of the known cardiovascular adverse effects associated with mirabegron use in the study subject, which might be associated with the higher daily dose,“ said Dr. Apovian.

“We certainly don’t want to put women on a drug at a dose that could increase adverse cardiovascular effects when we could get somewhat similar benefits to weight, glucose and insulin metabolism by telling them to engage in regular, mild exercise,” she said.

Dr. Cypess said: the higher dose of mirabegron might have contributed to reports of some women experiencing a slight increase in their resting heart rate, systolic blood pressure, and rate-pressure product, leading to Grade 1 experiences of palpitations, tachycardia, headaches, and a change in bowel habits. However, he added that all of these side effects resolved shortly after stopping the treatment.

Among the many metabolic benefits that were identified during this study:

  • Significant increase in detectable metabolic activity in brown fat confirmed with PET/CT
  • Increased brown fat volume
  • A nearly 6% increase in resting energy expenditure (REE) from baseline to day 28
  • Increased fasting levels of HDL-cholesterol, Apolipoprotein A1, Apolipoprotein E, total bile acids, total gastric inhibitory polypeptide, and adiponectin

According to Dr. Cypess, these findings suggest that mirabegron may potentially contribute favorably to metabolic health with benefits for hypercholesterolemia, fatty liver disease, and insulin resistance, in individuals with type 2 diabetes.2,3

Next Steps in Inciting Changes in Metabolic Function 

“We are not talking about eventually using mirabegron (or another β3-AR agonist) as a primary therapy, but perhaps as a second-line treatment perhaps in conjunction with other agents,” Dr. Cypee told EndocrineWeb.

“Of course, these potential uses are way down the road; right now, we are focused on following up on the numerous exciting metabolic findings from this trial,” he said. One initial focus is to identify which of the metabolic responses are directly attributable to mirabegron, and which are downstream effects, and another aim is to find out exactly how chronic use of mirabegron produces an improvement in glucose metabolism.

The investigators perceive that these beneficial changes may be the result of stimulating the β3-AR in human brown and white adipose tissue.2,3

“In light of the findings of increased brown fat-based thermogenesis, increased tissue glucose uptake and insulin sensitivity, and favorable serum cholesterol changes,2,3 one of our next steps will be to use an approved dose of mirabegron, possibly with a boosting agent, to ascertain the actions occurring in this pathway to understand the possibility of it becoming a safe treatment over the long-term,” said Dr. Cypess.

In the next phase, the researchers  intend to expand the population being studied to include greater diversity in age, health, and race/ethnicity; to include persons with metabolic disease; and to include a placebo arm.

Dr. Cypess said: since there are other β3-AR agonists in the pipelines, it is possible that one of these might have greater selectivity with an improved adverse effects profile.

As for this study—it may represent the tip of the iceberg, he said, as it is possible that future studies will demonstrate that chronic activation of the β3-AR will become an effective treatment for metabolic disease.3

Neither Dr. Cypess nor Dr. Apovian reported any financial disclosures of relevance to this study. 

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