Summary: Beta2-adrenergic receptors in human brown fat cells drive thermogenesis.
Source: University of Copenhagen
An international research team has identified how to pharmacologically activate brown adipose tissue (BAT) in humans, a discovery that could open new avenues for treating type 2 diabetes and obesity. The collaborative study between the Centre de recherche du Centre hospitalier universitaire de Sherbrooke (CRCHUS) and the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen appears in Cell Metabolism.
Brown fat is specialized to burn energy and produce heat—a process known as thermogenesis—when stimulated by cold exposure or certain chemical signals. Humans retain small but metabolically relevant deposits of brown fat, and researchers have long explored ways to activate this tissue pharmacologically as a strategy to improve metabolic health.
The research team discovered that the beta2-adrenergic receptor (β2-AR) expressed in human brown adipocytes is the principal driver of thermogenesis in human BAT. This finding helps explain why many previous clinical attempts targeting other adrenergic receptors, in particular the β3-adrenergic receptor, have had limited success in humans.
“It appears we may have been aiming at the wrong receptor in humans,” says Dr. Denis Blondin (CRCHUS). “Unlike rodents, human brown fat is activated primarily through β2-adrenergic receptors—the same receptor class that promotes lipolysis in white adipose tissue.”
Unlocking the therapeutic potential of brown fat
Associate Professor Camilla Schéele (CBMR) highlights the clinical significance: “Activating brown fat increases calorie burning, enhances insulin sensitivity and may influence appetite regulation. Our results reveal a previously unrecognized molecular switch in human BAT that could be harnessed to benefit people with obesity or type 2 diabetes.”
The team plans a second phase of research beginning in the autumn to validate the β2-AR finding by testing drugs that selectively target this receptor on human brown adipocytes. Professor André Carpentier (CRCHUS) explains the immediate aim:
“We will evaluate a compound that specifically activates β2-AR on brown fat to measure how effectively it increases fat and calorie burning in humans. If those results are promising, we will progress to clinical studies in people with type 2 diabetes to determine whether this approach improves metabolic control.”
About this research
Source: University of Copenhagen
Contacts:
Press Office – University of Copenhagen
Image credit:
Image is in the public domain.
Original Research: Closed access. “Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation” by Denis P. Blondin et al., Cell Metabolism (DOI: 10.1016/j.cmet.2020.07.005).
Abstract
Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation
Key findings
• A therapeutic oral dose (50 mg) of mirabegron does not reliably stimulate human BAT thermogenesis.
• Human brown adipocytes lack functional β3-adrenergic receptor expression and do not respond to mirabegron in vitro.
• Norepinephrine-induced respiration in human brown adipocytes is mediated by β2-adrenergic receptors, which co-localize with UCP1.
• β2-AR is the principal pharmacological target for activating human brown adipocytes.
Summary
Stimulating brown adipose tissue thermogenesis is an appealing strategy to enhance metabolic health in humans. Historically, pharmacological efforts focused on the β3-adrenergic receptor—the receptor believed, from rodent studies, to govern BAT activation. However, clinical trials targeting β3-AR in humans have generally shown limited effect. The present study demonstrates that, unlike in rodents, human BAT thermogenesis is not driven by β3-AR stimulation. Administration of the β3-AR agonist mirabegron only increased BAT activity when given at the highest approved dose, at which point off-target interactions with β1-AR and β2-AR occurred, producing cardiovascular effects and stimulating lipolysis in white adipose tissue, respectively. The gene encoding β2-AR (ADRB2) is co-expressed with UCP1 in human brown adipocytes. Pharmacological activation and inhibition experiments, along with targeted knockdown of ADRB1, ADRB2, and ADRB3 in human brown adipocytes, confirmed that lipolysis and thermogenesis in human BAT are mediated predominantly by β2-AR signaling (ClinicalTrials.gov NCT02811289).