Summary: Beta2-adrenergic receptors in brown fat cells are responsible for stimulating thermogenesis.
Source: University of Copenhagen
An international research team have discovered how to activate brown fat in humans, which may lead to new treatments for type 2 diabetes and obesity. The results of the collaboration 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 were published today in Cell Metabolism.
Brown fat burns energy and generates heat—a process called thermogenesis—after being activated by cold temperature or chemical signals. Humans have small deposits of brown fat, and scientists have long hypothesized that finding alternative ways to pharmacologically activate the fat could help improve metabolism.
Scientists have now discovered that beta2-adrenergic receptors (b2-AR) in brown fat cells are responsible for stimulating thermogenesis. According to Dr. Denis Blondin from CRCHUS, the finding could explain why most clinical trials, which have attempted to induce BAT to burn energy, have performed poorly.
“We show that perhaps we were aiming for the wrong target all along. In contrast to rodents, human BAT is activated through the stimulation of the beta2-adrenergic receptor, the same receptor responsible for the release of fat from our white adipose tissue.”
Unlocking the therapeutic potential of brown fat
According to Associate Professor Camilla Schéele at CBMR, this finding has clear therapeutic applications.”Activation of brown fat burns calories, improves insulin sensitivity and even affects appetite regulation. Our data reveals a previously unknown key to unlocking these functions in humans, which would potentially be of great gain for people living with obesity or type 2 diabetes”.
A second phase of research will begin in the autumn, which will attempt to validate the finding by activating brown fat with drugs that target b2-AR, explains Professor André Carpentier from CRCHUS:
“Our next step will be to use a drug that specifically activate that target on brown fat and determine how much it could be of use to burn fat and calories in humans. Once this is done, studies in patients with type 2 diabetes will start to determine if this approach can be useful to improve the metabolic control of the disease.”
About this neuroscience research article
Source:
University of Copenhagen
Contacts:
Press Office – University of Copenhagen
Image Source:
The 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.
Abstract
Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation
Highlights
• A therapeutic dose (50 mg) of mirabegron does not stimulate human BAT thermogenesis
• Human brown adipocytes lack β 3-AR and do not respond to mirabegron in vitro
• Norepinephrine-induced respiration is driven by β 2-AR, which co-localizes with UCP1
• β 2-AR is the main target for pharmacological activation of human brown adipocytes
Summary
Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β 3-adrenergic receptor (β 3-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of β 3-AR. Oral administration of the β 3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to β 1-AR and β 2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the β 2-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through β 2-AR signaling in humans ( ClinicalTrials.gov NCT02811289).