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NIH Research Festival

September 12 – 14, 2018

β3 adrenergic receptors are key to lipolysis and thermogenesis in humans

Thursday, September 13, 2018 – Poster Session IV
3:30 – 5:00 p.m.

FAES Terrace

NIDDK

PHARM-1

Authors

  • C Cero
  • A O'Mara
  • J Johnson
  • J Linderman
  • A Cypess

Abstract

Decades of preclinical studies in rodents has shown that activating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) lipolysis can treat obesity and confer a range of metabolic benefits. These models show that β3-adrenergic receptor (AR) agonists potently stimulate both tissues. The recent discovery of functional BAT in humans is encouraging, but several species differences in adipocyte cellular physiology must be addressed before true advances are possible. First, the contribution of the β3-AR signaling in human adipocytes may be different from rodents given the low abundance of such receptor in adipose tissue and access to only partial β3-AR agonists. Second, it is unknown how human tissue compares functionally to immortalized cell lines. Therefore, we first investigated the distribution and relative expression of β1/2/3-AR in (i) autopsy-derived WAT and BAT from the subcutaneous abdominal and supraclavicular neck regions, respectively, and (ii) immortalized human white (WA) and brown (BA) adipocytes. We show that in WAT and BAT, the β1-AR and β2-ARs are similarly expressed, whereas β3-AR has the highest expression in BAT. Similarly, differentiated BA have a significantly higher expression of the β3-AR than WA. To assess the contribution of each receptor toward lipolysis and thermogenesis, we differentiated WA and BA, respectively, and performed dose-response curves of agonist-stimulated lipolysis. We observed that stimulation of any one of the three β-ARs in human adipocytes induces an increase in glycerol release, a lipolytic byproduct. However, the human β3-AR-selective agonist mirabegron, was a more potent activator of lipolysis in both BA and WA than agonists selective for the β1-AR and β2-ARs. These findings were translated to a clinical trial in which mirabegron was given to healthy women, where we found that mirabegron induced an increase in BAT thermogenesis and WAT lipolysis. In summary, we identify a prominent physiological role for the β3-AR in the regulation of human BAT thermogenesis and WAT lipolysis that is consistent in both in vitro and in vitro human models. A selective β3-AR agonist may be the optimal choice for targeted stimulation of human WAT and BAT.

Scientific Focus Area: Molecular Pharmacology

This page was last updated on Friday, March 26, 2021

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2018 program

Download the 2018 Research Festival Schedule Overview (6 pages)

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