Adipocyte browning and resistance to obesity in mice is induced by expression of ATF3

Commun Biol. 2019 Oct 24:2:389. doi: 10.1038/s42003-019-0624-y. eCollection 2019.

Abstract

Billions of people have obesity-related metabolic syndromes such as diabetes and hyperlipidemia. Promoting the browning of white adipose tissue has been suggested as a potential strategy, but a drug still needs to be identified. Here, genetic deletion of activating transcription factor 3 (ATF3-/- ) in mice under a high-fat diet (HFD) resulted in obesity and insulin resistance, which was abrogated by virus-mediated ATF3 restoration. ST32da, a synthetic ATF3 inducer isolated from Salvia miltiorrhiza, promoted ATF3 expression to downregulate adipokine genes and induce adipocyte browning by suppressing the carbohydrate-responsive element-binding protein-stearoyl-CoA desaturase-1 axis. Furthermore, ST32da increased white adipose tissue browning and reduced lipogenesis in HFD-induced obese mice. The anti-obesity efficacy of oral ST32da administration was similar to that of the clinical drug orlistat. Our study identified the ATF3 inducer ST32da as a promising therapeutic drug for treating diet-induced obesity and related metabolic disorders.

Keywords: Diabetes; Drug discovery; Medical research; Obesity; Transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Activating Transcription Factor 3 / deficiency
  • Activating Transcription Factor 3 / genetics
  • Activating Transcription Factor 3 / metabolism*
  • Adipocytes, Brown / metabolism*
  • Adipocytes, Brown / pathology
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, Brown / pathology
  • Adipose Tissue, White / metabolism
  • Adipose Tissue, White / pathology
  • Animals
  • Anti-Obesity Agents / pharmacology
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Body Temperature Regulation / physiology
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Humans
  • Insulin Resistance
  • Lipogenesis / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / prevention & control
  • Orlistat / pharmacology
  • Plant Extracts / pharmacology
  • Plants, Medicinal / chemistry
  • Salvia miltiorrhiza / chemistry

Substances

  • ATF3 protein, human
  • Activating Transcription Factor 3
  • Anti-Obesity Agents
  • Atf3 protein, mouse
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Mlxipl protein, mouse
  • Plant Extracts
  • Orlistat