Inhibition of hedgehog signaling promotes white adipose tissue browning

Mol Cell Endocrinol. 2020 Dec 1;518:110970. doi: 10.1016/j.mce.2020.110970. Epub 2020 Jul 30.

Abstract

White adipose tissue (WAT) browning is a potential strategy to treat obesity, and is characterized by the formation of brown adipocytes induced by cold or β-3 adrenergic receptor (β-3AR) agonist treatment. The hedgehog (Hh) signaling at the primary cilium is closely related to obesity, and plays a key role in the differentiation and adipogenesis of adipocytes. However, little is known about its effects on WAT browning. In this study, browning models were used to evaluate the activity and effect of Hh signaling on WAT browning using Hh antagonists, agonist, and small-interfering RNAs (siRNAs) specific for glioma-associated oncogene homologue 1 (Gli1), smoothened (Smo), and suppressor of fused (Sufu). We observed that Hh signaling activity was inhibited during the browning process both in vivo and in vitro. Further, Hh signaling inhibition enhanced WAT browning, while its activation attenuated norepinephrine-induced browning. Thus, the inhibition of Hh signaling promotes WAT browning and therefore, Hh signaling may be a therapeutic target against obesity and associated comorbidities.

Keywords: Beige or brite adipocytes; Hedgehog; Obesity; Primary cilium; WAT browning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology*
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipogenesis
  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, White / metabolism*
  • Animals
  • Cell Differentiation
  • Cold Temperature
  • Dioxoles / pharmacology*
  • Energy Metabolism
  • Gene Expression Regulation / drug effects
  • Hedgehog Proteins / genetics*
  • Hedgehog Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Norepinephrine / pharmacology
  • Primary Cell Culture
  • Repressor Proteins / genetics
  • Signal Transduction / drug effects
  • Smoothened Receptor / genetics
  • Thermogenesis
  • Zinc Finger Protein GLI1 / genetics

Substances

  • Dioxoles
  • GLI1 protein, human
  • Hedgehog Proteins
  • Repressor Proteins
  • SMO protein, human
  • SUFU protein, human
  • Smoothened Receptor
  • Zinc Finger Protein GLI1
  • disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate
  • Norepinephrine