IL-25-induced shifts in macrophage polarization promote development of beige fat and improve metabolic homeostasis in mice

PLoS Biol. 2021 Aug 5;19(8):e3001348. doi: 10.1371/journal.pbio.3001348. eCollection 2021 Aug.

Abstract

Beige fat dissipates energy and functions as a defense against cold and obesity, but the mechanism for its development is unclear. We found that interleukin (IL)-25 signaling through its cognate receptor, IL-17 receptor B (IL-17RB), increased in adipose tissue after cold exposure and β3-adrenoceptor agonist stimulation. IL-25 induced beige fat formation in white adipose tissue (WAT) by releasing IL-4 and IL-13 and promoting alternative activation of macrophages that regulate innervation and up-regulate tyrosine hydroxylase (TH) up-regulation to produce more catecholamine including norepinephrine (NE). Blockade of IL-4Rα or depletion of macrophages with clodronate-loaded liposomes in vivo significantly impaired the beige fat formation in WAT. Mice fed with a high-fat diet (HFD) were protected from obesity and related metabolic disorders when given IL-25 through a process that involved the uncoupling protein 1 (UCP1)-mediated thermogenesis. In conclusion, the activation of IL-25 signaling in WAT may have therapeutic potential for controlling obesity and its associated metabolic disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Beige / physiology*
  • Adipose Tissue, Beige / growth & development*
  • Adrenergic beta-3 Receptor Agonists
  • Animals
  • Cold Temperature
  • Homeostasis
  • Insulin Resistance*
  • Interleukin-4 / metabolism
  • Interleukins / metabolism*
  • Macrophages / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / metabolism
  • Uncoupling Protein 1 / physiology

Substances

  • Adrenergic beta-3 Receptor Agonists
  • Interleukins
  • Mydgf protein, mouse
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Interleukin-4

Grants and funding

This work was funded by the National Nature Science Foundation of China(http://www.nsfc.gov.cn/, grant number No: 81570764, 81770808, 81701414, 81872165 and 81871211), National Key R&D Program of China (http://www.nsfc.gov.cn/, grant number No. 2018YFA0800403), Guangdong Provincial Key R&D Program (http://gdstc.gd.gov.cn/, grant number No: 2018B030337001 and 2019B020227003), Key Project of Nature Science Foundation of Guangdong Province, China (http://gdstc.gd.gov.cn/, grant number No. 2019B1515120077), Guangdong Natural Science Fund (http://gdstc.gd.gov.cn/, grant number No: 2019A1515011810 and 2020A1515010365), Guangdong Science and Technology Project (http://gdstc.gd.gov.cn/, grant number No. 2017A020215075), Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translation Research of Hakka Population (http://gdstc.gd.gov.cn/, grant number No. 2018B030322003KF01), Guangzhou Science and Technology Project (http://kjj.gz.gov.cn/, grant number No: 201807010069, 201803010017 and 202002020022) and Shenzhen Science and Technology Project (http://stic.sz.gov.cn/, grant number No. JCYJ20190807154205627) received by Weiwei Qi, Ti Zhou, Xia Yang, Guoquan Gao and Zhonghan Yang. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.