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TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue.

Authors
  • Zhao, Peng1
  • Wong, Kai In2
  • Sun, Xiaoli2
  • Reilly, Shannon M1
  • Uhm, Maeran3
  • Liao, Zhongji2
  • Skorobogatko, Yuliya1
  • Saltiel, Alan R4
  • 1 Division of Metabolism and Endocrinology, Department of Medicine, University of California-San Diego, La Jolla, CA 92093, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • 2 Division of Metabolism and Endocrinology, Department of Medicine, University of California-San Diego, La Jolla, CA 92093, USA.
  • 3 Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • 4 Division of Metabolism and Endocrinology, Department of Medicine, University of California-San Diego, La Jolla, CA 92093, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cell
Publication Date
Feb 08, 2018
Volume
172
Issue
4
Identifiers
DOI: 10.1016/j.cell.2018.01.007
PMID: 29425491
Source
Medline
Keywords
License
Unknown

Abstract

The noncanonical IKK family member TANK-binding kinase 1 (TBK1) is activated by pro-inflammatory cytokines, but its role in controlling metabolism remains unclear. Here, we report that the kinase uniquely controls energy metabolism. Tbk1 expression is increased in adipocytes of HFD-fed mice. Adipocyte-specific TBK1 knockout (ATKO) attenuates HFD-induced obesity by increasing energy expenditure; further studies show that TBK1 directly inhibits AMPK to repress respiration and increase energy storage. Conversely, activation of AMPK under catabolic conditions can increase TBK1 activity through phosphorylation, mediated by AMPK's downstream target ULK1. Surprisingly, ATKO also exaggerates adipose tissue inflammation and insulin resistance. TBK1 suppresses inflammation by phosphorylating and inducing the degradation of the IKK kinase NIK, thus attenuating NF-κB activity. Moreover, TBK1 mediates the negative impact of AMPK activity on NF-κB activation. These data implicate a unique role for TBK1 in mediating bidirectional crosstalk between energy sensing and inflammatory signaling pathways in both over- and undernutrition.

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