title: Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice.
abstract: OBJECTIVE
  Inflammatory factors secreted by macrophages play an important role in obesity-related insulin resistance. Being at the crossroads of a nutrient-hormonal signalling network, the mammalian target of rapamycin complex 1 (mTORC1) controls important functions in the regulation of energy balance and peripheral metabolism. However, the role of macrophage mTORC1 in insulin resistance is still unclear. In the current study, we investigated the physiological role of macrophage mTORC1 in regulating inflammation and insulin sensitivity.
  
  
  METHODS
  We generated mice deficient in the regulatory associated protein of mTOR (Raptor) in macrophages, by crossing Raptor (also known as Rptor) floxed mice (Raptor (flox/flox)) with mice expressing Cre recombinase under the control of the Lysm-Cre promoter (Mac-Raptor (KO)). We fed mice chow or high-fat diet (HFD) and assessed insulin sensitivity in liver, muscle and adipose tissue. Subsequently, we measured inflammatory gene expression in liver and adipose tissue and investigated the role of Raptor deficiency in the regulation of inflammatory responses in peritoneal macrophages from HFD-fed mice or in palmitic acid-stimulated bone marrow-derived macrophages (BMDMs).
  
  
  RESULTS
  Mac-Raptor (KO) mice fed HFD had improved systemic insulin sensitivity compared with Raptor (flox/flox) mice. Macrophage Raptor deficiency reduced inflammatory gene expression in liver and adipose tissue, fatty liver and adipose tissue macrophage content in response to HFD. In peritoneal macrophages from mice fed with an HFD for 12 weeks, macrophage Raptor deficiency decreased inflammatory gene expression, through attenuation of the inactivation of Akt and subsequent inhibition of the inositol-requiring element 1α/clun NH2-terminal kinase-nuclear factor kappa-light-chain-enhancer of activated B cells (IRE1α/JNK/NFκB) pathways. Similarly, mTOR inhibition as a result of Raptor deficiency or rapamycin treatment decreased palmitic acid-induced inflammatory gene expression in BMDMs in vitro.
  
  
  CONCLUSIONS
  The disruption of mTORC1 signalling in macrophages protects mice against inflammation and insulin resistance potentially by inhibiting HFD- and palmitic acid-induced IRE1α/JNK/NFκB pathway activation.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY, USA.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Jiang
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.forename: Chunjiong
authors.initials: C
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ding
authors.initials: D
authors.lastname: Ai
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008820:Mice, Obese; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases