Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice
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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.
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).
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.
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.
KeywordsInflammation Insulin resistance mTORC1
Activating transcription factor 6
Adipose tissue macrophage
Bone marrow-derived macrophage
Eukaryotic translation initiation factor 2α
Intraperitoneal glucose tolerance test
Intraperitoneal insulin tolerance test
Inositol-requiring element 1α
cJun NH2-terminal kinase
Mammalian target of rapamycin complex 1/2
Nuclear factor κB
Nuclear magnetic resonance
RNA-dependent protein kinase-like ER kinase
p70 S6 kinase
Regulatory associated protein of mTOR
Saturated fatty acid
Unfolded protein response
White adipose tissue
X box binding protein 1
The authors would like to thank A. Tall, Columbia University, New York, NY, USA, for his advice and help on experimental design and manuscript writing.
DA is supported by the National Natural Science Foundation of China (Nos 81322006 and 81370396). YZ is supported by the Major National Basic Research Grant of China (No. 2010CB912504). MW is supported by The Netherlands Organization of Scientific Research (NWO VENI – grant 916.11.072).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
HJ contributed to the concept and design, data acquisition, analysis and interpretation and drafting of the article. MW contributed to the concept and design, data acquisition and revision of the article. CW and YZ contributed to the data acquisition and analysis and revision of the article. DA contributed to the concept and design, data acquisition, analysis and interpretation of data and revision of the article. DA is the guarantor of the work. All authors approved the final version.
- 35.Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH (2006) Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol 26:3071–3084PubMedCrossRefPubMedCentralGoogle Scholar