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Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice

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Abstract

Aims/hypothesis

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/interpretation

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.

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Abbreviations

ATF6:

Activating transcription factor 6

ATM:

Adipose tissue macrophage

BMDM:

Bone marrow-derived macrophage

CD:

Chow diet

ConA:

Concanavalin A

DIO:

Diet-induced obesity

eIF2α:

Eukaryotic translation initiation factor 2α

ER:

Endoplasmic reticulum

HFD:

High-fat diet

IPGTT:

Intraperitoneal glucose tolerance test

IPITT:

Intraperitoneal insulin tolerance test

IRE1α:

Inositol-requiring element 1α

JNK:

cJun NH2-terminal kinase

mTORC1/2:

Mammalian target of rapamycin complex 1/2

NF-κB:

Nuclear factor κB

NMR:

Nuclear magnetic resonance

PERK:

RNA-dependent protein kinase-like ER kinase

p70S6k:

p70 S6 kinase

Raptor:

Regulatory associated protein of mTOR

SFA:

Saturated fatty acid

TG:

Triacylglycerol

TLR:

Toll-like receptor

UPR:

Unfolded protein response

WAT:

White adipose tissue

XBP1:

X box binding protein 1

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Acknowledgements

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.

Funding

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.

Contribution statement

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.

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Authors and Affiliations

  1. Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY, USA

    Hongfeng Jiang, Marit Westerterp & Ding Ai

  2. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Marit Westerterp

  3. Department of Physiology and Pathophysiology, Tianjin Medical University, 300070, Tianjin, People’s Republic of China

    Chunjiong Wang, Yi Zhu & Ding Ai

Authors
  1. Hongfeng Jiang
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  2. Marit Westerterp
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  3. Chunjiong Wang
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  4. Yi Zhu
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  5. Ding Ai
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Corresponding author

Correspondence to Ding Ai.

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Jiang, H., Westerterp, M., Wang, C. et al. Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice. Diabetologia 57, 2393–2404 (2014). https://doi.org/10.1007/s00125-014-3350-5

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  • DOI: https://doi.org/10.1007/s00125-014-3350-5

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