PMID- 25120095
OWN - NLM
STAT- MEDLINE
DCOM- 20150706
LR  - 20211203
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 57
IP  - 11
DP  - 2014 Nov
TI  - Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese 
      mice.
PG  - 2393-404
LID - 10.1007/s00125-014-3350-5 [doi]
AB  - 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 1alpha/clun NH2-terminal kinase-nuclear 
      factor kappa-light-chain-enhancer of activated B cells (IRE1alpha/JNK/NFkappaB) 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 IRE1alpha/JNK/NFkappaB pathway activation.
FAU - Jiang, Hongfeng
AU  - Jiang H
AD  - Division of Molecular Medicine, Department of Medicine, Columbia University, New 
      York, NY, USA.
FAU - Westerterp, Marit
AU  - Westerterp M
FAU - Wang, Chunjiong
AU  - Wang C
FAU - Zhu, Yi
AU  - Zhu Y
FAU - Ai, Ding
AU  - Ai D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140814
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Multiprotein Complexes)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Diet, High-Fat
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Immunohistochemistry
MH  - Insulin Resistance/*physiology
MH  - Macrophages/*metabolism
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Obese
MH  - Multiprotein Complexes/genetics/*metabolism
MH  - Obesity/genetics/*metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
EDAT- 2014/08/15 06:00
MHDA- 2015/07/07 06:00
CRDT- 2014/08/15 06:00
PHST- 2014/04/21 00:00 [received]
PHST- 2014/07/16 00:00 [accepted]
PHST- 2014/08/15 06:00 [entrez]
PHST- 2014/08/15 06:00 [pubmed]
PHST- 2015/07/07 06:00 [medline]
AID - 10.1007/s00125-014-3350-5 [doi]
PST - ppublish
SO  - Diabetologia. 2014 Nov;57(11):2393-404. doi: 10.1007/s00125-014-3350-5. Epub 2014 
      Aug 14.