PMID- 30723473
OWN - NLM
STAT- MEDLINE
DCOM- 20191220
LR  - 20200309
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 10
DP  - 2019
TI  - Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic 
      Abnormalities in Mice.
PG  - 17
LID - 10.3389/fimmu.2019.00017 [doi]
LID - 17
AB  - Chronic low-grade inflammation in visceral adipose tissues triggers the 
      development of obesity-related insulin resistance, leading to the metabolic 
      syndrome, a serious health condition with higher risk of cardiovascular disease, 
      diabetes, and stroke. In the present study, we investigated whether 
      Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator 
      of the Ras/Raf/ERK/MAPK pathway, plays a role in the development of high fat diet 
      (HFD)-induced obesity, adipose tissue inflammation, metabolic abnormalities, and 
      insulin resistance. Spred2 knockout (KO) mice, fed with HFD, exhibited an 
      augmented body weight gain, which was associated with enhanced adipocyte 
      hypertrophy in mesenteric white adipose tissue (mWAT) and deteriorated 
      dyslipidemia, compared with wild-type (WT) controls. The number of infiltrating 
      macrophages with a M1 phenotype, and the crown-like structures, composed of 
      macrophages surrounding dead or dying adipocytes, were more abundant in Spred2 
      KO-mWAT compared to in WT-mWAT. Exacerbated adipose tissue inflammation in Spred2 
      KO mice led to aggravated insulin resistance and fatty liver disease. To analyze 
      the mechanism(s) that caused adipose tissue inflammation, cytokine response in 
      mWAT was investigated. Stromal vascular fraction that contained macrophages from 
      Spred2 KO-mWAT showed elevated levels of tumor necrosis factor alpha (TNFalpha) and 
      monocyte chemoattractant protein-1 (MCP-1/CCL2) compared with those from WT-mWAT. 
      Upon stimulation with palmitate acid (PA), bone marrow-derived macrophages 
      (BMDMs) derived from Spred2 KO mice secreted higher levels of TNFalpha and MCP-1 than 
      those from WT mice with enhanced ERK activation. U0126, a MEK inhibitor, reduced 
      the PA-induced cytokine response. Taken together, these results suggested that 
      Spred2, in macrophages, negatively regulates high fat diet-induced obesity, 
      adipose tissue inflammation, metabolic abnormalities, and insulin resistance by 
      inhibiting the ERK/MAPK pathway. Thus, Spred2 represents a potential therapeutic 
      tool for the prevention of insulin resistance and resultant metabolic syndrome.
FAU - Ohkura, Takahiro
AU  - Ohkura T
AD  - Department of Pathology and Experimental Medicine, Okayama University Graduate 
      School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
FAU - Yoshimura, Teizo
AU  - Yoshimura T
AD  - Department of Pathology and Experimental Medicine, Okayama University Graduate 
      School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
FAU - Fujisawa, Masayoshi
AU  - Fujisawa M
AD  - Department of Pathology and Experimental Medicine, Okayama University Graduate 
      School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
FAU - Ohara, Toshiaki
AU  - Ohara T
AD  - Department of Pathology and Experimental Medicine, Okayama University Graduate 
      School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
FAU - Marutani, Rie
AU  - Marutani R
AD  - Department of Pathology and Experimental Medicine, Okayama University Graduate 
      School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
FAU - Usami, Kaya
AU  - Usami K
AD  - Department of Pathology and Experimental Medicine, Okayama University Graduate 
      School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
FAU - Matsukawa, Akihiro
AU  - Matsukawa A
AD  - Department of Pathology and Experimental Medicine, Okayama University Graduate 
      School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190122
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Fatty Acids)
RN  - 0 (Repressor Proteins)
RN  - 0 (Spred2 protein, mouse)
SB  - IM
MH  - Adipocytes/metabolism
MH  - Animals
MH  - Biomarkers
MH  - Biopsy
MH  - Cytokines/metabolism
MH  - Diet, High-Fat/*adverse effects
MH  - Disease Models, Animal
MH  - *Disease Susceptibility
MH  - Dyslipidemias/etiology/metabolism
MH  - Fatty Acids/metabolism
MH  - Hypertrophy
MH  - Insulin Resistance
MH  - Lipid Metabolism
MH  - Lipolysis
MH  - MAP Kinase Signaling System
MH  - Macrophages/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Obesity/etiology/metabolism
MH  - Panniculitis/diagnostic imaging/*etiology/*metabolism/pathology
MH  - Repressor Proteins/*genetics/metabolism
MH  - X-Ray Microtomography
PMC - PMC6349710
OTO - NOTNLM
OT  - Ras/Raf/ERK/MAPK
OT  - Spred2
OT  - adipocyte
OT  - inflammation
OT  - macrophage
OT  - obesity
EDAT- 2019/02/07 06:00
MHDA- 2019/12/21 06:00
PMCR- 2019/01/01
CRDT- 2019/02/07 06:00
PHST- 2018/10/05 00:00 [received]
PHST- 2019/01/04 00:00 [accepted]
PHST- 2019/02/07 06:00 [entrez]
PHST- 2019/02/07 06:00 [pubmed]
PHST- 2019/12/21 06:00 [medline]
PHST- 2019/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2019.00017 [doi]
PST - epublish
SO  - Front Immunol. 2019 Jan 22;10:17. doi: 10.3389/fimmu.2019.00017. eCollection 
      2019.