PMID- 35218776
OWN - NLM
STAT- MEDLINE
DCOM- 20220426
LR  - 20220531
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 298
IP  - 4
DP  - 2022 Apr
TI  - Moderate l-lactate administration suppresses adipose tissue macrophage M1 
      polarization to alleviate obesity-associated insulin resistance.
PG  - 101768
LID - S0021-9258(22)00208-3 [pii]
LID - 10.1016/j.jbc.2022.101768 [doi]
LID - 101768
AB  - As a crucial metabolic intermediate, l-lactate is involved in redox balance, 
      energy balance, and acid-base balance in organisms. Moderate exercise training 
      transiently elevates plasma l-lactate levels and ameliorates obesity-associated 
      type 2 diabetes. However, whether moderate l-lactate administration improves 
      obesity-associated insulin resistance remains unclear. In this study, we defined 
      800 mg/kg/day as the dose of moderate l-lactate administration. In mice fed with 
      a high-fat diet (HFD), moderate l-lactate administration for 12 weeks was shown 
      to alleviate weight gain, fat accumulation, and insulin resistance. Along with 
      the phenotype alterations, white adipose tissue thermogenesis was also found to 
      be elevated in HFD-fed mice. Meanwhile, moderate l-lactate administration 
      suppressed the infiltration and proinflammatory M1 polarization of adipose tissue 
      macrophages (ATMs) in HFD-fed mice. Furthermore, l-lactate treatment suppressed 
      the lipopolysaccharide-induced M1 polarization of bone marrow-derived macrophages 
      (BMDMs). l-lactate can bind to the surface receptor GPR132, which typically 
      drives the downstream cAMP-PKA signaling. As a nutrient sensor, AMP-activated 
      protein kinase (AMPK) critically controls macrophage inflammatory signaling and 
      phenotype. Thus, utilizing inhibitors of the kinases PKA and AMPK as well as 
      siRNA against GPR132, we demonstrated that GPR132-PKA-AMPKalpha1 signaling mediated 
      the suppression caused by l-lactate treatment on BMDM M1 polarization. Finally, 
      l-lactate addition remarkably resisted the impairment of 
      lipopolysaccharide-treated BMDM conditional media on adipocyte insulin 
      sensitivity. In summary, moderate l-lactate administration suppresses ATM 
      proinflammatory M1 polarization through activation of the GPR132-PKA-AMPKalpha1 
      signaling pathway to improve insulin resistance in HFD-fed mice, suggesting a new 
      therapeutic and interventional approach to obesity-associated type 2 diabetes.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Cai, Hao
AU  - Cai H
AD  - School of Food and Biological Engineering, Hefei University of Technology, Hefei, 
      Anhui, China.
FAU - Wang, Xin
AU  - Wang X
AD  - School of Food and Biological Engineering, Hefei University of Technology, Hefei, 
      Anhui, China.
FAU - Zhang, Zhixin
AU  - Zhang Z
AD  - School of Food and Biological Engineering, Hefei University of Technology, Hefei, 
      Anhui, China.
FAU - Chen, Juan
AU  - Chen J
AD  - School of Food and Biological Engineering, Hefei University of Technology, Hefei, 
      Anhui, China.
FAU - Wang, Fangbin
AU  - Wang F
AD  - School of Food and Biological Engineering, Hefei University of Technology, Hefei, 
      Anhui, China.
FAU - Wang, Lu
AU  - Wang L
AD  - School of Food and Biological Engineering, Hefei University of Technology, Hefei, 
      Anhui, China.
FAU - Liu, Jian
AU  - Liu J
AD  - School of Food and Biological Engineering, Hefei University of Technology, Hefei, 
      Anhui, China; Engineering Research Center of Bioprocess, Ministry of Education, 
      Hefei University of Technology, Hefei, Anhui, China. Electronic address: 
      liujian509@hfut.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20220224
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 33X04XA5AT (Lactic Acid)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - *Adipose Tissue/cytology/drug effects/metabolism
MH  - Animals
MH  - *Diabetes Mellitus, Type 2/drug therapy/metabolism
MH  - Diet, High-Fat
MH  - Inflammation/metabolism
MH  - *Insulin Resistance/genetics
MH  - *Lactic Acid/administration & dosage/pharmacology
MH  - *Macrophages/drug effects/metabolism
MH  - Mice
MH  - *Obesity/complications/drug therapy/genetics
MH  - Signal Transduction/drug effects
MH  - Weight Gain/drug effects
PMC - PMC8941214
OTO - NOTNLM
OT  - GPR132-PKA--AMPKalpha1 pathway
OT  - adipose tissue macrophage
OT  - insulin resistance
OT  - moderate l-lactate administration
OT  - obesity
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2022/02/27 06:00
MHDA- 2022/04/27 06:00
PMCR- 2022/02/24
CRDT- 2022/02/26 20:10
PHST- 2021/09/19 00:00 [received]
PHST- 2022/02/16 00:00 [revised]
PHST- 2022/02/17 00:00 [accepted]
PHST- 2022/02/27 06:00 [pubmed]
PHST- 2022/04/27 06:00 [medline]
PHST- 2022/02/26 20:10 [entrez]
PHST- 2022/02/24 00:00 [pmc-release]
AID - S0021-9258(22)00208-3 [pii]
AID - 101768 [pii]
AID - 10.1016/j.jbc.2022.101768 [doi]
PST - ppublish
SO  - J Biol Chem. 2022 Apr;298(4):101768. doi: 10.1016/j.jbc.2022.101768. Epub 2022 
      Feb 24.