PMID- 34821367
OWN - NLM
STAT- MEDLINE
DCOM- 20220217
LR  - 20220217
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Linking)
VI  - 136
IP  - 1
DP  - 2022 Jan 14
TI  - Augmented CCL5/CCR5 signaling in brown adipose tissue inhibits adaptive 
      thermogenesis and worsens insulin resistance in obesity.
PG  - 121-137
LID - 10.1042/CS20210959 [doi]
AB  - Chemokine (C-C motif) ligand 5 (CCL5) and CCR5, one of its receptors have been 
      reported to be highly expressed in white adipose tissue (WAT) and are associated 
      with the progression of inflammation and the development of insulin resistance in 
      obese humans and mice. However, the role of CCL5/CCR5 signaling in 
      obesity-associated dysregulation of energy metabolism remains unclear. Here, we 
      demonstrate that global CCL5/CCR5 double knockout (DKO) mice have higher cold 
      stress-induced energy expenditure and thermogenic function in brown adipose 
      tissue (BAT) than wildtype (WT) mice. DKO mice have higher cold stress-induced 
      energy expenditure and thermogenic function in BAT than WT mice. KEGG pathway 
      analysis indicated that deletion of CCL5/CCR5 further facilitated the 
      cold-induced expression of genes related to oxidative phosphorylation (OxPhos) 
      and lipid metabolic pathways. In primary brown adipocytes of DKO mice, the 
      augmentation of CL-316243-stimulated thermogenic and lipolysis responses was 
      reversed by co-treatment with AMPKalpha1 and alpha2 short interfering RNA (siRNA). 
      Overexpression of BAT CCL5/CCR5 genes by local lentivirus injection in WT mice 
      suppressed cold stress-induced lipolytic processes and thermogenic activities. In 
      contrast, knockdown of BAT CCL5/CCR5 signaling further up-regulated AMPK 
      phosphorylation as well as thermogenic and lipolysis responses to chronic 
      adrenergic stimuli and subsequently decreased level of body weight gain. Chronic 
      knockdown of BAT CCL5/CCR5 signaling improved high-fat diet (HFD)-induced insulin 
      resistance in WT mice. It is suggested that obesity-induced augmentation of 
      adipose tissue (AT) CCL5/CCR5 signaling could, at least in part, suppress energy 
      expenditure and adaptive thermogenesis by inhibiting AMPK-mediated lipolysis and 
      oxidative metabolism in thermogenic AT to exacerbate the development of obesity 
      and insulin resistance.
CI  - (c) 2022 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Chan, Pei-Chi
AU  - Chan PC
AD  - Department of Physiology and Biophysics, National Defense Medical Center (NDMC), 
      Taipei, Taiwan.
FAU - Hung, Li-Man
AU  - Hung LM
AD  - Department and Graduate Institute of Biomedical Sciences and Healthy Aging 
      Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
FAU - Huang, Jiung-Pang
AU  - Huang JP
AD  - Department and Graduate Institute of Biomedical Sciences and Healthy Aging 
      Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
FAU - Day, Yuan-Ji
AU  - Day YJ
AD  - Department of Anesthesiology, Tung's Taichung Metro Harber Hospital, Taichung, 
      Taiwan.
FAU - Yu, Chao-Lan
AU  - Yu CL
AD  - Department and Graduate Institute of Biomedical Sciences and Healthy Aging 
      Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
FAU - Kuo, Feng-Chih
AU  - Kuo FC
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, 
      Tri-Service General Hospital, NDMC, Taipei, Taiwan.
FAU - Lu, Chieh-Hua
AU  - Lu CH
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, 
      Tri-Service General Hospital, NDMC, Taipei, Taiwan.
FAU - Tian, Yu-Feng
AU  - Tian YF
AD  - Division of General Surgery, Department of Surgery, Yung Kung Campus, Chi-Mei 
      Medical Center, Tainan, Taiwan; Chia Nan University of Pharmacy and Science, 
      Tainan, Taiwan.
FAU - Hsieh, Po-Shiuan
AU  - Hsieh PS
AUID- ORCID: 0000-0002-3402-9851
AD  - Department of Physiology and Biophysics, National Defense Medical Center (NDMC), 
      Taipei, Taiwan.
AD  - Graduate Institute of Medical Science, NDMC, Taipei, Taiwan.
AD  - Department of Medical Research, Tri-Service General Hospital, Taipei, Taiwan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (CCR5 protein, mouse)
RN  - 0 (Chemokine CCL5)
RN  - 0 (Receptors, CCR5)
SB  - IM
MH  - Adipose Tissue, Brown/*metabolism
MH  - Animals
MH  - Chemokine CCL5/genetics/*metabolism
MH  - Diet, High-Fat
MH  - Gene Expression Regulation
MH  - *Insulin Resistance
MH  - Mice
MH  - Mice, Knockout
MH  - Obesity/*metabolism
MH  - Oxidative Phosphorylation
MH  - Receptors, CCR5/genetics/*metabolism
MH  - Signal Transduction
MH  - Thermogenesis
OTO - NOTNLM
OT  - AMPK
OT  - CCL5/CCR5 signaling
OT  - adaptive thermogenesis
EDAT- 2021/11/26 06:00
MHDA- 2022/02/19 06:00
CRDT- 2021/11/25 08:55
PHST- 2021/10/07 00:00 [received]
PHST- 2021/11/24 00:00 [revised]
PHST- 2021/11/24 00:00 [accepted]
PHST- 2021/11/26 06:00 [pubmed]
PHST- 2022/02/19 06:00 [medline]
PHST- 2021/11/25 08:55 [entrez]
AID - 230294 [pii]
AID - 10.1042/CS20210959 [doi]
PST - ppublish
SO  - Clin Sci (Lond). 2022 Jan 14;136(1):121-137. doi: 10.1042/CS20210959.