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Targeting PLD2 in adipocytes augments adaptive thermogenesis by improving mitochondrial quality and quantity in mice

Authors
 Hyung Sik Kim  ;  Min Young Park  ;  Nam Joo Yun  ;  Hye Sun Go  ;  Mi Young Kim  ;  Je Kyung Seong  ;  Minyoung Lee  ;  Eun Seok Kang  ;  Jaewang Ghim  ;  Sung Ho Ryu  ;  Brian A Zabel  ;  Ara Koh  ;  Yoe-Sik Bae 
Citation
 JOURNAL OF EXPERIMENTAL MEDICINE, Vol.219(2) : e20211523, 2021-12 
Journal Title
JOURNAL OF EXPERIMENTAL MEDICINE
ISSN
 0022-1007 
Issue Date
2021-12
MeSH
Adipocytes / metabolism* ; Animals ; Biomarkers ; Blood Glucose ; Diet, High-Fat ; Energy Metabolism ; Enzyme Inhibitors / pharmacology ; Gene Expression Regulation ; Immunohistochemistry ; Insulin Resistance ; Male ; Mice ; Mice, Knockout ; Mitochondria / genetics* ; Mitochondria / metabolism* ; Mitochondria / ultrastructure ; Obesity / etiology ; Obesity / metabolism ; Phospholipase D / antagonists & inhibitors ; Phospholipase D / genetics* ; Phospholipase D / metabolism ; Proteasome Endopeptidase Complex / metabolism ; Thermogenesis / genetics* ; Uncoupling Protein 1 / genetics ; Uncoupling Protein 1 / metabolism
Abstract
Phospholipase D (PLD)2 via its enzymatic activity regulates cell proliferation and migration and thus is implicated in cancer. However, the role of PLD2 in obesity and type 2 diabetes has not previously been investigated. Here, we show that during diet-induced thermogenesis and obesity, levels of PLD2 but not PLD1 in adipose tissue are inversely related with uncoupling protein 1, a key thermogenic protein. We demonstrate that the thermogenic program in adipose tissue is significantly augmented in mice with adipocyte-specific Pld2 deletion or treated with a PLD2-specific inhibitor and that these mice are resistant to high fat diet-induced obesity, glucose intolerance, and insulin resistance. Mechanistically, we show that Pld2 deletion in adipose tissue or PLD2 pharmacoinhibition acts via p62 to improve mitochondrial quality and quantity in adipocytes. Thus, PLD2 inhibition is an attractive therapeutic approach for obesity and type 2 diabetes by resolving defects in diet-induced thermogenesis.
Files in This Item:
T202126256.pdf Download
DOI
10.1084/jem.20211523
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Eun Seok(강은석) ORCID logo https://orcid.org/0000-0002-0364-4675
Lee, Minyoung(이민영) ORCID logo https://orcid.org/0000-0002-9333-7512
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/190662
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