PMID- 31925461
OWN - NLM
STAT- MEDLINE
DCOM- 20210401
LR  - 20210401
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 63
IP  - 4
DP  - 2020 Apr
TI  - An adipocyte-specific defect in oxidative phosphorylation increases systemic 
      energy expenditure and protects against diet-induced obesity in mouse models.
PG  - 837-852
LID - 10.1007/s00125-019-05082-7 [doi]
AB  - AIMS/HYPOTHESIS: Mitochondrial oxidative phosphorylation (OxPhos) is essential 
      for energy production and survival. However, the tissue-specific and systemic 
      metabolic effects of OxPhos function in adipocytes remain incompletely 
      understood. METHODS: We used adipocyte-specific Crif1 (also known as Gadd45gip1) 
      knockout (AdKO) mice with decreased adipocyte OxPhos function. AdKO mice fed a 
      normal chow or high-fat diet were evaluated for glucose homeostasis, weight gain 
      and energy expenditure (EE). RNA sequencing of adipose tissues was used to 
      identify the key mitokines affected in AdKO mice, which included fibroblast 
      growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). For in 
      vitro analysis, doxycycline was used to pharmacologically decrease OxPhos in 
      3T3L1 adipocytes. To identify the effects of GDF15 and FGF21 on the metabolic 
      phenotype of AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) 
      or global Fgf21 knockout (AdFKO). RESULTS: Under high-fat diet conditions, AdKO 
      mice were resistant to weight gain and exhibited higher EE and improved glucose 
      tolerance. In vitro pharmacological and in vivo genetic inhibition of OxPhos in 
      adipocytes significantly upregulated mitochondrial unfolded protein 
      response-related genes and secretion of mitokines such as GDF15 and FGF21. We 
      evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 
      and FGF21 differentially regulated energy homeostasis in AdKO mice. Both 
      mitokines had beneficial effects on obesity and insulin resistance in the context 
      of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice. 
      CONCLUSIONS/INTERPRETATION: The present study demonstrated that the adipose 
      tissue adaptive mitochondrial stress response affected systemic energy 
      homeostasis via cell-autonomous and non-cell-autonomous pathways. We identified 
      novel roles for adipose OxPhos and adipo-mitokines in the regulation of systemic 
      glucose homeostasis and EE, which facilitated adaptation of an organism to local 
      mitochondrial stress.
FAU - Choi, Min Jeong
AU  - Choi MJ
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea.
AD  - Department of Medical Science, Chungnam National University School of Medicine, 
      Daejeon, South Korea.
FAU - Jung, Saet-Byel
AU  - Jung SB
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea.
FAU - Lee, Seong Eun
AU  - Lee SE
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea.
FAU - Kang, Seul Gi
AU  - Kang SG
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea.
AD  - Department of Medical Science, Chungnam National University School of Medicine, 
      Daejeon, South Korea.
FAU - Lee, Ju Hee
AU  - Lee JH
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea.
AD  - Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 
      35015, South Korea.
FAU - Ryu, Min Jeong
AU  - Ryu MJ
AD  - Department of Biochemistry, Chungnam National University School of Medicine, 
      Daejeon, South Korea.
FAU - Chung, Hyo Kyun
AU  - Chung HK
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea.
FAU - Chang, Joon Young
AU  - Chang JY
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea.
AD  - Department of Medical Science, Chungnam National University School of Medicine, 
      Daejeon, South Korea.
FAU - Kim, Yong Kyung
AU  - Kim YK
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea.
FAU - Hong, Hyun Jung
AU  - Hong HJ
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea.
AD  - Department of Medical Science, Chungnam National University School of Medicine, 
      Daejeon, South Korea.
FAU - Kim, Hail
AU  - Kim H
AD  - Graduate School of Medical Science and Engineering, Korea Advanced Institute of 
      Science and Technology, Daejeon, South Korea.
FAU - Kim, Hyun Jin
AU  - Kim HJ
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea.
AD  - Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 
      35015, South Korea.
FAU - Lee, Chul-Ho
AU  - Lee CH
AD  - Animal Model Center, Korea Research Institute of Bioscience and Biotechnology, 
      Daejeon, South Korea.
FAU - Mardinoglu, Adil
AU  - Mardinoglu A
AD  - Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, 
      Sweden.
AD  - Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & 
      Craniofacial Sciences, King's College London, London, UK.
FAU - Yi, Hyon-Seung
AU  - Yi HS
AUID- ORCID: 0000-0002-3767-1954
AD  - Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 
      35015, South Korea. jmpbooks@cnuh.co.kr.
FAU - Shong, Minho
AU  - Shong M
AUID- ORCID: 0000-0002-0247-7115
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, 35015, South Korea. minhos@cnu.ac.kr.
AD  - Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 
      35015, South Korea. minhos@cnu.ac.kr.
LA  - eng
GR  - 2018R1C1B6004439/National Research Foundation of Korea/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200110
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Crif1 protein, mouse)
SB  - IM
MH  - Adipocytes/*metabolism/pathology
MH  - Animals
MH  - Cell Cycle Proteins/*genetics/metabolism
MH  - Diet, High-Fat
MH  - Disease Models, Animal
MH  - Energy Metabolism/*genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Obese
MH  - Obesity/*genetics/metabolism/prevention & control
MH  - Organ Specificity/genetics
MH  - Oxidative Phosphorylation
OTO - NOTNLM
OT  - Adipose tissue
OT  - Energy metabolism
OT  - Insulin resistance
OT  - Mitochondria
OT  - Mitokine
EDAT- 2020/01/12 06:00
MHDA- 2021/04/02 06:00
CRDT- 2020/01/12 06:00
PHST- 2019/07/16 00:00 [received]
PHST- 2019/10/30 00:00 [accepted]
PHST- 2020/01/12 06:00 [pubmed]
PHST- 2021/04/02 06:00 [medline]
PHST- 2020/01/12 06:00 [entrez]
AID - 10.1007/s00125-019-05082-7 [pii]
AID - 10.1007/s00125-019-05082-7 [doi]
PST - ppublish
SO  - Diabetologia. 2020 Apr;63(4):837-852. doi: 10.1007/s00125-019-05082-7. Epub 2020 
      Jan 10.