Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion.
Tre-2/USP6, BUB2, cdc16 domain family member 1 (the TBC domain is the GTPase activating protein domain) (TBC1D1) is a Rab GTPase activating protein that is phosphorylated on Ser(231) by the AMP-activated protein kinase (AMPK) in response to intracellular energy stress. However, the in vivo role and importance of this phosphorylation event remains unknown. To address this question, we generated a mouse model harboring a TBC1D1(Ser231Ala) knockin (KI) mutation and found that the KI mice developed obesity on a normal chow diet. Mechanistically, TBC1D1 is located on insulin-like growth factor 1 (IGF1) storage vesicles, and the KI mutation increases endocrinal and paracrinal/autocrinal IGF1 secretion in an Rab8a-dependent manner. Hypersecretion of IGF1 causes increased expression of lipogenic genes via activating the protein kinase B (PKB; also known as Akt)-mammalian target of rapamycin (mTOR) pathway in adipose tissues, which contributes to the development of obesity, diabetes, and hepatic steatosis as the KI mice age. Collectively, these findings demonstrate that the AMPK-TBC1D1 signaling nexus interacts with the PKB-mTOR pathway via IGF1 secretion, which consequently controls expression of lipogenic genes in the adipose tissue. These findings also have implications for drug discovery to combat obesity.
State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China;
Liang
L
Chen
State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China;
Qiaoli
Q
Chen
State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China;
Bingxian
B
Xie
State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China;
Chao
C
Quan
State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China;
Yang
Y
Sheng
State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China;
Sangsang
S
Zhu
State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China;
Ping
P
Rong
State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China;
Shuilian
S
Zhou
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom;
Kei
K
Sakamoto
Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom;
Carol
C
MacKintosh
State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China; Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China wanghy@nicemice.cn schen6@163.com.
Hong Yu
HY
Wang
State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China; Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China wanghy@nicemice.cn schen6@163.com.
Shuai
S
Chen
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D020690:GTPase-Activating Proteins; C095906:Tbc1d1 protein, mouse; D014280:Triglycerides; D012694:Serine; D007334:Insulin-Like Growth Factor I; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
AMPK; IGF1 secretion; TBC1D1; obesity; phosphorylation