TY - JOUR
T1 - The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner
AU - Srikantan, Subramanya
AU - Deng, Yilun
AU - Cheng, Zi Ming
AU - Luo, Anqi
AU - Qin, Yuejuan
AU - Gao, Qing
AU - Sande-Docor, Glaiza Mae
AU - Tao, Sifan
AU - Zhang, Xingyu
AU - Harper, Nathan
AU - Shannon, Chris E.
AU - Fourcaudot, Marcel
AU - Li, Zhi
AU - Kasinath, Balakuntalam S.
AU - Harrison, Stephen
AU - Ahuja, Sunil
AU - Reddick, Robert L.
AU - Dong, Lily Q.
AU - Abdul-Ghani, Muhammad
AU - Norton, Luke
AU - Aguiar, Ricardo C.T.
AU - Dahia, Patricia L.M.
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.
AB - Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.
UR - http://www.scopus.com/inward/record.url?scp=85073511942&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073511942&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12661-0
DO - 10.1038/s41467-019-12661-0
M3 - Article
C2 - 31624249
AN - SCOPUS:85073511942
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4720
ER -