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 - Funding Information:
We thank Nick Musi and Adam Salmon for insightful discussions, Martin Javors, Elizabeth Fernandez, Veronica Galvan, Yuji Ikeno, and Kat Fischer for access to technical resources; Myrna Garcia, Eric Baeuerle, An-Ping Lin, Jiyoon Ryu, Stacy Ann Hussong, Hak Joo Lee, Meenalakshmi M. Mariappan, Vanessa Martinez, and Vivian Diaz for technical support. This work was supported by the NIH/NIA T32AG021890 (S.S.); NIH/ NIGMS GM114102 (P.L.M.D.), NIH/NIDDK DK102965 (L.Q.D.), Cancer Prevention and Research Institute of Texas (CPRIT) Individual Investigator Grants RP101202 and RP140473 (P.L.M.D), RP170146, RP190043 (R.C.T.A) and Training Grant RP140105 (Y.D.); Department of Defense CDMRP W81XWH-12-1-0508 (P.L.M.D.), Leukemia and Lymphoma Society TRP-6524-17, and VA MERIT—I01 BX001882-08 (R.C.T.A.). Animal studies were also supported by the San Antonio Nathan Shock Center, and the CTSA-IIMS (NIH/NCATS Grant UL1 TR001120 and UL1 TR002645). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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.
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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 -