The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner

Subramanya Srikantan, Yilun Deng, Zi-Ming Cheng, Anqi Luo, Yuejuan Qin, Qing Gao, Glaiza-Mae Sande-Docor, Sifan Tao, Xingyu Zhang, Nathan Harper, Chris E. Shannon, Marcel Fourcaudot, Zhi Li, Balakuntalam S. Kasinath, Stephen Harrison, Sunil Ahuja, Robert L. Reddick, Lily Q. Dong, Muhammad Abdul-Ghani, Luke Norton, Ricardo C. T. Aguiar and Patricia L. M. Dahia ()
Additional contact information
Subramanya Srikantan: University of Texas Health Science Center at San Antonio (UTHSCSA)
Yilun Deng: University of Texas Health Science Center at San Antonio (UTHSCSA)
Zi-Ming Cheng: University of Texas Health Science Center at San Antonio (UTHSCSA)
Anqi Luo: University of Texas Health Science Center at San Antonio (UTHSCSA)
Yuejuan Qin: University of Texas Health Science Center at San Antonio (UTHSCSA)
Qing Gao: University of Texas Health Science Center at San Antonio (UTHSCSA)
Glaiza-Mae Sande-Docor: University of Texas Health Science Center at San Antonio (UTHSCSA)
Sifan Tao: University of Texas Health Science Center at San Antonio (UTHSCSA)
Xingyu Zhang: University of Texas Health Science Center at San Antonio (UTHSCSA)
Nathan Harper: University of Texas Health Science Center at San Antonio (UTHSCSA)
Chris E. Shannon: University of Texas Health Science Center at San Antonio (UTHSCSA)
Marcel Fourcaudot: University of Texas Health Science Center at San Antonio (UTHSCSA)
Zhi Li: University of Texas Health Science Center at San Antonio (UTHSCSA)
Balakuntalam S. Kasinath: University of Texas Health Science Center at San Antonio (UTHSCSA)
Stephen Harrison: University of Oxford
Sunil Ahuja: University of Texas Health Science Center at San Antonio (UTHSCSA)
Robert L. Reddick: UTHSCSA, 7703 Floyd Curl Drive
Lily Q. Dong: University of Texas Health Science Center at San Antonio (UTHSCSA)
Muhammad Abdul-Ghani: University of Texas Health Science Center at San Antonio (UTHSCSA)
Luke Norton: University of Texas Health Science Center at San Antonio (UTHSCSA)
Ricardo C. T. Aguiar: University of Texas Health Science Center at San Antonio (UTHSCSA)
Patricia L. M. Dahia: University of Texas Health Science Center at San Antonio (UTHSCSA)

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12661-0

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