Loss of Tmem127 Protects Against Insulin Resistance Due to Aging, High-Fat Diet and Rapamycin Treatment

Presentation Number: SAT 577
Date of Presentation: April 1st, 2017

Subramanya Srikantan*1, Yilun Deng1, Anqi Luo1, Yuejuan Qin1, Zi-Ming Cheng1, Qing Gao1, Myrna Garcia1, Zhi Li1, Adam Salmon2, Lily Q Dong1, Robert Reddick1, Luke Norton1, Muhammad Abdul-Ghani1 and Patricia L.M. Dahia1
1UTHSCSA, San Antonio, TX, 2South Texas Veterans Health Care System, San Antonio, TX


Obesity is associated with increase in Type 2 diabetes and linked to decreasing health span in aging populations. Reduction in obesity decreases the risk of diabetes and its associated insulin resistance. At the molecular level, increased activation of mechanistic target of Rapamycin (mTOR) is associated with obesity. Inhibition of mTOR complex1 (mTORC1) by rapamycin reduces body mass and increases life span in mammals and mTOR inhibitors are clinically used in cancers. However, rapamycin treatment leads to glucose intolerance and insulin resistance, potentially limiting its use as an anti-aging or anti-cancer agent. TMEM127 is a lysosomal protein that impinges on mTORC1 through mechanisms involving mTORC1 recruitment to its activation site at the lysosome. We investigated the effects of Tmem127 loss by targeted deletion of theTmem127gene in mice (KO). Chow diet-fed KO mice have reduced body weight and fat mass, and show resistance to age-dependent glucose and insulin intolerance. When challenged with insulin, KO liver, fat and muscle displayed higher Akt activation, consistent with increased insulin sensitivity. To better appreciate the protective role of Tmem127 deficiency we investigated the effect of other insulin resistance inducing stresses in the KO mice. High-fat diet (HFD) induced obesity in the KO mice (similar to that of WT) but the KO mice remained insulin-sensitive whereas the WT mice developed insulin resistance. When switched back to chow diet, the WT mice remained insulin resistant whereas KO mice improved their insulin sensitivity. Likewise, KO mice were protected from glucose and insulin intolerance after rapamycin exposure, suggesting a broader effect of Tmem127 deficiency against insulin resistance induced by distinct stimuli. Mechanistically, liver from HFD- and rapamycin-treated KO mice retained mTORC2 activity. We propose that the favorable insulin metabolism of Tmem127 KO mice may be due to heightened mTORC2 stability. Tissue-specific TMEM127 deletion will shed light on the primary tissue targeted by TMEM127 action (currently under development). However, our data suggest that TMEM127 inhibition might enhance effectiveness of interventions aiming to selectively block mTORC1 signaling.


Nothing to Disclose: SS, YD, AL, YQ, ZMC, QG, MG, ZL, AS, LQD, RR, LN, MA, PLMD