The Influence of GATOR1 Sub Complex NPRL2 on Anabolic Signaling During Insulin Resistance in Rats

Skeletal muscle metabolism plays a significant role in dysregulation of protein synthesis signaling pathways in skeletal muscle is a contributing factor in multiple disease states including Type 2 Diabetes (T2D). In insulin resistant rats, there is a well‐documented increase in mammalian target of Rapamycin (mTOR) activity, in contrast to observed muscle mass losses. In several types of cancer, the same mTOR increases were attributed to a deficiency in at least one of the GATOR1 sub complexes (DEPDC5, NPRL2, NPRL3). GATOR1 is a GTPase activating protein, which when active, is an mTOR inhibitor. When one or more of these sub complexes are deficient, GATOR1 will not inhibit mTOR. NPRL2 is specifically associated with the Gap activity observed with Gator1 and it's mTOR inhibition. It has been shown that specific knockout of NPRL2 in mouse skeletal muscle resulted in increased mTORC1 activity. While this deficiency and its relationship to downstream targets of mTOR are documented in multiple cancer models, the relationship of GATOR1 sub complexes with insulin resistance is less clear. The purpose of this study was to determine the relationship between NPRL2 and the observed mTOR response to insulin resistance as well as this relationship with or without exercise. METHODS Male obese and lean zucker rats were given twelve days of acclimation and then assigned to control or exercise groups blocked for lean mass. The exercise groups were put through 4 bouts of resistance exercise over an eight day period using the “squat” resistance model. RESULTS Our results indicate NPRL2 content is lower in the obese rats with or without prior exercise. This corresponds to higher mTOR activity, demonstrated by phosphorylation of p70S6k, being higher in the obese rats than in the lean rats. CONCLUSION These results contribute to the understanding of insulin resistance and muscle's metabolic role in that resistance. NPRL2 and the GATOR1 complex may be another key player in the understanding of the mTOR dysregulation with metabolic disease. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .