Project 458415

25% of the Canadian population is considered obese and it's becoming imperative that research find alternative ways to fight off obesity and its associated negative effects. One way to counter obesity is to 'burn' more calories, or energy. In muscle, a pump called SERCA uses energy and burns calories in order to regulate calcium levels in muscle. By doing so, SERCA accounts for up to 50% of energy usage in muscle and 25% of the energy used by our whole body. This means that the SERCA pump is a metabolic hub and increasing its energy usage can 'burn' more calories to combat obesity. To do this, our research aims to reduce SERCA efficiency. Like a fuel inefficient car requiring more gas per kilometers travelled, an inefficient SERCA pump will require more energy to regulate calcium levels in our muscles. Sarcolipin (SLN) is a small protein in our muscles that reduces SERCA's efficiency, and mice without SLN are more susceptible to obesity. Neuronatin (NNAT) is a protein that I have recently shown to be present in skeletal muscle and is structurally similar to SLN. My CIHR CGS-M funded master's work has shown that, in cultured cells, NNAT also reduces SERCA efficiency like SLN. For my dissertation, I plan to extend this work by specifically determining whether NNAT promotes SERCA inefficiency and attenuates diet-induced obesity in mice. To this end, I will assess body composition (i.e., fat content), energy expenditure, glucose regulation and SERCA efficiency in novel mouse models that will test whether increasing NNAT expression in muscle can prevent diet-induced obesity in mice that have, or don't have, sarcolipin. Lastly, I will also determine the effects of genetically modifying NNAT with a mutation known to be associated with human obesity on SERCA efficiency and diet-induced obesity. By using these approaches, I will solidify the role of NNAT as a modifier of SERCA efficiency, revealing a therapeutic target that could improve the health of millions of Canadians.