Obesity is a major health problem in the USA and the accumulated health cost due to obesity alone was reported to be ~80 billion USD in the year 2010, which is projected to cross 350 billion USD by the year 2025. Research in the last two decades has shown that in majority of the cases obesity is due to energy surplus and can be treated by increasing energy expenditure. In spite of significant progress in the understanding about ways to target cellular bioenergetics to increase energy expenditure most of these are reliant on uncoupling protein 1 (UCP1)-based mechanisms, that is a minor component in most adult human beings. Therefore, alternative mechanism of thermogenesis should be paid equal importance to enhance energy expenditure to treat obesity. We have recently discovered a novel thermogenic mechanism by a protein called Sarcolipin (SLN), published in Nature Medicine in 2012. SLN is a 31 amino acid single transmembrane protein, that regulate the function of SERCA pump. Binding of SLN to SERCA promotes uncouple ATP hydrolysis of SERCA pump from Ca2+ transport leading to futile cycling and increased ATP utilization contributing to muscle-based non-shivering thermogenesis (NST). We have shown that loss of SLN predisposes mice to develop obesity on high fat diet (HFD) but upregulation of SLN provide protection against HFD-induced obesity. Our next study shows that skeletal muscle specific overexpression of SLN drives mitochondrial biogenesis and fuels oxidative metabolism in skeletal muscle providing resistance to obesity, is under final stages of publication. Further, genetic alteration in chromosomal locus containing SLN has also been shown to be associated with obesity in humans, suggesting SLN-mediated energy consumption may be a factor in obesity. Skeletal muscle constitutes ~40% of mammalian body mass and accounts for ~80% of metabolic substrate consumption. Therefore skeletal muscle offers an ideal target to increase energy expenditure, pharmacologically as a strategy for the treatment of obesity. In this application, I propose to identify lead compounds enhancing SLN-mediated skeletal muscle-based energy expenditure, using a multifaceted approach including studies at the whole animal, tissue, cell and computational levels. I have data to indicate that capsaicin enhances SLN-SERCA binding. I have also developed a cell-based assay to screen compounds with ability to enhance SLN-mediated uncoupling of SERCA. I have designed and synthesized four different capsaicin analogs, by modifying the side-chains. My preliminary data suggest that one these four capsaicin-analogs possess better activity than capsaicin itself. These facts provide more confidence in my initial hypothesis and I propose the following three aims towards achieving my final goal.
In Aim 1, I will try to identify the best capsaicin-analog to increase SLN-mediated energy expenditure and anti- obesity lead.
In Aim 2, I will further explore other classes of compounds (many chemical libraries are available in college of pharmacy on campus) known to affect SERCA function and/or increase energy consumption, to Identify chemicals that increase SLN-mediated uncoupling of SERCA and possess anti-obesity activity.
In AIM 3, I am working to develop a responsive atomistic model of SLN-SERCA-ligand interaction to define the pharmacophores and optimize the shortlisted anti-obesity agents. We believe that identification of chemical compounds with ability to enhance SLN action on SERCA will provide an exciting new opportunity to pharmacologically increase muscle-based energy consumption and control obesity.
Obesity is a major health issue in the USA and obesity-related financial burden is expected to exceed 350 billion US dollars by 2025. However, pharmaceutical strategies that enhance energy expenditure to treat obesity rely mainly on brown adipose tissue (BAT)-based thermogenesis that plays a minor role in adult humans. We have discovered sarcolipin (SLN)-based thermogenesis in skeletal muscle as an alternate mechanism to increase energy expenditure. SLN is expressed abundantly in the skeletal muscles of healthy humans and genetic alteration in the chromosomal locus containing SLN has also been shown to be associated with obesity in humans, suggesting SLN-SERCA interaction in skeletal muscle may be a factor in obesity. Binding of SLN to SERCA promotes uncoupling of SERCA pump from Ca2+ transport leading to increased ATP utilization and energy expenditure. In this grant, I propose to identify compounds that can enhance SLN-mediated energy expenditure using a multifaceted approach including structural chemistry, and computational, cell, tissue and whole animal level studies. These studies will pave the way for further investigation to target muscle-energy metabolism towards the treatment of obesity.
| Periasamy, Muthu; Maurya, Santosh Kumar; Sahoo, Sanjaya Kumar et al. (2017) Role of SERCA Pump in Muscle Thermogenesis and Metabolism. Compr Physiol 7:879-890 |
| Bal, Naresh C; Singh, Sushant; Reis, Felipe C G et al. (2017) Both brown adipose tissue and skeletal muscle thermogenesis processes are activated during mild to severe cold adaptation in mice. J Biol Chem 292:16616-16625 |
| Pant, Meghna; Bal, Naresh C; Periasamy, Muthu (2016) Sarcolipin: A Key Thermogenic and Metabolic Regulator in Skeletal Muscle. Trends Endocrinol Metab 27:881-892 |
| Rowland, Leslie A; Maurya, Santosh K; Bal, Naresh C et al. (2016) Sarcolipin and uncoupling protein 1 play distinct roles in diet-induced thermogenesis and do not compensate for one another. Obesity (Silver Spring) 24:1430-3 |
| Bal, Naresh C; Maurya, Santosh K; Singh, Sushant et al. (2016) Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function. J Biol Chem 291:17247-57 |
