Obesity is a significant public health burden in both developed and developing nations that contributes to the incidence of several other chronic diseases including diabetes, cardiovascular disease, and cancer. Due to the growing economic and health costs of obesity, discovering novel drugs that act as anti-obesity therapeutics is a critical area of research. Brown and beige fat have been identified as possible targets for obesity therapy, as these types of adipose tissue burn fat to increase energy expenditure and reduce fat storage. Peroxisome proliferation-activated receptor gamma coactivator-1? (PGC-1??) is a metabolic regulator that is activated in brown and beige fat with cold stimulation and acts to increase energy expenditure and oxidative metabolism. The activity of PGC-1?? can be modulated through its acetylation status, with acetylation by the acetyltransferase general control of amino acid synthesis 5 (GCN5) leading to a decrease in its activity. Our lab has conducted a high-throughput screen to identify novel drugs that can modify the acetylation status of PGC-1?? in order to find novel therapies for obesity and its related disorders. We have identified one compound, which we have named compound 22, which effectively deacetylates PGC-1?? and activates thermogenic and oxidative metabolic gene expression in brown and beige adipocytes. Thus, we hypothesize that compound 22 can act as an anti-obesity drug through its effects on PGC-1?? deacetylation and energy expenditure. To test this hypothesis, we will address three specific aims in this proposal: 1) determine the mechanism through which compound 22 inhibits GCN5 to increase PGC-1?? deacetylation; 2) elucidate the effects of compound 22 on metabolism in primary brown and beige adipocytes, and whether these effects depend on GCN5; 3) delineate the in vivo effects of compound 22 on brown and beige fat physiology and obesity in mice, and discover whether the mechanism of these effects occurs through GCN5 inhibition.
For Aim 1, we will determine whether compound 22 either directly inhibits GCN5 or inhibits GCN5 indirectly through a kinase.
For Aim 2, we will investigate the effects of compound 22 on mitochondrial metabolism in brown and beige adipocytes with and without cAMP stimulation and GCN5 knockdown.
In Aim 3, we will treat control and brown and beige fat-specific UCP1-Cre GCN5 knockout mice with compound 22 with and without cold stress or a high fat diet and assess their metabolism and obesity to determine whether compound 22 can behave as anti-obesity therapeutic. These studies will reveal the mechanisms of action of compound 22, and will demonstrate whether this compound can act as a novel drug to stimulate oxidative metabolism and energy expenditure and reduce obesity.
The aim of this proposal is to characterize a novel drug that activates brown and beige fat, which are forms of fat in humans that can burn energy and reduce fat storage. We will test whether brown and beige fat stimulation by this drug can be used to reduce the development of obesity, a significant public health burden that is associated with the progression of many chronic diseases.
| Hatting, Maximilian; Rines, Amy K; Luo, Chi et al. (2017) Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting. Cell Metab 25:428-437 |
| Sharabi, Kfir; Lin, Hua; Tavares, Clint D J et al. (2017) Selective Chemical Inhibition of PGC-1? Gluconeogenic Activity Ameliorates Type 2 Diabetes. Cell 169:148-160.e15 |
| Rines, Amy K; Sharabi, Kfir; Tavares, Clint D J et al. (2016) Targeting hepatic glucose metabolism in the treatment of type 2 diabetes. Nat Rev Drug Discov 15:786-804 |
| Sharabi, Kfir; Tavares, Clint D J; Rines, Amy K et al. (2015) Molecular pathophysiology of hepatic glucose production. Mol Aspects Med 46:21-33 |
