UCLA researchers in the Department Human Genetics have identified small molecules that induce UCP1 expression and thermogenic mitochondrial activity in adipocytes, providing a novel class of potential therapeutics for obesity and related conditions.
BACKGROUND: Obesity affects more than 93 million Americans and continues to rise in prevalence. Modulating thermogenesis in adipocytes is an attractive strategy for treating obesity and related metabolic disorders. In brown adipose tissue, UCP1 uncouples fatty acid oxidation from ATP synthesis, which results in heat production rather than energy storage. This process increases energy expenditure and can reduce adipocity. Thus, enhancing UCP1 expression and mitochondrial activity represents a promising therapeutic approach for obesity, as well as associated conditions like dyslipidemia, cardiovascular disease, and type 2 diabetes.
INNOVATION: UCLA researchers performed a high-throughput screen of 12,000 small molecules to identify compounds that induce UCP1 expression in adipocytes. This effort led to the discovery of a novel compound family that robustly increases endogenous UCP1 levels in mouse brown adipocytes and human brown and white adipocytes. Lead compounds from this family activate a thermogenic transcriptional program characterized by increased mitochondrial gene expression, enhanced mitochondrial respiration, and elevated lipolysis. Mechanistically, the compounds modulate mitochondrial PKA signaling, with evidence supporting the involvement of A-kinase anchoring proteins (AKAPs), which spatially organize PKA activity at the mitochondria. In addition to their effects of adipocytes, these compounds have been shown to influence mitochondrial function in other cell types, including protective effects in cardiomyocytes, suggesting broad therapeutic applicability. Altogether, these findings highlight a novel mechanism for inducing thermogenesis and treating obesity and related diseases.
POTENTIAL APPLICATIONS:
ADVANTAGES:
DEVELOPMENT-TO-DATE: Lead compounds have been evaluated in mouse brown adipocytes and human white adipocytes. Compounds have also been shown to support in vivo thermogenic activity and beneficial effects in primary cardiomyocytes, including protection against hypertrophic stress.
Related Papers (from the inventors only):
Laurent Vergnes, Jason Y. Lin, Graeme R. Davies, Christopher D. Church, Karen Reue, Induction of UCP1 and thermogenesis by a small molecule via AKAP1/PKA modulation, Journal of Biological Chemistry, Volume 295, Issue 44, 2020, Pages 15054-15069, ISSN 0021-9258, https://doi.org/10.1074/jbc.RA120.013322.
TDG Keywords:
Therapeutics > Metabolism and endocrinology
Therapeutics > Cardiovascular
Life Science Research Tools > Other reagents
Keywords: Mitochondria, PKA, AKAP, adipocytes, UCP1, high-throughput screen, lipolysis, obesity, metabolic disease, thermogenesis, cardiovascular disease