Inhibiting TRPV4 protects against diet-induced obesity, inflammation and insulin resistance

Sep 28 2012

Ember Therapeutics, Inc., a company harnessing breakthroughs in brown fat biology and insulin sensitization to revolutionize the treatment of metabolic disease, today announced the publication of key preclinical data demonstrating that inhibition of the Transient Receptor Potential Vanilloid (TRPV) family of ion channels - specifically TRPV4 - resulted in activation of brown/beige fat and protection from diet-induced obesity, inflammation and insulin resistance. Ember holds an exclusive option to license these TRPV4 findings and technology.    

This breakthrough TRPV4 research was led by Ember co-founder Bruce Spiegelman, Ph.D., professor of cell biology at Dana-Farber Cancer Institute and Harvard Medical School, in collaboration with fellow company co-founder Patrick Griffin, Ph.D., professor and chair of the department of molecular therapeutics and director of the Translational Research Institute at The Scripps Research Institute. Additional co-authors on the paper included researchers from Boston Children's Hospital, Duke University Medical Center and Massachusetts General Hospital. The research was supported by grants from the National Institutes of Health (NIH).

"This research is exciting in that it looks at the role of TRPV4 and, from high throughput screening to in vivo pharmacological inhibition, demonstrates the important impact it could have on obesity and metabolic disease," said Louis Tartaglia, Ph.D., president and interim chief executive officer of Ember. "Not only do these findings identify TRPV4 as a compelling therapeutic target, but they continue to build out our understanding of the role of brown fat in humans and in developing novel brown fat treatments for metabolic disease."

The publication details how researchers first developed a high throughput screen to identify molecules that increase PGC1 gene expression in white fat cells. PGC1 is a key regulator of energy metabolism and drives the browning of white fat and increased thermogenesis. The researchers then demonstrated that small molecule inhibition of TRPV4 not only increased PGC1 levels, but also expression of UCP1 - a gene that is specifically expressed in brown/beige fat. In cultured fat cells, blocking TRPV4 resulted in reduced expression of multiple proinflammatory genes that are involved in the development of insulin resistance. Finally, preclinical mouse models using either mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist demonstrated increased thermogenesis in brown/beige fat tissues and protection from diet-induced obesity, inflammation and insulin resistance. Collectively, these findings demonstrate the compelling therapeutic potential of small molecule TRPV4 inhibition in obesity, type 2 diabetes and other metabolic diseases.    

Source: Ember Therapeutics, Inc.