12:00 AM
Feb 02, 2012
 |  BC Innovations  |  Cover Story

Browning fat

Dana-Farber Cancer Institute researchers have identified a new hormone dubbed irisin that is induced by exercise and triggers the conversion of white fat to brown-like fat in mice, leading to increased energy expenditure.1Ember Therapeutics Inc. has licensed the findings and is generating stabilized versions of irisin in preparation for clinical trials in obesity and type 2 diabetes.

In a separate study, Harvard University researchers have developed a method for converting human pluripotent stem cells into white and brown adipocytes.2 The Harvard team is collaborating with Roche to use the cell lines for multiple screens, including looking for molecules that promote brown-like phenotypes in white adipocytes.

There are two types of fat-white and brown. White adipose tissue (WAT) stores energy as triglycerides, whereas brown adipose tissue (BAT) metabolizes triglycerides to generate heat. The mobilization of triglycerides by BAT helps control weight and overall metabolic status.

BAT was long known to exist in rodents and human infants, but it was not until 2009 that a trio of papers in The New England Journal of Medicine identified BAT in human adults.3-5

The hope is that molecules that activate brown fat or induce the conversion of white fat to brown-like fat could help treat metabolic diseases such as obesity and diabetes.

Muscling in

A team led by Bruce Spiegelman, professor in the Department of Cell Biology at Dana-Farber, was intrigued by the previous observation that transgenic mice with increased levels of peroxisome proliferation-activated receptor-g coactivator 1a (Ppargc1a; Pgc-1α) in muscle were resistant to age-related obesity and diabetes.6PGC-1a is induced in muscle by exercise.

Spiegelman's team hypothesized that exercise-induced PGC-1a might be stimulating the secretion of factors from muscle that have beneficial effects on tissues involved in regulating metabolism.

The team first looked for a protein that was upregulated in response to PGC-1a expression and identified the membrane protein fibronectin type III domain containing 5 (FNDC5) as a potential transcriptional target of PGC-1a.

The next question was whether FNDC5 could be secreted. When FNDC5 was expressed in cells, it was proteolytically cleaved to release a shorter, previously uncharacterized variant that Spiegelman's team named irisin. Strikingly, the amino acid sequence of...

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