Trigger turns muscle stem cells into brown fat: Discovery identifies potential obesity treatment

Feb. 5, 2013 Ottawa scientists have discovered a trigger that turns muscle stem cells into brown fat, a form of good fat that could play a critical role in the fight against obesity. The findings from Dr. Michael Rudnicki's lab, based at the Ottawa Hospital Research Institute, were published today in the journal Cell Metabolism.

"This discovery significantly advances our ability to harness this good fat in the battle against bad fat and all the associated health risks that come with being overweight and obese," says Dr. Rudnicki, a senior scientist and director for the Regenerative Medicine Program and Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute. He is also a Canada Research Chair in Molecular Genetics and professor in the Faculty of Medicine at the University of Ottawa.

Globally, obesity is the fifth leading risk for death, with an estimated 2.8 million people dying every year from the effects of being overweight or obese, according to the World Health Organization. The Public Health Agency of Canada estimates that 25% of Canadian adults are obese.

In 2007, Dr. Rudnicki led a team that was the first to prove the existence of adult skeletal muscle stem cells. In the paper published today, Dr. Rudnicki now shows (again for the first time) that these adult muscle stem cells not only have the ability to produce muscle fibres, but also to become brown fat. Brown fat is an energy-burning tissue that is important to the body's ability to keep warm and regulate temperature. In addition, more brown fat is associated with less obesity.

Perhaps more importantly, the paper identifies how adult muscle stem cells become brown fat. The key is a small gene regulator called microRNA-133, or miR-133. When miR-133 is present, the stem cells turn into muscle fibre; when reduced, the stem cells become brown fat.

Dr. Rudnicki's lab showed that adult mice injected with an agent to reduce miR-133, called an antisense oligonucleotide or ASO, produced more brown fat, were protected from obesity and had an improved ability to process glucose. In addition, the local injection into the hind leg muscle led to increased energy production throughout the body -- an effect observed after four months.

Using an ASO to treat disease by reducing the levels of specific microRNAs is a method that is already in human clinical trials. However, a potential treatment using miR-133 to combat obesity is still years away.

"While we are very excited by this breakthrough, we acknowledge that it's a first step," says Dr. Rudnicki, who is also scientific director of the Stem Cell Network. "There are still many questions to be answered, such as: Will it help adults who are already obese to lose weight? How should it be administered? How long do the effects last? Are there adverse effects we have not observed yet?"

The full article, "MicroRNA-133 Controls Brown Adipose Determination in Skeletal Muscle Satellite Cells by Targeting Prdm16," was published by Cell Metabolism online ahead of print on February 5, 2013. The article's authors are: Hang Yin, Alessandra Pasut, Vahab D. Soleimani, C. Florian Bentzinger, Ghadi Antoun, Stephanie Thorn, Patrick Seale, Pasan Fernando, Wilfred van IJcken, Frank Grosveld, Robert A. Dekemp, Robert Boushel, Mary-Ellen Harper, and Michael A. Rudnicki.

This research was funded by the Canadian Institutes of Health Research, the National Institutes of Health, the Stem Cell Network, the Ontario Research Fund and EuTRACC, a European Commission 6th Framework grant. It was a collaboration that included researchers from the Ottawa Hospital Research Institute, University of Ottawa, University of Ottawa Heart Institute, Nordion, Erasmus Medical Centre in the Netherlands and University of Copenhagen.

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Trigger turns muscle stem cells into brown fat: Discovery identifies potential obesity treatment