Can Gene Manipulation Reverse Obesity?

BOSTON — A research team led by investigators at Beth Israel Deaconess Medical Center and Hebrew SeniorLife?s Institute for Aging Research (IFAR), in collaboration with MIT and other international institutes, reveal that manipulation of a genetic circuit may help reduce obesity by shifting energy storage and expenditures in human tissues. Findings from this study published today in the New England Journal of Medicine.

Obesity—when energy intake exceeds expenditure—is a major health concern that contributes to type 2 diabetes, cardiovascular disease, and cancer. According to the World Health Organization (WHO) obesity has more than doubled worldwide since 1980. Moreover, a previous study by Adams et al. (NEJM 2006) looked at obesity rates in those 50 to 71 years of age and found that more than 500 million people worldwide are obese.

Lead investigator and corresponding author Melina Claussnitzer, Ph.D., with Harvard Medical School-affiliated Hebrew SeniorLife IFAR and Beth Israel Deaconess Medical Center, and Visiting Professor at MIT?s Computer Science and Artificial Intelligence Laboratory (CSAIL) and the Broad Institute comments, “Understanding how the body balances energy—beyond food consumption and physical activity—is important to combating obesity. Our study aims to identify the genetic variant that regulates physiological processes leading to obesity.”

The researchers analyzed information from the Roadmap Epigenomics project, which maps chemical or „epigenetic? modifications within chromosomes that switch genes on or off. They discovered that the genomic region associated with obesity showed the strongest activity in adipocyte progenitor cells derived from fat tissue, rather than the brain.
“The field of obesity has primarily focused on the brain,” explains Dr. Claussnitzer. “Large-scale epigenomic datasets give us the opportunity to revisit our preconceptions with an unbiased view of the cell types, tissues, and organs likely to underlie genetic variants. In this particular case, the data overwhelmingly points us to adipocyte functions, rather than brain functions.”

The team then conducted further analysis that showed that two distant genes in adipocyte progenitor cells act as master regulators of a process known as thermogenesis, or 'heat generation'. By altering the expression of either gene, the researchers could alter adipocyte metabolism between energy storage and energy dissipation, providing new hope for tissue-independent therapeutic manipulation of global energy balance in humans, when many mouse-based therapeutic approaches have failed.

“Our study provides evidence that manipulation of a specific genetic circuit has significant pro- and anti-obesity effects,” concludes Dr. Claussnitzer. “This is an important finding that shows in addition to diet and exercise, obesity may result from changes at the cellular level. This understanding could pave the way for precision medicine approaches to prevent or reverse obesity in older adults.”

About the New England Journal of Medicine
The New England Journal of Medicine (NEJM) is the most widely read, cited, and influential general medical journal in the world and the oldest continuously published medical periodical. In 2012, NEJM completes its second century of service to the medical community. Throughout its existence, NEJM has published the very best research at the interface of biomedical science and clinical practice and presented it in an understandable and clinically useful format.

About the Institute for Aging Research
Scientists at the Institute for Aging Research seek to transform the human experience of aging by conducting research that will ensure a life of health, dignity and productivity into advanced age. The Institute carries out rigorous studies that discover the mechanisms of age-related disease and disability; lead to the prevention, treatment and cure of disease; advance the standard of care for older people; and inform public decision-making. The Aging Brain Center within IFAR studies cognitive aging and conditions affecting brain health.

About Hebrew SeniorLife
Hebrew SeniorLife, an affiliate of Harvard Medical School, is a national senior services leader uniquely dedicated to rethinking, researching and redefining the possibilities of aging. Based in Boston, the non-profit, non-sectarian organization has provided communities and health care for seniors, research into aging, and education for geriatric care providers since 1903. For more information about Hebrew SeniorLife, visit https://www.hebrewseniorlife.org, follow us on Twitter @H_SeniorLife, like us on Facebook, or read our blog.