Born to be Obese?

The brain circuitry that controls appetite might be wired differently in some people, and that could predispose them to obesity, researchers suggest.

The study was conducted in rats, not humans, and yet it could ultimately lead to novel obesity treatments, said Philip Smith, director of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases.

"It is not just about drugs that modify short-term appetite," he said, "there may be drugs that stimulate development of the appropriate neural pathways. So, it is an exciting, but very early, time in this field."

The study was published in the Cell Metabolism. Sebastien Bouret, an assistant professor of neuroscience at the University of Southern California, and his colleagues examined neural circuits emanating from the appetite, hunger and body-weight control center of the brain -- the so-called arcuate nucleus of the hypothalamus (ARH) -- in a series of rats bred to be either prone to, or resistant to, obesity.

The team found fewer neural connections projecting from the ARH in obesity-prone animals than in their leaner counterparts. Surprisingly, Bouret said, this deficiency developed very early in life, before the animals became obese, and appeared to extend into adulthood. "Somehow, these animals are programmed to become obese," Bouret said. "The obesity is hard-wired into the brain."

When the researchers then looked at why the brains of obese rats differed from their normal-weight counterparts, they found that the neurons from obesity-prone animals were less responsive to leptin, a hormone that controls the development of these circuits, and which also signals the body's energy status and controls metabolic rate.

"This paper presumes to say, these animals must be leptin-resistant, and that is why the pathways are not developing," said Smith. But that doesn't mean they are doomed to a life of severe obesity, said Dr. Barbara Kahn, chief of the Division of Endocrinology, Diabetes and Metabolism at Beth Israel Deaconess Medical Center, in Boston. How they live their lives also matters.

"It is important not to 'blame' the obese person or imply that he/she is responsible for being obese," Kahn noted. "Having said that, reasonable, healthy caloric restriction and a safe and sustainable program of physical activity can help limit weight gain and often bring about some degree of weight loss. In addition, healthy eating and regular exercise can reduce the complications of obesity such as type 2 diabetes and cardiovascular disease." At the same time, she added, not everyone can wear a size 4.

"There is a certain aspect of genetics that sets somebody in a certain range of possible body weights, and then how that person lives his or her life will determine whether they are at the bottom or top of the range," she explained.

Human obesity has both genetic and environmental roots. The rats used in this study, like most humans, developed obesity when fed a high-energy diet. On a normal diet, they were heavier than normal rats, but not yet obese. "This is quite an exciting paper," said Smith, "because it links more closely to human behavior than most rodent models we have seen."

The findings also suggest a possible therapeutic approach to combating human obesity. If drugs could be designed to influence the formation of neural circuits during development and targeted to at-risk pregnancies, Smith said, "there is a good likelihood we could have successful interventions that improve the health of the mother, and which have a major impact on disease risk for the infant, during pregnancy."

A related study from Boston University researchers in the same journal found that bulking up muscle mass can lead to a general metabolic improvement in obese individuals. "Interventions designed to increase skeletal muscle mass in at-risk human populations may prove to be critical weapons in the fight against obesity and obesity-related comorbidities, including diabetes, heart disease, stroke, hypertension and cancer." an accompanying editorial stated.

by Jeffrey Perkel
via WashingtonPost