Penn Vet researcher unravels the science of obesity

Though daily cheeseburgers and ice cream sundaes can help pave the way, the road to obesity begins in the brain, where metabolism is regulated by the activity of various hormones and signaling molecules.

With a new study, the School of Veterinary Medicine’s Kendra Bence, an associate professor of animal biology, has expanded our understanding of how obesity unfolds at the molecular level. Her team’s findings point to a potential target for therapies that may one day help people who are obese arrive at a healthier weight.

In previous work, Bence and colleagues showed that an enzyme called protein tyrosine phosphatase 1B (PTP1B) is an important player in regulating body weight. PTP1B blocks the effect of leptin, a hormone produced by fat cells that suppresses appetite and can thus lead to weight loss. Mice bred to lack PTP1B in their brains were trim even when they had unlimited access to food.

But the researchers wanted to know more precisely how the absence of PTP1B in the brain affected body weight.

To find out, they bred mice that lacked PTP1B only in the hypothalamus, the “control center” of the brain that is believed to play a leading role in regulating metabolism. These mice were indeed leaner than control mice, but not as thin as mice lacking PTP1B throughout their entire brains.

“This shows us that about half of the beneficial metabolic effects mediated by PTP1B deficiency are mediated outside of the hypothalamus,” Bence says, noting that other studies have implicated other brain regions, such as the hindbrain, as playing a role.

In a second set of experiments, the researchers bred mice that lacked not only PTP1B but also leptin receptors in the hypothalamus. These mice had increased food intake and experienced weight gain akin to that of mice that lacked only the leptin receptor but had normal levels of PTP1B.

“In a way, this was surprising to us,” Bence says. “We went in thinking that we were going to prove that PTP1B’s influence on weight control wasn’t all about leptin, but that’s not what we found, at least in the hypothalamus.”

Bence says the results of the study, which will be published in the June issue of the journal Molecular Metabolism, help steer a search for a possible treatment for obesity and diabetes.

“We obviously can’t knock out PTP1B in humans, but if we’re going to be giving a hypothetical PTP1B inhibitor to an obese adult, we want to know what will happen and precisely how it works.”

The next step for Bence’s lab is to determine additional brain sites of PTP1B action outside of the hypothalamus, and to establish whether PTP1B may act on novel targets in these locations.