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How To Get Obese Mice Moving -- And Cure Their Diabetes

ScienceDaily (June 2, 2009) —
Mice lacking the fat hormone leptin or the ability to respond to it
become morbidly obese and severely diabetic—not to mention downright
sluggish. Now, a new study in the June Cell Metabolism shows
that blood sugar control in those animals can be completely restored by
returning leptin sensitivity to a single class of neurons in the brain,
which account for only a small fraction of those that normally carry
the hormone receptors.

"Just the receptors in this little group of neurons are sufficient
to do the job," said Christian Bjorbaek of Harvard Medical School.

What's more, animals with leptin receptors only in the so-called
pro-opiomelanocortin (POMC) neurons spontaneously increase their
physical activity levels despite the fact that they remain profoundly
obese. While understanding exactly how the POMC neurons act on other
organs remains a future challenge, the discovery suggests that drugs
designed to tap into the pathway—turning up or down the dial, so to
speak—might have benefit for those with severe diabetes and obesity,
according to the researchers.

Such drugs might even encourage obese individuals to get moving.
"This gives us the opportunity to search for drugs that might induce
the desire or will to voluntarily exercise," Bjorbaek said.

Leptin was first identified 15 years ago and made famous for its
ability to curb appetite and lead to weight loss. It is known to play a
pivotal role in energy balance through its effects on the central
nervous system, specifically by acting on a hypothalamic brain region
known as the arcuate nucleus (ARC). The ARC contains two types of
leptin-responsive neurons, the POMC neurons, which cause a loss of
appetite, and the so-called Agouti-related peptide (AgRP) neurons,
which do the opposite.

Studies had also revealed a role for leptin in blood sugar control
and activity level, also via effects on the ARC. However, scientists
still didn't know which neurons were responsible, until now.

When the researchers restored leptin receptor activity in POMC
neurons of otherwise leptin-resistant, obese, and diabetic mice, the
animals began eating about 30 percent fewer calories and lost a modest
amount of weight. Remarkably, the researchers report, their blood sugar
levels returned to normal independently of any change in their eating
habits or weight. The animals also doubled their activity levels.

Whether this particular bunch of neurons also plays a similarly
important role in animals that are lean remains uncertain, Bjorbaek
said. "It may be that in the context of severe obesity and diabetes,
these neurons do something they don't normally do," he said. But, he
added, even if that were the case, it may not matter when it comes to
its potential as a therapeutic target.

The researchers include Lihong Huo, Beth Israel Deaconess Medical
Center and Harvard Medical School, Boston, MA, Kevin Gamber, Beth
Israel Deaconess Medical Center and Harvard Medical School, Boston, MA,
Sarah Greeley, Beth Israel Deaconess Medical Center and Harvard Medical
School, Boston, MA, Jose Silva, Beth Israel Deaconess Medical Center
and Harvard Medical School, Boston, MA; Nicholas Huntoon, Beth Israel
Deaconess Medical Center and Harvard Medical School, Boston, MA,
Xing-Hong Leng, Baylor College of Medicine, Houston, TX; and Christian
Bjørbæk, Beth Israel Deaconess Medical Center and Harvard Medical
School, Boston, MA.

LINK: http://www.sciencedaily.com/releases/2009/06/090602122617.htm