Now, a study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) sheds further light on the subject. Reported in tomorrow's issue of the journal Cell Metabolism, the findings demonstrate that when leptin sensitivity is restored to a tiny area of POMC neurons in the brain's hypothalamus, a group of mice deficient in the leptin-receptor are cured of severe diabetes - and also spontaneously double their activity levels - independent of any change in weight or eating habits.
"This discovery suggests a new therapeutic pathway for drugs to treat insulin-resistant diabetes in humans with severe obesity, and possibly even to stimulate their urge to exercise," explains Christian Bjorbaek, PhD, an investigator in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Associate Professor of Medicine at Harvard Medical School. "We know that the majority of humans with Type 2 diabetes are obese and that weight loss can often ameliorate the disease. However, in many cases, it's difficult for these individuals to lose weight and can keep weight off. If, as these findings suggest, there is a system in the brain that can control blood-glucose directly, it offers hope for the identification of novel anti-diabetic drug targets."
First identified in 1994 as an appetite and weight-regulation hormone, leptin plays a key role in energy homeostasis through its effects on the central nervous system. Over the years, investigators have pinpointed a region of the brain's hypothalamus known as the arcuate nucleus (ARC) as one key area where leptin exerts its influence, and within the ARC, they have identified two types of leptin-responsive neurons, the Agouti-related peptide (AgRP) neurons, which stimulate appetite and the pro-opiomelanocortin (POMC) neurons, which curb appetite.
"Still other studies had indicated that, by way of the ARC, leptin also had a function in both blood-sugar control and in activity levels," notes Bjorbaek. "We hypothesised that, in both cases, the POMC neurons were involved."
To test their hypothesis, the scientists studied a group of leptin-receptor-deficient laboratory mice. "The animals were severely obese and profoundly diabetic," he explains. "Using Cre-Lox technology we were able to genetically and selectively re-express leptin receptors only in the POMC neurons. When leptin receptor activity was restored to just this very small group of neurons, the mice began eating about 30 percent fewer calories and lost a modest amount of weight." And, he adds, even more dramatically, the animals' blood sugar levels returned to normal independent of any change in weight or eating habits, and their activity levels spontaneously doubled.
While more research is needed to explain the mechanisms at play, it may be that the POMC neurons reduce blood glucose by regulating key organs such as the liver or muscle tissue. "Normally, the liver is critical for increasing glucose production between meals in order to provide fuel for the brain, while skeletal muscle is important for the removal of glucose from the blood immediately after a meal," he notes. In this case, however, the POMC neurons may be decreasing glucose release into the blood by the liver and/or increasing glucose uptake from the blood into muscle.
"The fact that normal glucose levels were restored independent of food or weight changes is important because it suggests that it is possible to normalise blood glucose even without weight loss," explains Bjorbaek. "Furthermore, our finding that the mice had greatly increased activity levels despite still being highly overweight provides hope that POMC neurons and downstream neuronal systems might eventually be tapped to develop drugs that increase the will to voluntarily exercise in individuals who are overweight or obese."
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Contact: Kevin Stacey
kstacey@press.uchicago.edu
773-834-0386
University of Chicago Press Journals
When evolution is not so slow and gradual
Study finds guppies adapt to new surroundings in just a few years
What's the secret to surviving during times of environmental change? Evolve...quickly.
A new article in The American Naturalist finds that guppy populations introduced into new habitats developed new and advantageous traits in just a few years. This is one of only a few studies to look at adaptation and survival in a wild population.
A research team led by Swanne Pamela Gordon from the University of California, Riverside studied 200 guppies that had been taken from the Yarra River in Trinidad and introduced into two different environments in the nearby Damier River, which previously had no guppies. One Damier environment was predator-free. The other contained fish that occasionally snack on guppies.
Eight years after their introduction, the team revisited the Damier guppies to see what adaptive changes they might have picked up in their new environments. The researchers found that the females had altered their reproductive effort to match their surroundings. In the environment where predators were present, females produced more embryos each reproductive cycle. This makes sense because where predators abound, one might not get a second chance to reproduce. In less dangerous waters, females produced fewer embryos each time, thus expending fewer resources on reproduction.
Finally, the researchers wanted to see if these adaptive changes actually helped the new population to survive. So they took more guppies from the Yarra, marked them, and put them in the Damier alongside the ones that had been there for eight years. They found that the adapted guppies had a significant survival advantage over the more recently introduced group.
In particular, juveniles from the adapted population had a 54 to 59 percent increase in survival rate over those from the newly introduced group. In the long run, survival of juveniles is crucial to the survival of the population, the researchers say.
The fact that fitness differences were found after only eight years shows just how fast evolution can work-for short-lived species anyway.
"The changes in survival in our study may initially seem encouraging from a conservation perspective," the authors write. "[B]ut it is important to remember that the elapsed time frame was 13-26 guppy generations. The current results may therefore provide little solace for biologists and managers concerned with longer-lived species."
