Gene Identified for Obesity, Physical Activity, Sex Behaviors in Mice

AMHERST, Mass. – A team led by University of Massachusetts Amherst researcher Deborah J. Good has identified a gene that appears to play a role in obesity, physical activity, and sex behaviors in mice. Good works with so-called “knock-out” mice, which have a specific gene deleted. Scientists then monitor the animals for changes in their physiology and behavior, in an effort to determine the gene’s role. Her findings are detailed in the current issue of the journal Physiology and Behavior. The project is funded with a four-year, $1 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases, and a two-year, $70,000 grant from the National Institute of Child Health and Human Development, both of the National Institutes of Health.

Good is studying the mechanisms in the brain and nervous system that regulate appetite and body weight. Although more than 20 genes have been implicated in the regulation of body weight, the mechanisms through which these genes work remain unclear, she says. Recent evidence by Good suggests that a gene called Nhlh2 plays a key role in the regulation of genes controlling body weight, as well as physical activity levels and mating behavior.

“The knock-out mice can weigh up to 100 grams or more, while most normal mice weigh 25 to 30 grams. Thus, the knock-outs are the equivalent of a 450-pound person,” Good says. Two issues contribute to their obesity: the all-too-familiar diet and exercise factors. The mice eat far past what should be the point of satiety, and show a marked disinterest in running on an exercise wheel. “Most mice love to run on a little exercise wheel when you put it in their cage,” notes Good, “but not these guys. They run less than other mice before they become obese. Once they do put the extra weight on, their decreased physical activity contributes to their weight gain even more than their food intake.”

But these mice can legitimately blame their weight on their genes ? or rather, their lack of the Nhlh2 gene. “The gene is responsible for giving them the message, ‘You’re full, so stop eating,’ or ‘You need to increase your activity, so get some exercise.'” Without Nhlh2, the message is sent but can’t be received on a molecular level, so their body weight continues to increase, Good explains. “It’s as if someone is sending you e-mail, but you’re not reading the message. The message has been sent, but it’s not useful.”

“There are humans who have this mutation,” notes Good. “If we understand the molecular mechanisms that deal with obesity, perhaps we’ll be able to develop pharmaceuticals for people whose enzyme activity is offset.” She also notes that humans can be coached to increase their exercise levels and lower their food intake.

In addition, the gene deletion appears to affect sex behaviors. The knock-out mice have a smaller genital size and lower sperm counts than typical mice. In addition, they show disinterest in mating when they share a cage with a receptive female. (They are able to produce offspring through in vitro methods.) Good cautions that the findings may not be analogous in human beings, in terms of infertility. “We don’t know what would happen in humans,” Good says. “There might be fertility problems, but human sex behavior is greatly affected by sociological and cultural expectations that certainly aren’t a factor among mice.”

In a related project, Good is studying the molecular control of male reproduction. Although more than 16 specialized proteins are implicated in controlling fertility, the molecular mechanisms of reproduction remain unclear, Good says. She and her team are working toward understanding the molecular control of reproduction and fertility by a specific gene known as Nhlh2.