Hunger Gene May Help Regulate Sleep And Body Temperature

By Dawn Wenzel

Mice deficient for the gene that produces the hunger hormone are helping researchers at Washington State University probe the relationship between sleep, hunger, and energy expenditure.

"Humans who sleep less than five to six hours a night are more prone to becoming obese," says Eva Szentermai, lead author of the study published in a recent issue of the Proceedings of the National Academy of Sciences. Because obesity is linked with myriad of other health problems such as diabetes and hypertension, finding out how we balance our energy levels is a question with big implications for health and human disease.

In a collaborative effort with researchers in Texas, the new study focuses on the effects of deleting preproghrelin, a gene that produces at least two hormones: ghrelin, which stimulates hunger and wakefulness; and obestatin, a newly discovered hormone that may have the exact opposite effects as ghrelin, although its role is still somewhat controversial.

Researchers found that unlike normal mice, preproghrelin-deficient mice are unable to integrate the competing needs of maintaining body temperature (thermoregulation) and energy conservation when food is scarce.

In the study, mice lived for three days at low temperature (63°F). On the fourth day, food was removed from their cages for 24 hours. The temperature challenge wasn't severe, but "for a mouse, twenty-four hours without food is forever," says James Kreuger, the principal investigator of the study and Regents Professor in the Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology at Washington State University.

Although preproghrelin-deficient mice could handle the low temperature or fasting, when challenged with the combination, the mice showed sleep deficits, and they lost control of their body temperature, so much so that it plunged from about 98 degrees F to near ambient levels, a shocking 74 degrees. A scan of the mice brain waves showed essentially no activity. "In a hospital, as a human, they'd be considered dead," says Krueger, although some of the mice could be revived from this state.

To tease apart the roles of the two different gene products of preproghrelin (ghrelin vs. obstatin), researchers gave the preproghrelin-deficient mice obestatin. For a short time, these mice were slightly better at maintaining body temperature during the cold and fasting challenge.

Although the effect of obestatin is short-lived, it definitely seems significant, agrees Richard Palmiter, a biochemistry professor at the University of Washington. The result hints at a potential role for obestatin in regulating energy expenditure and may shed new light on how metabolism, thermoregulation and sleep are all intertwined. Understanding the roles of these two hormones may potentially lead to new drugs to combat obesity.

The fact that the preproghrelin-deficient mice reached almost ambient temperatures suggested to Krueger that he had induced a hibernation-like state in the mice. This prompted him to look at ghrelin levels in an organism most noted for hibernation: the bear.

In a collaboration with the Washington State University Bear Program, Krueger and colleagues measured ghrelin (hunger-stimulating) levels in grizzly bear blood both before and during hibernation. They found that before the bears go into hibernation, their blood ghrelin levels are elevated, encouraging the bears to eat huge amounts in preparation for their long sleep.

In humans, the hormonal relationship between hunger and sleep is less clear. In an article in the October 2009 edition of Obesity Reviews, James Gangwisch from Columbia University gives an evolutionary perspective on how human sleep and metabolism might have come to be intertwined. In the hunter-gatherer lifestyle of our ancestors, longer days in summer meant shorter sleep cycles, and more abundant foods like fruit, high in simple sugars. As a response, our bodies may have adapted to these environmental cues through metabolic changes that increased food intake and enhanced the storage of fats to prepare for times of scarcity. A short sleep may still evoke the same metabolic effects, which could be why sleep deprivation is often linked with obesity.

Dawn Wenzel is a graduate student at the University of Washington in the Department of Biochemistry.

Images

Top: The energy balance. Our bodies are constantly balancing the competing demands of sleep, hunger, and keeping warm.

Bottom: James Krueger, Regents Professor in the Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology at Washington State University