Hunger protein links stress, obesity

A neurotransmitter that acts as a central controller for appetite also regulates stress-induced obesity in the body's periphery, according to a paper in this month's Nature Medicine. The authors found that abdominal fat increased in stressed mice through the actions of neuropeptide Y (NPY) and one of its receptors. Blocking this receptor's signaling prevented stress-induced obesity."It's really quite an important study, both from a basic point of view as well as for potential clinical applications," said Esther Sabban of New York Medical College in Valhalla, who was not involved in the work.Previous work has found that stress stimulates NPY release from sympathetic nerves. NPY activity also promotes obesity through central mechanisms, primarily by increasing appetite, senior author Zofia Zukowska of Georgetown University Medical Center in Washington, D.C., told The Scientist. However, NPY's "peripheral role has really never been studied," she said.Zukowska's lab previously discovered that NPY promotes blood vessel growth through one of its receptors, NPY2R. So she and her colleagues suspected that NPY might control peripheral fat development by building blood vessels to feed fat cells.Led by Lydia E. Kuo, also of Georgetown, the researchers found that NPY cultured with adipose tissue stimulated the proliferation and differentiation of fat cells. They blocked both of these effects with an NPY2R antagonist. The researchers also found that injecting NPY under the abdominal skin led to 50% increased adipose tissue in both obese and lean mice, while injecting the NPY2R antagonist decreased fat tissue by 50%. This antagonist also caused blood vessel atrophy in the abdominal fat, as expected from the researchers' previous work.Since the NPY2R antagonist blocks development of both fat cells and blood vessels, it's "preventing the growth of abdominal fat by two similar but distinct mechanisms," said Markus Heilig, clinical director of the National Institute on Alcohol Abuse and Alcoholism in Bethesda, Md., who studies NPY signaling and was not involved in the work. The authors next found that two weeks of daily exposure to a stressor -- either cold water baths or an aggressive mouse -- increased both NPY levels and abdominal fat deposits in mice fed a diet high in sugar and fat. Neither stress nor the high-calorie diet alone led to fat gain. Stress combined with the high-calorie diet also increased blood vessel development in abdominal fat tissue. NPY2R knockout mice, however, were resistant to stress-induced obesity."If the receptors are not there, nothing happens," said Juan Saavedra of the National Institute of Mental Health in Bethesda, Md., who did not participate in the study. "So apparently, this is a very important link."Kuo and her colleagues next induced obesity in wild-type mice by extending the high-calorie diet to three months. Daily stress boosted the degree of fat gain and induced several symptoms of metabolic syndrome, including lipid accumulation in the liver and skeletal muscle, impaired glucose tolerance, and hypertension. Mice treated with the NPY2R antagonist did not develop these symptoms."It's really quite convincing and quite striking that they're able to affect stress-induced obesity with NPY2 receptor antagonists," Sabban said. NPY's role in peripheral fat tissue "hasn't been known before and it's really extremely important.""This is very innovative research," Heilig told The Scientist. "Based on these data, this would be a fantastic target" for drugs to treat obesity, he said. Several years ago, scientists tried to create drugs to inhibit NPY's appetite-stimulating effects, Heilig said, but those drugs didn't pan out, probably because of redundancies in the body's feeding impulse. The current study involves a "completely novel peripheral mechanism, and I predict that will rekindle the interest considerably" in drug development based on NPY, he said.According to Saavedra, a potential drug's success would depend on its specificity for fat tissue. NPY also signals in many other areas of the body, he said, so "the issue would be whether or not these compounds have central effects."Melissa Lee Phillips mail@the-scientist.comLinks within this articleS. Blackman, "The enormity of obesity," The Scientist, May 24, 2004. http://www.the-scientist.com/article/display/14698/L.E. Kuo et al., "Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome," Nature Medicine, published online July 1, 2007. http://www.nature.com/nm/S. Blackman, "A flavor for fat?" The Scientist, November 2, 2005. http://www.the-scientist.com/article/display/22819/B. Calandra, "Be a stress buster," The Scientist, March 24, 2003. http://www.the-scientist.com/article/display/13651/Esther Sabban http://www.nymc.edu/people/indviewg.asp?which=esther_sabbanZ. Zukowska-Grojec, "Neuropeptide Y. A novel sympathetic stress hormone and more," Annals of the New York Academy of Sciences, December 29, 1995. http://www.the-scientist.com/pubmed/8597401Zofia Zukowska http://gumc.georgetown.edu/departments/physiology/zukowska.htmlE.W. Lee et al., "Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles," Journal of Clinical Investigation, June 2003. http://www.the-scientist.com/pubmed/1281302Markus Heilig http://www.niaaa.nih.gov/ResearchInformation/IntramuralResearch/AboutDICBR/LCTS/chief.htmJuan Saavedra http://neuroscience.nih.gov/Lab.asp?Org_ID=201C. Day, "Metabolic syndrome, or What you will: definitions and epidemiology," Diabetes and Vascular Disease Research, March 2007. http://www.the-scientist.com/pubmed/17469041C. Gerald et al., "A receptor subtype involved in neuropeptide-Y-induced food intake," Nature, July 11, 1996. http://www.the-scientist.com/pubmed/8700207

Hunger protein links stress, obesity

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