In obesity, brain becomes 'unaware' of fat
March 7, 2007
Critical portions of the brain in those who are obese don’t really know they are overweight, researchers have reported in the March issue of the journal Cell Metabolism, published by Cell Press. These findings in obese mice show that a sensor in the brain that normally detects a critical fat hormone—causing a cascade of events that keeps energy balance in check—fails to engage. Meanwhile, the rest of the metabolic pathway remains ready to respond.
“Obesity is not a failure of will power, it is a biological failure,” said Michael Cowley of Oregon Health & Science University of his group’s findings in the mice. “The brain is not aware that the body is obese.”
If the same is true in humans, he added, people may be consciously aware that they are overweight, but “that’s different from the homeostatic circuitry being aware.”
The new results also bolster evidence that a suppressor called SOCS-3 may be responsible for the loss of sensitivity to the fat hormone known as leptin. Therapeutic strategies designed to inhibit SOCS-3 may therefore bypass leptin resistance in obese animals to restore energy balance, according to the researchers.
In most adults, body weight is relatively constant despite large variations in daily food intake and energy expenditure, Cowley explained. Energy balance is regulated by neural and hormonal signals that are integrated in the brain.
Leptin sends signals to the brain about the body’s fat reserves, modifying appetite and energy expenditure accordingly. The arcuate nucleus in the brain’s hypothalamus, known as the ARH, is a major site of leptin sensing, harboring neurons that control appetite.
More than 60 percent of American adults are now overweight or obese, and obesity prevalence in both adults and children is growing dramatically. When scientists first discovered leptin, it was heralded as a potential obesity cure, Cowley said. If obese individuals lacked normal leptin levels, simply restoring the hormone might have been a means for weight loss.
It soon became clear that there was a problem: obesity isn’t the result of a lack of leptin, but rather a lack of leptin response. In fact, obese individuals tend to have high levels of circulating leptin.
“They have enough, but it’s not doing its job,” Cowley said. “It’s an example of classic hormone resistance.”
Cowley’s group set out to show exactly where that breakdown occurs. The researchers fed mice a high-fat diet for 20 weeks, a long time for the mice, which live only for a couple of years. For reasons that remain unclear, some of the genetically identical mice became obese when fed such a diet, while others did not.
“On a high-fat diet, not all of the animals become fat,” Cowley said. “About 60 percent become fat, while others on the same diet, same calories, don’t gain weight, and leptin levels remain normal. Something else must protect them.”
The animals that did become obese maintained normal levels of the ARH brain receptors that respond to leptin, the researchers showed, while the level of SOCS-3 rose. Leptin hormone in those heavy animals failed to elicit “any element of the leptin signaling cascade.” The researchers demonstrated that those later players in the leptin pathway remained ready for action. Indeed, the downstream factors were actually found to be hypersensitive to stimulation.
“Previous studies have suggested that SOCS-3 is a negative regulator of leptin,” Cowley said. “As animals become bigger and fatter and leptin increases, SOCS-3 may rise to decrease the signal. It seems that in obesity, SOCS-3 might end up overriding the [leptin] signal completely.”
When the amount of fat in the animals’ diets was reduced—even without any reduction in calories—the mice continuously lost weight until they reached a size comparable to control animals. Their brains’ appetite control centers also regained sensitivity to leptin.
“That was a surprise, a nice surprise,” Cowley said. “We had thought it might be more irreversible than that.”
However, Cowley cautioned, previous studies in humans haven’t always supported the idea that reducing fat intake alone has a major effect on obesity, noting that the digestive systems of mice and humans differ substantially. His team has plans to examine these effects in overweight primates, whose digestive systems have much more in common with people.
The findings do “strongly support the case” that leptin resistance in critical brain regions is a cause of obesity induced by diet, the researchers concluded. The results also “strongly validate” SOCS-3 as a target for antiobesity drug development.
The researchers include Pablo J. Enriori, Anne E. Evans, Puspha Sinnayah, Luciana Tonelli-Lemos, Sonja K. Billes, Maria M. Glavas, Bernadette E. Grayson, Kevin L. Grove, and Michael A. Cowley of Oregon Health and Science University in Beaverton, OR; Erin E. Jobst of Oregon Health and Science University in Beaverton, OR and Pacific University in Hillsboro, OR; Mario Perello of Brown Medical School/Rhode Island Hospital in Providence, RI; Eduardo A. Nillni of Brown Medical School/Rhode Island Hospital and Brown University in Providence, RI.
Work supported by the following grants: P.J.E. (TW/HD-00668), E.A.N. (NIDDK/NIH R01 DK 58148, NINDS/NIH R01 NS 045231), K.L.G. (DK 60685 NIH RR 0163), and M.A.C. (NIH DK 62202, NIH RR 0163).
Enriori et al.: “Diet-Induced Obesity Causes Severe but Reversible Leptin Resistance in Arcuate Melanocortin Neurons.” Publishing in Cell Metabolism 5, 181–194, March 2007 DOI 10.1016/j.cmet.2007.02.004 www.cellmetabolism.org
Contact: Erin Doonan
Researchers show how obesity causes breakdown in system which regulates appetite and weight
March 7, 2007
PORTLAND, Ore. – New research led by scientists at the Oregon National Primate Research Center demonstrates how obesity causes the breakdown of a brain system that regulates appetite. The research provides a clear picture of some factors involved in obesity. More than 60 percent of American adults are overweight and more than 30 percent are obese The study results may have also identified possible targets for new drug therapies aimed at assisting individuals in weight loss. The research is published in the March issue of Cell Metabolism.
The research provides new understanding of leptin resistance. Leptin is a hormone secreted by fat cells. It can suppress food intake by affecting brain cells that control appetite. However, high levels of leptin which can be found in severely overweight individuals, can lead to leptin resistance. Leptin resistance means that the body no longer responds to the hormone's weight suppressing effects.
The research was conducted in mice and involved two separate groups that were fed high-fat and low-fat diets. Over time, the high-fat diet group developed symptoms of diabetes and obesity, as is often the case in humans. The low-fat diet group did not develop these health problems.
"This research demonstrates how a portion of the hypothalamus of the brain, called the arcuate nucleus, is negatively impacted by an overabundance of leptin," explained Michael Cowley, Ph.D., an associate scientist in the Division of Neuroscience at ONPRC. "By developing a special test of neuronal function, we were able to witness the breakdown in this group of specialized cells. Eventually the cells behaved as if there was no leptin present, even though levels were 40-times higher than in normal animals. We were also able to witness the eventual repair of this important system which occurs as the mice lost weight when returned to a low fat diet."
More specifically, the scientists determined that leptin resistance prevented the arcuate nucleus from taking part in an important signaling function that regulates appetite and body weight. Meanwhile, other portions of the weight regulation system remained intact and in fact became more responsive, thereby suggesting that arcuate nucleus function is the point of breakdown during leptin deficiency.
Finally the research highlighted a key gene called SOCS-3 involved in leptin deficiency. By targeting the gene with therapeutics, scientists may be able to repair leptin deficiency, aiding in weight loss.
"Of course these findings are quite far from the development of a weight loss drug," explained Cowley. "This work further highlights the essential role of SOCS-3 in this critical regulation system."
"One of the surprising things was when we put the genetically identical mice on the high fat diet, some became obese, and some did not. One major difference between these groups of mice was the activity of SOCS-3," said Pablo Enriori Ph.D. of Cowley's lab, first author of the paper. The research was conducted in conjunction with Brown University in Rhode Island.
The ONPRC is a registered research institution, inspected regularly by the United States Department of Agriculture. It operates in compliance with the Animal Welfare Act and has an assurance of regulatory compliance on file with the National Institutes of Health. The ONPRC also participates in the voluntary accreditation program overseen by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).
Contact: Jim Newman
Oregon Health & Science University
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