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How Appetite-stimulating Brain Cells Work Overtime During Fasting

Date:
January 5, 2007
Source:
Cell Press
Summary:
During periods of fasting, brain cells responsible for stimulating the appetite make sure that you stay hungry. Now, a new study of mice reported in the January issue of the journal Cell Metabolism, published by Cell Press, reveals the complex series of molecular events that keep those neurons active.

During periods of fasting, brain cells responsible for stimulating the appetite make sure that you stay hungry. Now, a new study of mice reported in the January issue of the journal Cell Metabolism, published by Cell Press, reveals the complex series of molecular events that keep those neurons active.

The researchers revealed a link between active thyroid hormone in the brain and increases in an "uncoupling" protein (UCP2) that boosts the number of power-generating mitochondria in neurons that drive hunger. The increase in mitochondria, in turn, allows the brain's hunger center to remain active when periods of food scarcity result in a "negative energy balance," said Sabrina Diano of Yale University School of Medicine, who led the study.

Indeed, the researchers found, animals lacking either UCP2 or an enzyme that stimulates thyroid hormone's production ate less than normal after a period of food deprivation.

"This shows the key importance of UCP in the brain and its effect on neuronal activity," Diano said. "It's how neurons 'learn' that food is missing, and it keeps them ready to eat when food is introduced."

The mechanism involved is very similar to the one that regulates core body temperature in peripheral body tissues, Diano added.

Thyroid hormones are known to play major roles during development as well as in adulthood, the researchers said. In adults, the thyroid gland is essential to regulating metabolism. Previous studies had also established a key physiological role for the active thyroid hormone, triiodothyronine (T3), in the regulation of body temperature by heat-generating brown fat.

The molecular underpinning of heat production, or thermogenesis, in brown fat is the activation of mitochondrial uncoupling protein 1 (UCP1) by T3, the researchers said. The UCP1 activation, which is controlled by the sympathetic nervous system, also leads to an increase in the number of mitochondria.

The role of the related protein, UCP2, which is present at high levels in the hypothalamic arcuate nucleus--considered to be the key brain site that responds to changes in peripheral tissue metabolism--had remained less clear. However, scientists did know that that portion of the brain harbors thyroid hormone receptors and has the capacity for local production of T3.

Now, the researchers found that support cells in the hypothalamus producing an enzyme that catalyzes active thyroid hormone production are side by side with appetite-stimulating neurons that express UCP2. In mice that were fasted for 24 hours, the arcuate nucleus showed an increase in the "DII" enzyme's activity and local thyroid production, in parallel with increased UCP2 activity.

This fasting-induced, T3-mediated UCP2 activation resulted in mitochondrial proliferation in the neurons, an event that was critical for the brain cells' increased excitability and consequent rebound feeding by the animals following food deprivation.

"Our results indicate that this mechanism is critical in sustaining an increased firing rate in these [hunger-stimulating] cells so that appetite remains elevated during fasting," Diano's group concluded. "Overall, our study provides strong evidence for an interplay between local T3 production and UCP2 during fasting and reveals a central thermogenic-like mechanism in the regulation of food intake."

While it is as yet unproven, the rise in UCP2 in the brain likely also causes changes in temperature in the same way that UCP1 does in brown fat, Diano said.

"It's possible that heat may act like a neurotransmitter of a sort," Diano said. Neurotransmitters are chemical messengers that relay signals to and from neurons. "Changes in temperature could have a strong effect on brain function."

The findings emphasize the complexity of the feeding circuitry, which once "seemed so simple," wrote Charles Mobbs of Mount Sinai School of Medicine in an accompanying preview article. Researchers had thought that decreased levels of the fat-produced hormone leptin alone signaled the hypothalamus that fat levels have fallen, leading hypothalamic neurons to activate a program, including hunger, to preserve energy and restore fat levels, he said.

Now, "a series of studies, including those reported in this issue of Cell Metabolism by [Diano and colleagues] have elegantly demonstrated that hypothalamic responses to food deprivation involve at least three hormones, two cell types, and an unexpected interlocutor, uncoupling protein 2."

The researchers include Anna Coppola, Zhong-Wu Liu, Zane B. Andrews, Tamas L. Horvath, Xiao-Bing Gao, and Sabrina Diano of Yale University School of Medicine in New Haven, CT; Eric Paradis, Marie-Claude Roy, and Denis Richard of Laval Hospital Research Center, Université Laval in Quebec, Canada; Jeffrey M. Friedman of Rockefeller University in New York, NY; Daniel Ricquier of CNRS, Université René Descartes in Paris, France.

This work was supported by NIH grants DK061619 and DK070039 to S.D.; DK070723 to X.-B.G.; and DK074386, DK060711, and AG022880 to T.L.H. and a grant from the Juvenile Diabetes Research Foundation to S.D.

Coppola et al.: "A Central Thermogenic-like Mechanism in Feeding Regulation: An Interplay between Arcuate Nucleus T3 and UCP2." Publishing in Cell Metabolism 5, 21--33, January 2007 DOI 10.1016/j.cmet.2006.12.002 http://www.cellmetabolism.org


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The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.


Cite This Page:

Cell Press. "How Appetite-stimulating Brain Cells Work Overtime During Fasting." ScienceDaily. ScienceDaily, 5 January 2007. <www.sciencedaily.com/releases/2007/01/070102132530.htm>.
Cell Press. (2007, January 5). How Appetite-stimulating Brain Cells Work Overtime During Fasting. ScienceDaily. Retrieved September 17, 2014 from www.sciencedaily.com/releases/2007/01/070102132530.htm
Cell Press. "How Appetite-stimulating Brain Cells Work Overtime During Fasting." ScienceDaily. www.sciencedaily.com/releases/2007/01/070102132530.htm (accessed September 17, 2014).

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