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.