Lose Weight or Get Old Faster: Catch 22 Dilemma Found in Yale Study
Free radicals - molecules tied to aging and tissue damage - are at heart of increased appetite
Aug. 29, 2011 Do you want to lose weight, or get old faster? That seems to be a dilemma discovered by Yale School of
Medicine researchers trying to find an answer to the alarming increase in obesity around the world.
The biggest culprit is overeating, but a study of brain circuits that control hunger, and the feeling of having eaten
enough, finds that molecular mechanisms controlling free radicals - molecules tied to aging and tissue damage - are at the heart of increased
appetite in diet-induced obesity.
Published Aug. 28 in the advanced online issue of Nature Medicine, the study found that elevating free radical levels in
the hypothalamus directly or indirectly suppresses appetite in obese mice by activating satiety (satisfied feeling) - promoting melanocortin
neurons.
The hypothalamus is area on the underside of the brain, and controls involuntary functions. such as body temperature and
the release of hormones
Free radicals, however, are also thought to drive the aging process.
"It's a catch-22," said senior author Tamas Horvath, the Jean and David W. Wallace Professor of Biomedical Research,
chair of comparative medicine and director of the Yale Program on Integrative Cell Signaling and Neurobiology of Metabolism.
"On one hand, you must have these critical signaling molecules to stop eating. On the other hand, if exposed to them
chronically, free radicals damage cells and promote aging."
"That's why, in response to continuous overeating, a cellular mechanism kicks in to suppress the generation of these free
radicals," added lead author Sabrina Diano, associate professor of Ob/Gyn, neurobiology and comparative medicine.
"While this free radical-suppressing mechanism - promoted by growth of intracellular organelles, called peroxisomes -
protects the cells from damage, this same process will decrease the ability to feel full after eating."
Free Radical Theory of Aging
The free-radical theory of aging (FRTA) states that organisms
age
because cells accumulate
free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few
free radicals such as
melanin
are not
chemically reactive, most biologically-relevant free radicals are highly reactive. For most biological structures, free radical damage is
closely associated with
oxidative damage.
Antioxidants are
reducing agents, and limit oxidative damage to biological structures by
passivating free radicals.
More at
Wikipedia
After the mice ate, the team saw that the neurons responsible for stopping overeating had high levels of free radicals.
This process is driven by the hormone leptin and glucose, which signal the brain to modulate food intake.
When mice eat, leptin and glucose levels go up, as does free radical levels.
However, in mice with diet-induced obesity, these same neurons display impaired firing and activity (leptin resistance);
in these mice, levels of free radicals were buffered by peroxisomes, preventing the activation of these neurons and thus the ability to feel
sated after eating.
According to Horvath and Diano, the crucial role of free radicals in promoting satiety as well as degenerative processes
associated with aging may explain why it has been difficult to develop successful therapeutic strategies for obesity without major side
effects.
Current studies address the question of whether, under any circumstance, satiety could be promoted without sustained
elevation of free radicals in the brain and periphery.
The study was supported by grants form the National Institutes of Health and the American Diabetes Association.
Other authors on the study include Zhong-Wu Liu, Jin Kwoan Jeong, Marcelo O. Dietrich, Hai-Bin Ruan, Esther Kim,
Shigetomo Suyama, Kaitlin Kelly, Erika Gyengesi, Jack L. Arbiser, Denise D. Belsham, David A. Sarruf, Michael W. Schwartz, Anton M. Bennett,
Marya Shanabrough, Charles V. Mobbs, Xiaoyong Yang, and Xiao-Bing Gao.
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