U.S. Department of Health and Human Services

Inflammation in the Brain Links Obesity and Aging

Two studies further clariied the role of brain signaling in aging and metabolic disease. This research, done in mice, suggests that decreasing inlammation in the brain may reduce the signs of aging and age-related disease. Aging involves gradual functional decline and affects many tissues and organs. However, how aging determines lifespan is poorly 
understood, as is why the risk of certain diseases, like type 2 diabetes, increases with age. Inlammation plays a role in type 2 diabetes and other age-related diseases, but how inlammation inluences aging is unclear. The brain has emerged as a potential regulator of aging and metabolism, and therefore understanding how metabolic disease and inlammation affect the brain— and vice versa—are key research goals. 

Toward those goals, in a recent study researchers examined the role of the hypothalamus, a region of the brain, in aging. The hypothalamus plays a key role in growth, reproduction, and metabolism. Given these important roles, researchers investigated whether the hypothalamus could also control aging and lifespan. Because previous research showed that inlammatory changes contribute to the development of metabolic syndrome, they focused on two inlammatory signaling proteins, IKK-β and NF-κB, which act together to trigger downstream inlammatory responses. The researchers found that NF-κB is more active in the hypothalamus of older mice than that of younger mice. To determine the effect of NF-κB on aging, researchers increased or decreased IKK-β/NF-κB activation in the hypothalamus of mice and evaluated age-related physiology. Mice with decreased NF-κB activation performed better on cognitive and strength tests, displayed more robust physical characteristics, and lived longer, while the mice with increased NF-κB activation performed poorly and had shorter lifespans than their normal counterparts. The effects of IKK-β/NF-κB on aging were further traced to gonadotropin-releasing hormone (GnRH), which is depleted as IKK-β/NF-κB activation increases. To test whether replenishing GnRH might reverse the effects of aging, researchers gave mice GnRH injections and found that this therapy prevented age-induced brain cell loss and reduced age-related skin, muscle, and cognitive degeneration. These results suggest that inlammatory responses in the hypothalamus orchestrate aging throughout the body and may give clues to how aging occurs and how lifespan can be increased.

In another study, several of the researchers who conducted the irst study found a link between obesity-related inlammation and neurodegeneration, or loss of neuron function. They discovered that IKK-β/NF-κB signaling promoted metabolic disease by disrupting adult neural stem cells (NSCs) in the hypothalamus. NSCs are a type of stem cell; like other stem cells they are self-renewing and can develop into many different types of cells. NSCs, in particular, can become many different types of brain cells. The researchers sought to identify adult NSCs in the hypothalamus and to determine if disruption of normal NSC function plays a role in diseases such as obesity and diabetes. They found that in adult mice NSCs were particularly numerous in the hypothalamus, where they slowly produced new brain cells. A high-fat diet, however, reduced the NSCs’ generation of new brain cells and prevented their development into different types of brain cells. The scientists found that increased IKK-β/NF-κB activation was responsible for these effects: reducing IKK-β/NF-κB activation promoted NSC proliferation and development into different brain cell types. Moreover, mice with increased IKK-β also developed glucose intolerance—a symptom of prediabetes and diabetes—and displayed overeating 
and weight gain, resulting in the onset of severe obesity. These results suggest that high-fat diets in mice are associated with inlammatory responses in the hypothalamus that can reduce the number and activity of neural stem cells, leading to neurodegeneration, obesity, and diabetes. Together, these indings in mice may provide a greater understanding of human aging and metabolism and lead to prevention or treatment strategies for obesity-related diseases, such as type 2 diabetes.

Zhang G, Li J, Purkayastha S, et al. Hypothalamic 
programming of systemic ageing involving IKK-β, NF-κB 
and GnRH. Nature 497: 211-216, 2013. 

Li J, Tang Y, and Cai D. IKKβ/NF-κB disrupts 
adult hypothalamic neural stem cells to mediate a 
neurodegenerative mechanism of dietary obesity and 
pre-diabetes. Nat Cell Biol 14: 999-1012, 2012.
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