High blood pressure, diabetes, smoking and obesity in middle age may shrink brain, damage thinking

ScienceDaily (Aug. 2, 2011) — A new study suggests smoking, high blood pressure, diabetes and being overweight in middle age may cause brain shrinkage and lead to cognitive problems up to a decade later. The study is published in the August 2, 2011, print issue of Neurology®, the medical journal of the American Academy of Neurology.

"These factors appeared to cause the brain to lose volume, to develop lesions secondary to presumed vascular injury, and also appeared to affect its ability to plan and make decisions as quickly as 10 years later. A different pattern of association was observed for each of the factors," said study author Charles DeCarli, MD, with the University of California at Davis in Sacramento and a Fellow of the American Academy of Neurology. "Our findings provide evidence that identifying these risk factors early in people of middle age could be useful in screening people for at-risk dementia and encouraging people to make changes to their lifestyle before it's too late."

The study involved 1,352 people without dementia from the Framingham Offspring Study with an average age of 54.

Participants had body mass and waist circumference measures taken and were given blood pressure, cholesterol and diabetes tests. They also underwent brain MRI scans over the span of a decade, the first starting about seven years after the initial risk factor exam. Participants with stroke and dementia at baseline were excluded, and between the first and last MRI exams, 19 people had a stroke and two developed dementia.

The study found that people with high blood pressure developed white matter hyperintensities, or small areas of vascular brain damage, at a faster rate than those with normal blood pressure readings and had a more rapid worsening of scores on tests of executive function, or planning and decision making, corresponding to five and eight years of chronological aging respectively.

People with diabetes in middle age lost brain volume in the hippocampus (measured indirectly using a surrogate marker) at a faster rate than those without diabetes. Smokers lost brain volume overall and in the hippocampus at a faster rate than nonsmokers and were also more likely to have a rapid increase in white matter hyperintensities.

People who were obese at middle age were more likely to be in the top 25 percent of those with the faster rate of decline in scores on tests of executive function, DeCarli said. People with a high waist-to-hip ratio were more likely to be in the top 25 percent of those with faster decrease in their brain volume.

The study was supported by the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke and the National Institute on Aging.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by American Academy of Neurology.

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Treating obesity via brain glucose sensing

ScienceDaily (July 26, 2011) — The past two decades have witnessed an epidemic spread of obesity-related diseases in Western countries. Elucidating the biological mechanism that links overnutrition to obesity could prove crucial in reducing obesity levels. In the July 26 issue of PLoS Biology, Dr. Dongsheng Cai and his research team at Albert Einstein College of Medicine describe a pathway that directs the brain to sense the body's glucose dynamics, and they find that a defect of this glucose sensing process contributes to the development of obesity and related disease. Importantly, the team also found that correction of this defect can normalize the whole-body energy balance and treat obesity.

The hypothalamus in the brain plays a key role in controlling energy and body weight balance. To maintain balance between energy intake and energy expenditure, the hypothalamus constantly gauges the whole-body's energy levels by sampling circulating hormones (e.g. insulin and leptin) as well as nutrients (e.g., glucose). Although we know quite a bit about the hormonal pathways in the hypothalamic regulation of feeding, the mechanisms for hypothalamic nutrient sensing are much less clear. Moreover, a causal link between a nutrient sensing defect and obesity remains to be established. The team led by Dr. Cai discovered a novel role of a protein complex, hypoxia-inducible factor (HIF), in hypothalamic glucose sensing and whole-body energy balance in mice.

HIF is a nuclear transcription factor which induces hypoxia response. When tissue oxygen level is low, HIF is activated to promote cellular metabolic adaption and survival. Recent research has appreciated the involvement of HIF in the metabolism of tumor cells. "However, an intriguing but unexplored question is whether HIF can be important for the regulation of whole-organism metabolism, and if so, which tissue and cells are responsible." says Cai, who is an expert in neuroendocrinology and metabolism.

Cai and his group examined HIF in the hypothalamus and, surprisingly, found that it can be activated by glucose and that this regulation was associated with appetite control in mice. In identifying the cellular and molecular basis, the team found that in response to glucose, HIF acts in a unique group of hypothalamic nutrient-sensing neurons to induce expression of POMC gene -- a gene which has been known to play a key part in hypothalamic control of feeding and body weight. Most excitingly, the team demonstrated the therapeutic potential of targeting hypothalamic HIF to control obesity. By enhancing the hypothalamic HIF activity via gene delivery, mice become resistant to obesity despite the condition of nutritional excess.

"It was an exciting discovery," explains Cai, "Our study is the first to show that beyond its classical oxygen-sensing function in many cells, HIF in the hypothalamic neurons can sense glucose to control the whole-body balance of energy intake and expenditure which is critical for body weight homeostasis." Overall, this study reveals a crucial role for neuronal HIF in bridging the brain's glucose sensing with the brain's regulation of body weight and metabolic physiology. These findings also highlight a potential implication for developing neuronal HIF activators in treating and preventing obesity and related diseases.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Public Library of Science, via EurekAlert!, a service of AAAS.

Journal Reference:

Hai Zhang, Guo Zhang, Frank J. Gonzalez, Sung-min Park, Dongsheng Cai. Hypoxia-Inducible Factor Directs POMC Gene to Mediate Hypothalamic Glucose Sensing and Energy Balance Regulation. PLoS Biology, 2011; 9 (7): e1001112 DOI: 10.1371/journal.pbio.1001112

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