To Ditch Dessert, Feed The Brain

Brain reward regions are activated when glucose falls below normal levels (blue). In lean people -- but not obese people -- the prefrontal cortex which is involved in decision making and regulating impulses is activated (red) when glucose levels are normal.

If the brain goes hungry, Twinkies look a lot better, a study led by researchers at Yale University and the University of Southern California has found.

Brain imaging scans show that when glucose levels drop, an area of the brain known to regulate emotions and impulses loses the ability to dampen desire for high-calorie food, according to the study published online September 19 in The Journal of Clinical Investigation.

“Our prefrontal cortex is a sucker for glucose,” said Rajita Sinha, the Foundations Fund Professor of Psychiatry, and professor in the Department of Neurobiology and the Yale Child Study Center, one of the senior authors of the research.

The Yale team manipulated glucose levels intravenously and monitored changes in blood sugar levels while subjects were shown pictures of high-calorie food, low-calorie food and non-food as they underwent fMRI scans.

When glucose levels drop, an area of the brain called the hypothalamus senses the change. Other regions called the insula and striatum associated with reward are activated, inducing a desire to eat, the study found. The most pronounced reaction to reduced glucose levels was seen in the prefrontal cortex. When glucose is lowered, the prefrontal cortex seemed to lose its ability to put the brakes upon increasingly urgent signals to eat generated in the striatum. This weakened response was particularly striking in the obese when shown high-calorie foods.

“This response was quite specific and more dramatic in the presence of high-calorie foods,” Sinha said.

“Our results suggest that obese individuals may have a limited ability to inhibit the impulsive drive to eat, especially when glucose levels drop below normal,” commented Kathleen Page, assistant professor of medicine at the University of Southern California and one of the lead authors of the paper.

A similarly robust response to high-calorie food was also seen in the striatum, which became hyperactive when glucose was reduced. However, the levels of the stress hormone cortisol seemed to play a more significant role than glucose in activating the brain’s reward centers, note the researchers. Sinha suggests that the stress associated with glucose drops may play a key role in activating the striatum.

“The key seems to be eating healthy foods that maintain glucose levels,” Sinha said. “The brain needs its food.”



Page KA, Seo D, Belfort-Deaguiar R, Lacadie C, Dzuira J, Naik S, Amarnath S et al. Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. J Clin Invest 2011 Sep 19. [Epub ahead of print]


Treating Obesity Via Brain Glucose Sensing


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.



Zhang H, Zhang G, Gonzalez FJ, Park S-m, Cai D.  Hypoxia-Inducible Factor Directs POMC Gene to Mediate Hypothalamic Glucose Sensing and Energy Balance Regulation. PLoS Biol 2011; 9 (7):  e1001112. doi:10.1371/journal.pbio.1001112



Too Much Sugar Is Bad, But Which Sugar Is Worse: Fructose Or Glucose?

In 2005, the average American consumed 64 kg of added sugar, a sizeable proportion of which came through drinking soft drinks. Now, in a 10-week study, Peter Havel and colleagues, at the University of California at Davis, Davis, have provided evidence that human consumption of fructose-sweetened but not glucose-sweetened beverages can adversely affect both sensitivity to the hormone insulin and how the body handles fats, creating medical conditions that increase susceptibility to heart attack and stroke.

In the study, overweight and obese individuals consumed glucose- or fructose-sweetened beverages that provided 25% of their energy requirements for 10 weeks. During this period, individuals in both groups put on about the same amount of weight, but only those consuming fructose-sweetened beverages exhibited an increase in intraabdominal fat. Further, only these individuals became less sensitive to the hormone insulin (which controls glucose levels in the blood) and showed signs of dyslipidemia (increased levels of fat-soluble molecules known as lipids in the blood). As discussed in an accompanying commentary by Susanna Hofmann and Matthias Tschöp, although these are signs of the metabolic syndrome, which increases an individual’s risk of heart attack, the long-term affects of fructose over-consumption on susceptibility to heart attack remain unknown.


Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009;119 (5): 1322-34.

Hofmann SM, Tschöp MH. Dietary sugars: a fat difference. J Clin Invest. 2009;119 (5): 1089-92.


Krill Oil Demonstrates Beneficial Regulation of Genes Involved in Glucose, Lipid & Cholesterol Metabolism in the Liver

Aker BioMarine announces a publication of a new preclinical study on krill oil. The study results showed a significantly higher impact on gene regulation in the liver when the omega-3 fatty acids were given in the form of phospholipids (krill oil), compared to the triglyceride form (fish oil). More specifically, krill oil downregulated the activity of pathways involved in hepatic glucose production as well as lipid and cholesterol synthesis. The data also suggested that krill oil-supplementation increases the activity of the mitochondrial respiratory chain.

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