Brain May Play Part in Obesity and Diabetes
Researchers discover mechanism of neurons' response to glucose


by Faith Hickman Brynie

October 1, 2007

Recent research has revealed that certain neurons in the brain become "excited" by glucose, but it has been unclear how or why the action of those glucose-sensing neurons is significant. New evidence from an international team of researchers shows that a gene active in those neurons interacts with fat and glucose in ways that suggest a brain link in disorders such as diabetes and obesity. 

The team, working at Harvard, the University of Texas Southwestern Medical School and Oregon Health and Science University, reports its findings in a recent issue of the journal Nature.

Glucose-sensing neurons

Glucose excites certain neurons in the brain called POMC neurons (short for proopiomelanocortin neurons). These neurons are found—among other places—in the metabolically active hypothalamus. When glucose levels rise in the spaces outside them, POMC neurons fire rapidly.

The trigger is another molecule, ATP, which stores and delivers the energy derived from glucose. ATP levels regulate channels in the cell membrane that let potassium ions pass into the neuron, closing the channel when glucose levels are rising and opening it when levels drop. When there are low levels of potassium, POMC neurons are more likely to fire. When glucose and ATP levels drop, the channels open and potassium enters the cell, and the POMC neurons slow or cease their firing.

This raises the question, is this firing response disrupted in type 2 diabetes?

Diabetes and POMC neurons

The team developed a strain of transgenic mice whose POMC neurons did not function normally. When ATP levels rose, the potassium channels did not close.  Predictably, the cells did not respond normally to rising glucose levels.

The genetic modification took its toll on the health of the animals. Their body weight was normal, but they “failed” their glucose tolerance tests. Their blood sugar rose too high after they consumed glucose.

“Although mice do not ever become diabetic naturally,” says team member Michael Cowley, a neuroscientist at the Oregon Health and Science University in Beaverton, Oregon, “they do show glucose intolerance that is similar to that found in diabetic humans.”

These mice, Cowley explains, “were already showing signs of glucose intolerance. They had the same glucose tolerance tests as mice that were obese.” They concluded that POMC neurons play a part in controlling the balance of glucose in blood and body cells.

The research team also fed a high-fat diet to some nonengineered mice whose POMC neurons initially functioned normally. The animals became obese. At the same time, the glucose-sensing capability of their POMC neurons became defective. The scientists concluded that POMC neurons lose their ability to sense glucose when a high-fat diet brings on obesity.

What causes the loss?

The team experimented to find out what causes the obesity-induced loss of glucose-sensing in POMC neurons.  They zeroed in on a protein called UCP2. An increase in UCP2 in the brain makes POMC neurons less sensitive to glucose. Its level increases in the brains of normal mice that eat a high-fat diet and become obese.

To learn more, researchers used another strain of transgenic mice, which lacked the gene for making UCP2. A high-fat diet did not impair glucose-sensing in these animals. Their POMC neurons responded normally to an increase in blood glucose.

“We found that mice that didn’t have UCP2 did not become insulin resistant on a high-fat diet, and the POMC neurons behaved normally, even if they were from mice fed a high-fat diet. So loss of UCP2 made the animals resistant to high-fat-diet-induced [insulin] resistance, systemically and at the neuron level,” says Cowley.

In other experiments, the investigators gave the anti-diabetes drug genipin to normal mice fed a high-fat diet. Genipin is known to block the action of UCP2. The drug restored the normal action of POMC neurons.

The researchers suggest UCP2 disrupts ATP production. Less ATP means that potassium channels stay open and the neuron grows less responsive to glucose. 

Why is this research so important? Brad Lowell, a professor of medicine at Harvard and a member of the research team, offers an answer. “The first step in treating a disorder it to understand its cause,” he says. “Our work identifies a previously unknown mechanism that could be an important contributor to type 2 diabetes.”

Diabetic Mice - Spotlight 

Mice on a high-fat diet (45 percent fat) grow much larger than those on regular chow (12 percent fat). (photo courtesy of Pablo Enriori, Oregon Health and Science University)