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News — Could obesity be caused in part by a miscommunication in the brain?

Scientists at  and have discovered a pathway through which communications are regulated in the brain, and a misfire in the messaging can result in overeating, slower burning of calories, and other metabolic problems linked to obesity.

The pathway involves receptors on astrocytes in the ventromedial hypothalamus, a part of the brain which controls hunger and promotes glycemic (blood sugar) control. and, until recently, had been thought to play at best a supporting role in critical functions controlled by the brain and nervous system. 

Working in a mouse model, the scientists focused on a protein called brain-derived neurotrophic factor (BDNF), a signaling molecule that has long been known to be essential for maintaining energy and glucose balance within the central nervous system. Studies to date have mostly focused on BDNF’s effects in nerve cells, however, while its role in astrocytes and other cell types within the brain have remained poorly understood.

“It was long assumed that the mechanism by which BDNF worked to control eating was through signaling receptors on neurons called TrkB,” says Dominique Ameroso, GBS21, first author on the new study who completed her doctoral research in the lab of neuroscience professor , senior author on the study.

However, what the study, which was , revealed is that truncated TrkB receptors for BDNF present on astrocytes actually play a much more significant role in the body’s process of knowing when to eat, when the body is sated, how quickly or slowly the body burns calories, utilize glucose, and other key functions related to obesity and type 2 diabetes.

Mice engineered to not produce these receptors on astrocytes overeat, become more sedentary, burn less calories, are less able to regulate their glucose levels, and develop a number of other problems similar to those seen in obesity and type 2 diabetes in humans.

“In comparison, if you remove TrkB receptors from neurons in the ventromedial hypothalamus, the result is an impairment in glucose regulation, which is not good, but none of the other problems develop,” Ameroso says.

Not only did the scientists come to realize that the truncated TrkB receptors on astrocytes play a much bigger role in controlling the process of feeding and fasting in this part of the brain, they also identified the process by which the BDNF interaction with the truncated receptors performs this role.

It turns out that through a multi-step process, the BDNF-to-truncated TrkB signaling on astrocytes controls how much glutamate is circulating among nearby synapses, which are structures that facilitate communication between neurons. Glutamate is the most abundant neurotransmitter in the brain and central nervous system. It plays a major role in a host of functions, ranging from learning and memory to eating and fasting. It serves as a chemical signal traveling through synapses to excite and increase the activity of neurons.

The scientists observed that when the animals are fasting, the multi-step signaling process results in glutamate levels in synapses dropping to reduce the activity of appetite-suppressing neurons and stimulate an urge for the animal to eat. When the animals are feeding and become full, the astrocyte-based signaling kicks into higher gear to increase synaptic glutamate levels and prevent the animal from overeating.

“Our lab is deeply interested in the cellular and molecular mechanisms acting in the brain to regulate energy balance and glycemic control,” says Rios. “We want to better understand how the tightly regulated equilibrium between calories taken in and calories expended becomes dysregulated, leading to over-eating, obesity, and metabolic dysfunction. We are particularly interested in BDNF because it is a highly conserved protein and alterations in its function have been linked to obesity susceptibility in humans. By altering certain genes in mice and seeing what the effects are, we can learn a great deal about these malfunctions and how they occur, and whether they are sex-specific or occur in both males and females.

“In this most recent research, the effects were found in both males and females,” Rios adds.

“For years scientists assumed neurons alone shaped brain function,” says Ameroso, who is now a scientist at Alnylam, a biotechnology and pharmaceutical company. “But the brain is still really a black box.”

“We can no longer just assume that neurons alone shape brain action,” she adds. “For years, scientists have lumped together astrocytes, microglial cells and oligodendrocytes together as a single group of cells called glial cells that they believed did not perform significant roles in the brain and nervous system when compared to neurons. What we are now discovering is that these cells, and in particular astrocytes, play very significant roles that could ultimately lead to the development of new drugs and treatments for a whole host of conditions, including obesity and diabetes.”

Co-authors of the study with Ameroso and Rios are , a PhD student in cell, molecular and developmental biology; , a graduate student in the MD/PhD program in neuroscience; , N11, NG16; and , associate professor of neuroscience.

This work was supported by grants from the National Institute of Neurological Disorders and Stroke and the National Institute of Diabetes and Digestive and Kidney Diseases (1R21NS091871 and 1R01DK117935-01) and (1F31DK118789-01A1), the Synapse Neurobiology Training Program (5T32NS061764-09) and the Training Program in Nutrition, Obesity and Metabolic Disorders (T32DK124170). Complete information on authors, funders and conflicts of interest is available in the published papers.

DISCLAIMER: This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.