01.17 Appetite Control - MSMR: What A Year!

01.17 Appetite Control

Appetite Control

Highlights

This study demonstrates a direct connection between the gene known as O-GlcNAc transferase or OGT and appetite control in mice.
Mice without the OGT gene overate and could not control their appetite. If the amount of food given the OGT-deficient mice was controlled, these animals would not gain weight.
OGT senses how many calories are ingested during a meal by regulating the activity of specific neurons in the appetite center of the brain.

How do you know when to stop eating? Do you suddenly feel full and leave the food on your plate? Or do you eat until there is nothing left?

Many studies have focused on these questions in both humans and animals. This is because appetite control is critical for the development of obesity and weight loss. Researchers focus on external cues such as plate size, environment, routines and habits, and internal cues like gene expression and hormone regulation.

In a novel contribution to this field of research, Dr. Richard Huganir and a team of scientists at Johns Hopkins University, who were originally studying something else, have identified a genetic pathway directly linked to appetite control in mice. The researchers hope their findings will contribute to our understanding of brain-gut connections, with specific applications for patients attempting to lose weight.

Dr. Huganir’s work on appetite control was an unexpected finding that occurred during experiments on learning and memory.

Dr. Richard Huganir is the Director of the Department of Neuroscience at John Hopkins University. His research focuses on the processes involved in human learning and memory, a field that has intrigued him since his high school days. Dr. Huganir’s work on appetite control was an unexpected finding that occurred during experiments on learning and memory on the specific gene known as O-GlcNAc transferase (OGT).

OGT was previously shown to be involved in neuron development in mice. In order to determine the function of OGT in adult mice, the researchers used a mouse model in which the OGT gene was selectively deleted from the neurons of the mice when they reached adulthood. Such mouse models are known as “conditional knock-out” models because one or more specific gene(s) are knocked out of the genome at a time point chosen by the researchers.

Something unusual about those mice

While planning the learning- and memory-related behavioral tests, Olof Lagerlöf, a graduate student in Dr. Huganir’s laboratory, noticed the mice became obese very quickly. In fact, Olof noticed just days after birth that the mice ate two to three times the amount that mice usually eat, and they weighed about two to three times the usual weight as well.

Figure 1. Knock-out OGT mouse (left) and normal mouse

Reasoning that the mechanism by which OGT controls eating might give important insights into the biology of how OGT regulates neuronal function, Dr. Huganir and his colleagues wanted to know why the OGT knock-out mice were so obese. It seemed unlikely that parts of the brain involved in learning and memory would explain the dramatic loss of appetite control. For this reason, they began searching for different parts of the brain that might have been affected by the deletion of OGT.

The researchers identified the hypothalamus as the area where appetite regulation occurs, and genetic analysis revealed that OGT was indeed missing from this part of the brain, too. In order to be sure that they had correctly identified the hypothalamus, and in particular a subsection of the hypothalamus called the paraventricular nucleus (PVN), the researchers used a more specific method for deleting the OGT gene that would target only this very small region of the brain. The researchers found that mice with the specific OGT deletion exhibited the same overeating behavior as the mice with the general OGT deletion. From these findings, Dr. Huganir and his team concluded that lack of OGT in the PVN resulted in loss of appetite control in mice.

External control vs internal control

Interestingly, the researchers found that if they controlled the amount of food intake, the OGT-deficient mice would not gain weight. On their own, however, the mice had lost the ability to control how much they ate.

The team studied the function of OGT in the PVN: they found that OGT senses how many calories are ingested during a meal. In normal mice, the neurons in the PVN become activated and start firing when the mice eat. However, without OGT, the neurons no longer responded, suggesting that OGT couples caloric intake with meal size by regulating the activity of these neurons.

To further examine the relationship between OGT and appetite control, the researchers next stimulated the neurons in the PVN. They did this using a technique known as optogenetics. [see What A Year! Silencing Your Cells for more on optogenetics.] The activity of neurons can be controlled directly using florescent light. When stimulating the neurons, Dr. Huganir and his team observed that the mice stopped eating altogether. In other words, too much activity had the exact opposite effect as too little OGT. “It is very unusual that genetic experiments are so clear-cut,” comments Dr. Huganir. “We were pleasantly surprised.”

“It is very unusual that genetic experiments are so clear-cut. We were pleasantly surprised.”

Dr. Huganir cautions that mouse brains and human brains are very different, and it is unclear whether OGT would have similar effects in humans. The research is just in the beginning stages, but it does provide important groundwork for new areas of exploration into the development of obesity and potential therapeutic options.

Dr. Olof Lagerlöf, MD, PhD, is a Physician-Scientist at the Karolinska University Hospital and Institutet.

Dr. Richard Huganir is Professor of Neuroscience and Director of the Department of Neuroscience at Johns Hopkins University. He is also president-elect of the Society for Neuroscience. His research focuses on the processes of learning and memory with specific attention on therapeutic targets for autism and Alzheimer’s Disease. When not in the laboratory, Dr. Huganir enjoys traveling, biking and gardening.

For More Information:

Lagerlöf, O. et al. 2016. “The nutrient sensor OGT in PVN neurons regulates feeding.” Science, 351(6279): 1293-6.
Volk, L. et al. 2015. “Glutamate synapses in human cognitive disorders.” Annual Review of Neuroscience, 38: 127-49.
Araki ,Y. et al. 2015. “Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP.” Neuron, 85: 173-89.
Zhang, Y. et al. 2015. “Visualization of NMDA receptor-dependent AMPA receptor synaptic plasticity in vivo.” Nature Neuroscience, 18(3): 402-407.

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