Fighting Obesity: Uncovering a Pathway to Change

A team of researchers led by Xiaoyong Yang in the Integrative Cell Signaling & Neurobiology of Metabolism Program at the Yale School of Medicine has identified the pathway in the brain that regulates the browning of white fat. Their discovery leads to an improved understanding of the biological mechanisms of hunger and energy homeostasis, which can help scientists better address the rising issue of obesity.

Image courtesy of Xiaoyong Yang
Image courtesy of Xiaoyong Yang

A key finding in this study was that the hunger-promoting neuron can direct the adipose tissue to stop the conversation from white fat to brown fat or “browning” when a body is hungry. White fat consists of energy stored as lipids, while the purpose of brown fat is to burn lipids to maintain body temperature.  From an evolutionary standpoint, this brain adaptation is essential. The body has energy priorities, such as maintaining a heartbeat and breathing, and thus it is important to conserve energy in the form of white fat and not dissipate it as brown fat while in a state of starvation. When people have enough food or are exposed to cold, browning produces heat. Strikingly, the body is able to prioritize hunger over cold, as starvation inhibits browning even in the face of colder temperatures.

Associate Professor of Comparative Medicine and Physiology Xiaoyong Yang’s previous research focused on the effects of protein modification by a sugar known as O-linked β-N-acetylglucosamine (O-GlcNAc) on the regulation of protein function in peripheral tissues, such as liver and adipose tissue (commonly known as fat). This sugar modification has been found to be critical in understanding glucose metabolism in liver and fat. Yang and his team were interested in the neurological role of this sugar modification and asked the question: How does this sugar modification function in the brain and what are the biological consequences of this process?

“We focus on the area in the brain called the hypothalamus,” explained Yang, “because this area is crucial and fundamental for physiology, as it serves as the headquarter for metabolic control and energy balance for the whole body.”

The team began by genetically engineering mice through deletion of O-GlcNAc transferase (OGT), the enzyme that catalyzes O-GlcNAc modification, from the AgRP neuron. This neuron, one of many in the hypothalamus, is known as a hunger-promoting neuron. When fasting occurs, this neuron is excited and incites hunger. O-GlcNAc is a critical enabler of this process; when OGT was removed from the mouse genome, the browning process was stimulated and identified by a dramatic change in the usually neglected fat depot called retroperitoneal white adipose tissue.

Recently, it was found that when hunger occurs, this neuron sends a signal to the liver to begin producing glucose in order to maintain a constant blood-glucose level. This study expands this concept of neural signaling by explaining the regulatory circuitry for fat burning. Through this experiment, it is now known that the hunger-promoting neuron can directly send messages to the adipose tissue and catalyze fat burning.

The construction of the molecular pathway for this process was another major contribution of this paper. The sugar modification serves as a nutrient sensor in that OGT is able to regulate neuronal activity through adding the sugar onto the potassium channel. Activation of the potassium channel excites the AgRP neuron to transduce the hunger signal to the adipose tissue.

Researchers will now investigate how OGT senses nutrient availability and alters the activity of the potassium channel in the neurons and how the neural circuits could be projected into different fat depots.

This more complete characterization of the fat browning pathway can help scientists better face the problem of obesity. Moving forward, Yang explained, “it is highly likely that a similar pathway exists in human beings, and if we are able to inhibit neurons from sending the hunger signal to fat tissue, that can lead to continued fat browning and weight loss.” In the future, an established mechanism can help scientists develop a drug to directly target the pathway and fight obesity.