Sophie Henry

The enzyme OGT plays a crucial role in regulating body weight and curbing obesity, according to a new paper published by Yale researchers. 

In the paper published on Aug. 31, first author Qi Wang GRD ’23, a doctoral student in cellular and molecular physiology, established the link between the absence of OGT and increased body weight in mice models. Xiaoyong Yang, professor of comparative medicine and cellular and molecular physiology at the School of Medicine, was the principal investigator of this study. 

“Let me give you an example of energy balance,” Wang said. “You have a daily eating process. You have a daily, baseline energy expenditure. You will also have energy expenditure when you exercise. So, at the same time, there is energy going into your body and energy going out of your body. The brain can definitely regulate that by telling you when to eat, when you are full and when you need to expend more energy.”

The study focuses on a small area of the brain called the hypothalamus, which is responsible for regulating body weight by receiving and processing information gathered from the rest of the body. 

More specifically, this part of the brain receives information from the digestive system about the individual’s diet. 

“It’s like a headquarter for regulating metabolic homeostasis, which is a very critical tool,” Yang said. “The hypothalamus receives the message from the peripheral tissue, then sends the message back to the peripheral tissue to control the body weight and the blood glucose level.”

Previously, researchers have studied this area of the brain to determine its role in blood glucose and weight regulation. Despite its small size, the hypothalamus is home to various types of neurons, each of which can play a role in this metabolic process. For example, AgRP neurons are essential for triggering a hunger response to increase food intake, according to Yang. 

These various neurons in the brain regulate different parts of the body to try and fight against nutrient deficiencies or surpluses to maintain homeostasis within the whole body. For example, when a healthy individual eats more than usual, the brain will notice this surplus and trigger an increased energy burning response to maintain the balance. 

According to Wang, the brain plays two roles in the regulation of body weight. The first part is the balance of energy, and the second part is the balance of metabolism within the body. The brain intervenes in both of these processes to regulate body weight. 

However, if an individual continually consumes excessive amounts of high-calorie meals, the body’s homeostatic response can no longer burn off enough energy to maintain the current body weight. The individual’s weight increases, eventually leading to obesity. 

“Your body weight will enter a new set point and stay there,” Yang said. “At this new body weight, it is very hard to change the set point of body weight.”

OGT is an enzyme that catalyzes a post-transcriptional modification responsible for sensing nutrient and hormone levels in the body. In other words, OGT regulates cellular processes in response to the amount of food an individual consumes and the amount of energy that individual has expended.

OGT’s role, as an enzyme within these neurons, is to respond to nutrient and stress factors in the body, thereby triggering an appropriate remedial response given the energy and nutrient level in the body, according to Yang. 

“What we found here is that OGT can potentially impact the activity of the neurons, the ventromedial hypothalamus neurons,” Wang said. “In the absence of OGT, these neurons are downregulated  […] this leads to a body weight increase.”

To identify OGT’s role in regulating body weight, the researchers established two animal models. In the first model, they deleted OGT from mice embryos and observed the mice’s body weights as they grew to adulthood. In the second model, they deleted OGT after the mice reached adulthood.

Then, they measured the body weight and energy expenditure of these genetically modified mice. 

“Genetic ablation of OGT in the VMH [ventromedial hypothalamus] leads to obesity and reduced energy expenditure in mice fed a normal chow diet,” the paper states. “These findings reveal that OGT in the VMH is required for promoting lipid catabolism and maintaining energy balance.”

Yang added that his laboratory wants to investigate different peripheral tissues, such as the liver and the pancreas. He explained that, in the hypothalamus, some neurons respond to low glucose levels while others respond to high glucose levels. They work together to attempt to bring the glucose level in the blood back to the normal range. He believes that this finding can be applied to research on cells called alpha cells and beta cells in the pancreas. Alpha cells respond to starvation, or hypoglycemia, whereas beta cells respond to excessive satiety, or hyperglycemia. 

One potential therapeutic application of this research is the development of a new drug to treat obesity. According to Wang, some pharmaceutical drugs designed to treat obesity target the brain to suppress hunger signals. These drugs have many adverse effects and can be an unpleasant treatment. Since OGT only regulates energy expenditure and does not impact food intake, Wang hopes a potential OGT-based drug would be a more effective and pleasant treatment option for those suffering from obesity. 

Yang has worked at the School of Medicine since 2008.