Yale researchers have linked the lack of an enzyme called OGT to increased body weight and the incidence of obesity.
The OGT enzyme plays a crucial role in regulating body weight and fighting obesity, according to a new paper published by Yale researchers.
In the paper published on August 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 mouse models. Xiaoyong Yang, professor of comparative medicine and cellular and molecular physiology in 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 food process. You have a basic daily 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 certainly regulate this by telling you when to eat, when you’re 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.
Specifically, this part of the brain receives information from the digestive system about the individual’s diet.
“It’s like a headquarters for regulating metabolic homeostasis, which is a very critical tool,” Yang said. “The hypothalamus receives the message from the peripheral tissue and then sends the message back to the peripheral tissue to control body weight and blood sugar.”
Previously, researchers have studied this area of the brain to determine its role in regulating blood sugar and weight. Despite its small size, the hypothalamus houses different 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 different neurons in the brain regulate different parts of the body in an attempt to combat nutrient deficiencies or excesses in order to maintain homeostasis throughout the body. For example, when a healthy individual eats more than usual, the brain will notice this excess and trigger an increased energy-burning response to maintain balance.
According to Wang, the brain plays two roles in regulating body weight. The first part is energy balance and the second part is the balance of metabolism in the body. The brain is involved 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 enough energy to maintain current body weight. The weight of the individual increases, eventually leading to obesity.
“Your body weight will go into a new set point and stay there,” Yang said. “At this new body weight, it is very difficult to change the body weight set point.”
OGT is an enzyme that catalyzes post-transcriptional modification responsible for sensing nutrient and hormone levels in the body. In other words, OGT regulates cellular processes in response to how much food an individual consumes and how much energy they have expended.
The role of OGT, as an enzyme in these neurons, is to respond to nutrient and stress factors in the body, thereby triggering an appropriate corrective response given the level of energy and nutrients in the body, according to Yang.
“What we found here is that OGT can potentially impact the activity of neurons, neurons in the ventromedial hypothalamus,” Wang said. “In the absence of OGT, these neurons are down-regulated […] this leads to an increase in body weight.
To identify the role of OGT in regulating body weight, the researchers established two animal models. In the first model, they removed the OGT from mouse embryos and observed the mice’s body weight as they grew into adulthood. In the second model, they deleted the OGT after the mice reached adulthood.
Next, they measured the body weight and energy expenditure of these genetically modified mice.
« Genetic ablation of the OGT in the VMH [ventromedial hypothalamus] leads to obesity and reduced energy expenditure in mice fed a normal diet,” the paper states. “These results reveal that OGT in VMH is required to promote lipid catabolism and maintain energy balance.”
Yang added that his lab wants to study different peripheral tissues, such as the liver and pancreas. He explained that, in the hypothalamus, some neurons react to low levels of glucose while others react to high levels of glucose. They work together to try to bring the blood glucose level back to normal. He thinks this finding can be applied to research on cells called alpha cells and beta cells in the pancreas. Alpha cells react to starvation or hypoglycemia, while beta cells react to excessive satiety or hyperglycemia.
A 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 cues. These drugs have many side effects and can be an unpleasant treatment. Since OGT only regulates energy expenditure and does not impact food intake, Wang hopes that a potential drug based on OGT would be a more effective and enjoyable treatment option for patients. people with obesity.
Yang has worked at the School of Medicine since 2008.