Stress can influence how much people eat and how their bodies regulate weight, but how the brain connects stress with obesity has remained unclear.
However, new research from McGovern Medical School at UTHealth Houston is uncovering part of that connection and is showing that the relationship may be more complicated than previously thought.
A new study led by Qingchun Tong, PhD, professor and associate director of the Center for Neuroimmunology and Glial Biology in the Brown Foundation Institute of Molecular Medicine, found that two chemical messengers released by the same group of stress-responsive brain cells can have dramatically different effects on developing diet-induced obesity.
Tong’s research, published in Nature Communications, focuses on neurons that produce corticotropin-releasing hormone, or CRH. The neurons help initiate the body’s response to stress through a system known as the hypothalamic-pituitary-adrenal axis.
Although these neurons have been studied for their role in stress, not much is known about how they contribute to body weight regulation. The neurons release both corticotropin-releasing hormone and glutamate, one of the brain’s primary excitatory neurotransmitters. The team set out to determine how each of these affects the development of obesity.
Previous studies of CRH neurons have relied on murine models with corticotropin-releasing hormone, or its receptors were removed during embryonic development. However, because those models exhibit developmental abnormalities, it can be difficult for researchers to separate normal functions from changes caused by abnormal development.
“Our current study uses models with manipulations of gene expressions in adult CRH neurons, which bypassed potential developmental complications and allows investigations on physiological roles of the neurons in body weight regulation and the HPA axis function,” Tong said.
The team then examined how increasing or decreasing the release of the two chemical messengers affected body weight, particularly when the models consumed a high-fat, high-calorie diet. These manipulations did not affect body weight when the animals ate a standard diet, but showed differences when they were exposed to the high-fat diet.
The researchers found that reducing glutamate release from CRH neurons, or increasing CRH release, led to severe diet-induced obesity. In contrast, reducing CRH, or increasing glutamate release, did not significantly affect the development.
“Our results demonstrate contrasting and opposite roles between CRH and glutamate in mediating CRH neuron function, suggesting a change in the action of CRH neurons in either direction may cause obesity development,” Tong said. “Surprisingly, our results also showed that loss of CRH or glutamate release from CRH neurons caused mild changes in corticosterone levels, the final functional mediator of the HPA axis. This challenges the well-accepted dogma that CRH is essential for the HPA axis activity.”
Going forward, Tong and his team will work to identify neurons that receive glutamate signals from CRH neurons and determine how those neural pathways contribute to diet-induced obesity.
Tong is the Hans J. Muller-Eberhard, MD, PhD, and Irma Gigli, MD, Distinguished Chair in Immunology and the Cullen Chair in Molecular Medicine at McGovern Medical School. He also holds appointments at UTHealth Houston School of Behavioral Health Sciences and The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences.