Qingchun Tong, PhD

Research on arcuate (Arc) neurons from the lab of Qingchun Tong, PhD, associate professor at the Brown Foundation Institute of Molecular Medicine (IMM), published in Nature Metabolism may help shed light on the phenomenon of easy obesity development and difficulty in weight loss.

The paper titled “Profound and Redundant Functions of Arcuate Neurons in Obesity Development,” was co-authored by Canjun Zhu, PhD; Zhiying Jiang, PhD; and Yuanzhong Xu, PhD, from the IMM as well as Zhao-Lin Cai, PhD; Qingyan Jiang, PhD; Yong Xu, MD, PhD; Mingshan Xue, PhD; Benjamin R. Arenkiel, PhD; Qi Wu, PhD; and Gang Shu, PhD.

“Obesity has reached epidemic levels, and continues to cause an enormous burden to human health and society,” the paper says. “Despite extensive research, and increasing civil and governmental efforts aiming to reverse obesity trends, worldwide obesity rates are still rising.”

Previous studies have shown that Agouti-related protein (AgRP) neurons can regulate short-term feeding behavior. However, AgRP neuron-specific deletion or restoration of leptin receptor (LepR) shows little effect on body-weight, meaning AgRP neurons play a mild role in mediating leptin action.

Conversely, deletion of leptin receptors in GABAergic (GABA+) neurons led to obesity comparable to that of mice with leptin deficiencies, leading to a belief that non-AgRP GABAergic neurons play an important role in mediating leptin action.

Using mouse genetics and molecular targeting, the lab concentrated on Arc neurons with the expression of the bacterial sodium channel (NachBac) to cause chronic activation or the inward rectifying potassium channel Kir2.1 to cause chronic inhibition.

With the research, the lab found that activation of a random subsets of arcuate neurons in the hypothalamus is sufficient to cause comparable massive obesity, while inhibition of the whole arcuate neurons is required in order to reduce body weight or obesity. “The approach of chronic activation or inhibition is unique and important to reveal the effect on body weight, which requires long-term action,” Tong said.

The knowledge that arcuate neurons play both a major and redundant role in obesity development may help clear the phenomenon of easy obesity development and difficulty in weight loss, leading to the next phase of research for Tong’s lab.

“Despite extensive research, the mechanism for easy obesity development and difficulty in weight loss is unknown,” Tong said. “Our results provide an important insight on this. We will explore the relevance of these findings to diet-induced obesity, the major reason for the current human obesity epidemic, and try to unravel the real cause of human obesity.”