Melanocortin pathway research published in Nature Communications
Recent research on asymmetry in the melanocortin pathway, from the lab of Qingchun Tong, PhD, professor at the Brown Foundation Institute of Molecular Medicine and Cullen Chair in Molecular Medicine, has been published in Nature Communications.
The melanocortin pathway is long believed to modulate body weight both by causing obesity when action is reduced, and reversing obesity and causing leanness when the pathway becomes more active. The ability of this pathway to regulate obesity has led researchers to failed attempts at creating pharmaceutical weight loss drugs targeting the melanocortin receptor 4 (MC4Rs).
The lab was able to follow and characterize body weight and other metabolic processes by generating preclinical models with either chronic activation or inhibition of key neurons in the melanocortin pathway in either normal conditions or obese states.
Through their research, the lab was able to determine that models expressing an inhibition of the pathway showed severe obesity. However, the models that showed activation in the melanocortin pathway had no apparent effect on obesity reduction or reversal.
“We revealed an asymmetry in the melanocortin pathway in body weight regulation,” Tong said. “This pathway is only able to produce a gain in body weight, but not the opposite. This may serve as a basis for largely failed efforts in pursuing MC4Rs as anti-obesity therapeutics as well as the known predisposition to obesity development in humans.”
Moving forward, the lab will examine the underlying mechanism causing the asymmetry by looking at whether the brain has parallel and redundant pathways to promote positive energy balance. This could mean that if one pathway is inhibited, other pathways may still be able to maintain body weight by functioning normally.
Further clarification of the pathway may help to provide research for future pharmaceuticals that could help reduce obesity using MC4Rs.
“The drug Setmelanotide (IMCIVREE) is a recently FDR-approved drug, but only for patients with obesity caused by mutations in the melanocortin pathway,” Tong said. “This suggests that a precision medicine is required for effective obesity treatment, like the use of drugs that rescue the function of obesity-causing dysfunctional neural pathways.
Contributing authors for the paper titled, “The melanocortin action is biased toward protection from weight loss in mice,” are Hongli Li, PhD, visiting scientist in the Tong Lab and Yuanzhong Xu, PhD, assistant professor at the Institute of Molecular Medicine. Collaborators from Baylor College of Medicine include Ben Arenkiel, PhD, and Yong Xu, MD, PhD.