Researchers Find Evidence of Novel Pathway in Regulation of Body Weight, Temperature

Leptin receptor signaling in single-minded homolog gene (Sim1) neurons plays a role in the regulation of body weight and temperature, according to a mouse study recently published in Endocrinology.

Researchers led by Masoud Ghamari-Langroudi, MD, PhD, of the Vanderbilt School of Medicine in Nashville, Tenn., point out that the obesity epidemic continues to grow, and that two-thirds of the U.S. population are now overweight and obese. They write that there are a variety of circulating factors that play a role in regulating body weight, the most well-studied of which is leptin. The central expression and function of leptin receptor B (LepRb) have been studied for 20 years, the authors write, but the mechanisms by which LepRb signaling dysregulation contributes to obesity aren’t clear. “The role of LepRb expression in the PVN in regard to the regulation of physiological function of leptin has been controversial,” the authors write. “[Sim1] is densely expressed in the PVN and in parts of the amygdala, making Sim1-Cre mice a useful model for examining molecular mechanisms regulating PVN function.”

The researchers generated a mouse line with LepRb deleted from their Sim1 neurons and found that these mice grow at a normal rate while eating normal chow but when fed a high-fat diet they developed obesity. These mice also had a decreased body temperature and a defective thermoregulatory response when exposed to cold temperatures associated with the inability to upregulate uncoupling protein 1 in the brown adipose tissue and total thyroxine (T4) in serum. “These data shed light on the role of Sim1 neurons LepRb function in the regulation of energy homeostasis and adaptive thermoregulatory neuroendocrine responses,” the authors write.

The authors go on to write that activation of central thermogenic circuits to increase the UCP1-induced thermogenesis may provide a therapeutic approach to treat obesity. “In this context,” the authors conclude, “our data suggest that LepRb signaling expressed in this pathway could be potentially targeted by positive allosteric modulators to increase signaling in the presence of endogenous agonists.”