Drug target that revs up energy expenditure, reduces appetite identified
A drug that promotes energy expenditure in the body while suppressing appetite could be a powerful weight loss therapy. Researchers at The University of Texas Health Science Center at San Antonio, the Second Xiangya Hospital of Central South University-China and Baylor College of Medicine reported a possible drug target Jan. 2 in the journal Nature Metabolism.
Juli Bai, PhD, assistant professor in the departments of pharmacology and cell systems and anatomy at UT Health San Antonio, is a co-first author on the study, which found that a protein called Grb10 (growth factor receptor-bound protein 10) stimulates leptin signaling. Leptin, a hormone derived from adipose (fatlike) tissue, is essential in the brain, where it signals our bodies to maintain healthy energy balance by reducing food intake and raising energy expenditure.
“Because obese persons have leptin resistance, their leptin is not utilized efficiently, energy expenditure is impaired, and appetite is not fully suppressed,” said Bai, who joined UT Health San Antonio in 2011.
This resistance makes it very difficult to use leptin itself as a therapeutic strategy, she said. Grb10 doesn’t directly raise leptin levels but instead regulates leptin signaling and its functions that result in the desirable energy-balance traits.
To researchers like Bai, this is provocative. “It represents an alternative strategy,” she said. “It provides another choice for the possible treatment of obesity.”
This study is the first to show that Grb10 is a positive regulator of leptin signaling, Bai said. “We think this finding is very important for that reason,” she said.
Grb10 increases leptin activity in two types of neurons of the hypothalamus, a brain region that coordinates functions such as controlling hunger, thirst and body temperature. In mice, the researchers examined both the deletion and the overexpression of Grb10 in these neurons. Deletion of Grb10 promoted weight gain, whereas overexpression of Grb10 reduced body weight.
The studies were conducted in obese mice fed a high-fat diet. “We found that having more Grb10 will counteract nutrition-induced obesity,” Bai said.
Hypothalamic Grb10 enhances leptin signaling and promotes weight loss
Hailan Liu, Yang He, Juli Bai, Chuanhai Zhang, Feng Zhang, Yongjie Yang, Hairong Luo, Meng Yu, Hesong Liu, Longlong Tu, Nan Zhang, Na Yin, Junying Han, Zili Yan, Nikolas Anthony Scarcelli, Kristine Marie Conde, Mengjie Wang, Jonathan Carter Bean, Camille Hollan Sidell Potts, Chunmei Wang, Fang Hu, Feng Liu and Yong Xu
First published: Jan. 2, 2023, Nature Metabolism
https://www.nature.com/articles/s42255-022-00701-x