Obesity is a major contributor to the epidemic of metabolic diseases including dyslipidemia, hypertension, cardiovascular disease, and type II diabetes. Numerous studies suggest that increasing energy expenditure can effectively decrease body weight; however, no current therapeutic compounds safely or selectively activate energy expenditure. We have demonstrated that the endocrine hormone fibroblast growth factor 21 (FGF21) selectively activates sympathetic outflow to adipose tissue to increase energy expenditure. Moreover, FGF21 potently decreases both fat and body mass in obese animals and human patients. However, the mechanism of how FGF21 increases energy expenditure remains unknown. Our previous studies and work from other labs have demonstrated that FGF21 acts in the central nervous system to promote weight loss. In addition, several lines of evidence suggest that FGF21 requires intact signaling from the adipose-derived hormone, leptin, to elicit its full effects. Finally, our preliminary data demonstrates that the obligate FGF21 co-receptor, ?-klotho, is expressed in the arcuate nucleus of the hypothalamus (ARC), the primary site of leptin action in the brain, and that leptin activates signaling in ?-klotho-expressing cells in the ARC. Thus, we hypothesize that FGF21 signals, at least in part, to leptin-sensitive cells in the ARC to modulate energy expenditure. This proposal employs novel mouse genetic models, chemogenetic and optogenetic manipulation of specific cell populations in the brain and circuit mapping to investigate the crosstalk between FGF21 and leptin in the central control of energy expenditure.
According to the CDC, obesity has reached epidemic proportions, with over 60% of the U.S. population being overweight or obese, thus, there is a serious demand for the development of new therapeutics to combat obesity and its sequelae. Fibroblast growth factor 21 (FGF21) is a secreted endocrine factor that acts in the central nervous system to increase energy expenditure during obesity. By investigating the mechanism by which FGF21 stimulates energy expenditure, we hope to discover a novel, effective and safe target for the treatment of obesity.
| Morselli, Lisa L; Claflin, Kristin E; Cui, Huxing et al. (2018) Control of Energy Expenditure by AgRP Neurons of the Arcuate Nucleus: Neurocircuitry, Signaling Pathways, and Angiotensin. Curr Hypertens Rep 20:25 |
