A Role for Brain-Specific Homeobox Factor Bsx in the Control of Hyperphagia and Locomotory Behavior

Abstract

Food intake and activity-induced thermogenesis are important components of energy balance regulation. The molecular mechanism underlying the coordination of food intake with locomotory behavior to maintain energy homeostasis is unclear. We report that the brain-specific homeobox transcription factor Bsx is required for locomotory behavior, hyperphagia, and expression of the hypothalamic neuropeptides Npy and Agrp, which regulate feeding behavior and body weight. Mice lacking Bsx exhibit reduced locomotor activity and lower expression of Npy and Agrp. They also exhibit attenuated physiological responses to fasting, including reduced increase of Npy/Agrp expression, lack of food-seeking behavior, and reduced rebound hyperphagia. Furthermore, Bsx gene disruption rescues the obese phenotype of leptin-deficient ob/ob mice by reducing their hyperphagia without increasing their locomotor activity. Thus, Bsx represents an essential factor for NPY/AgRP neuronal function and locomotory behavior in the control of energy balance.

Conceptual heuristic models of the interrelationships between obesity and the occupational environment

“…Such evidence supports the idea that sedentary behavior and physical activity are separate behaviors. Current thinking suggests that degree of activity may be influenced by environment and genetics (49,(95)(96)(97) …”

“…Such evidence supports the idea that sedentary behavior and physical activity are separate behaviors. Current thinking suggests that degree of activity may be influenced by environment and genetics (49,(95)(96)(97). Studies have Pandalai et al found that animals can be bred to be "obesity resistant" demonstrating more spontaneous physical activity (96), and certain genes, such as the brain-specific Bsx or "fidget" gene, may impact spontaneous physical activity (97), although these findings have not been confirmed among humans.…”

“…Current thinking suggests that degree of activity may be influenced by environment and genetics (49,(95)(96)(97). Studies have Pandalai et al found that animals can be bred to be "obesity resistant" demonstrating more spontaneous physical activity (96), and certain genes, such as the brain-specific Bsx or "fidget" gene, may impact spontaneous physical activity (97), although these findings have not been confirmed among humans. A recent examination of the impact of sedentary behavior (hours of TV watching) on the BMI of individuals with a genetic predisposition for obesity (32 well-established BMI-associated genetic variants) found that prolonged sedentary activity exacerbated genetic effects, but increased physical activity independently weakened this genetic association (98).…”

Ghrelin and lipid metabolism: key partners in energy balance

“…Overall, these results indicate that the BSX-FOXO1-pCREB signaling pathway plays a key role in integrating hypothalamic ghrelin actions. Further experiments, using BSX KO mice (Sakkou et al 2007), are essential to confirm the existence of alternative pathways to BSX linking ghrelin fatty acid metabolism and neuropeptide expression. Actually, taking into account that BSX KO mice exhibit lower fasting-induced response in Agrp and Npy mRNA levels (Sakkou et al 2007), the involvement of alternative additional transcription factors cannot be excluded.…”

“…It has been recently reported that the hypothalamic homeobox domain transcription factor BSX is highly expressed in AGRP/NPY neurons in the ARC and regulates ghrelin's stimulatory effect on Agrp and Npy gene expression in male and female rodents (Sakkou et al 2007, Nogueiras et al 2008a. Although both genes share BSX as a common transcriptional factor, BSX needs to interact with another two transcription factors to activate Agrp and Npy mRNA expression: the forkhead box O1 (FOXO1) for Agrp gene and the phosphorylated cAMP responseelement-binding protein (pCREB) for Npy gene …”