The role of the homeobox transcription factor BSX in the regulation of energy homeostasis in mice

Abstract

Consuming sufficient food to maintain adequate energy stores is critical for survival for all species in the animal kingdom. To ensure that this activity takes a high priority in brain function, mammalian brains have evolved several potent and inter-related neuronal circuitries that drive and control the balance between food consumption and energy expenditure, and this is a fundamental aspect of energy homeostasis. The neuronal circuitries that regulate energy balance include the hypothalamic neuropeptide Y, Agouti related peptide (NPY/AgRP) and pro-opiomelanocortin, cocain-amphetamin regulated transcript (POMC/CART) expressing neurons. NPY/AgRP neurons constitute a potent feeding system that is activated during a negative energy balance situation. This is actively opposed by the POMC/CART satiety system which is stimulated upon excess of energy storage. Peripheral hormones like Leptin, an adipocyte derived cytokine that signals starvation of the body to the brain upon down-regulation, Insulin, a pancreas derived hormone signaling glucose levels or Ghrelin, a gut secreted peptide that triggers the feeling of hunger, utilize both NPY/AgRP and POMC/Cart expressing neurons to mediate their functions. They achieve this by modifying the activity of these neurons at both the physiological and transcriptional level. To investigate the transcriptional network underlying the function of NPY/AgRP and POMC expressing neurons we identified Bsx, a homeodomain transcription factor that exerts specific expression in the orexigenic NPY/AgRP neurons of the arcuate nucleus. In order to characterize genetically the role of Bsx in the orexigenic neurons I generated two mouse strains deficient for the gene. I could show by this loss of function experiment in mice, that Bsx is required in the NPY/AgRP neurons both to maintain the expression of Npy and Agrp peptides, and to modulate spontaneous physical activity at the physiological level. In addition, mutant mice lacking Bsx can partially rescue the obesity phenotype caused by Leptin deficiency in ob/ob mutant mice. Food intake is reduced in these mice, due to the down-regulation of Npy, but the locomotory activity defect that ob/ob mice display is not rescued. These results provide evidence that the proposed relationship between levels of physical activity, resting thermogenesis, food intake and body weight can be genetically uncoupled and suggests the existence of a specific molecular control for subcomponents of energy balance regulation within subsets of hypothalamic neurons.