Bsx, a novel hypothalamic factor linking feeding with locomotor activity, is regulated by energy availability

Es un estudio en modelos de rata acerca del papel de BSX, la actividad y la alimentación.We recently reported that the hypothalamic homeobox domain transcription factor Bsx plays an essential role in the central nervous system control of spontaneous physical activity and the generation of hyperphagic responses. Moreover, we found Bsx to be a master regulator for the hypothalamic expression of key orexigenic neuropeptide Y and agouti gene-related protein. We now hypothesized that Bsx, which is expressed in the dorsomedial and arcuate nucleus (ARC) of the hypothalamus, is regulated by afferent signals in response to peripheral energy balance. Bsx expression was analyzed using in situ hybridization in fed vs. fasted (24 h) and ghrelin vs. leptin-treated rats, as well as in mice deficient for leptin or the ghrelin signaling. Ghrelin administration increased, whereas ghrelin receptor antagonist decreased ARC Bsx expression. Leptin injection attenuated the fasting-induced increase in ARC Bsx levels but had no effect in fed rats. Dorsomedial hypothalamic nucleus Bsx expression was unaffected by pharmacological modifications of leptin or ghrelin signaling. Obese leptin-deficient (ob/ob) mice, but not obese melanocortin 4 receptor-knockout mice, showed higher expression of Bsx, consistent with dependency from afferent leptin rather than increased adiposity per se. Interestingly, exposure to a high-fat diet triggered Bsx expression, consistent with the concept that decreased leptin signaling due to a highfat diet induced leptin resistance. Our data indicate that ARC Bsx expression is specifically regulated by afferent energy balance signals, including input from leptin and ghrelin. Future studies will be necessary to test if Bsx may be involved in the pathogenesis of leptin resistance

Ο ρόλοςτου ομοιοτικού μεταγραφικού παράγοντα BSX στον έλεγχο της ενεργαιακής ομοιόστασης στα ποντίκια

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

A role for brain-specific homeobox factor Bsx in the control of hyperphgia and locomotory behavior

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.status: publishe

The long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis.

Although patients with rheumatoid arthritis (RA) typically exhibit symmetrical joint involvement, some patients develop alternative disease patterns in response to treatment, suggesting that different molecular mechanism may underlie disease progression depending on joint location. Here, we identify joint-specific changes in RA synovium and synovial fibroblasts (SF) between knee and hand joints. We show that the long non-coding RNA HOTAIR, which is only expressed in knee SF, regulates more than 50% of this site-specific gene expression in SF. HOTAIR is downregulated after stimulation with pro-inflammatory cytokines and is expressed at lower levels in knee samples from patients with RA, compared with osteoarthritis. Knockdown of HOTAIR in knee SF increases PI-Akt signalling and IL-6 production, but reduces Wnt signalling. Silencing HOTAIR inhibits the migratory function of SF, decreases SF-mediated osteoclastogenesis, and increases the recruitment of B cells by SF. We propose that HOTAIR is an important epigenetic factor in joint-specific gene expression in RA

Bsx, a Novel Hypothalamic Factor Linking Feeding with Locomotor Activity, Is Regulated by Energy Availability

We recently reported that the hypothalamic homeobox domain transcription factor Bsx plays an essential role in the central nervous system control of spontaneous physical activity and the generation of hyperphagic responses. Moreover, we found Bsx to be a master regulator for the hypothalamic expression of key orexigenic neuropeptide Y and agouti gene-related protein. We now hypothesized that Bsx, which is expressed in the dorsomedial and arcuate nucleus (ARC) of the hypothalamus, is regulated by afferent signals in response to peripheral energy balance. Bsx expression was analyzed using in situ hybridization in fed vs. fasted (24 h) and ghrelin vs. leptin-treated rats, as well as in mice deficient for leptin or the ghrelin signaling. Ghrelin administration increased, whereas ghrelin receptor antagonist decreased ARC Bsx expression. Leptin injection attenuated the fasting-induced increase in ARC Bsx levels but had no effect in fed rats. Dorsomedial hypothalamic nucleus Bsx expression was unaffected by pharmacological modifications of leptin or ghrelin signaling. Obese leptin-deficient (ob/ob) mice, but not obese melanocortin 4 receptor-knockout mice, showed higher expression of Bsx, consistent with dependency from afferent leptin rather than increased adiposity per se. Interestingly, exposure to a high-fat diet triggered Bsx expression, consistent with the concept that decreased leptin signaling due to a high-fat diet induced leptin resistance. Our data indicate that ARC Bsx expression is specifically regulated by afferent energy balance signals, including input from leptin and ghrelin. Future studies will be necessary to test if Bsx may be involved in the pathogenesis of leptin resistance

Hypothalamic κ-Opioid Receptor Modulates the Orexigenic Effect of Ghrelin

The opioid system is well recognized as an important regulator of appetite and energy balance. We now hypothesized that the hypothalamic opioid system might modulate the orexigenic effect of ghrelin. Using pharmacological and gene silencing approaches, we demonstrate that ghrelin utilizes a hypothalamic κ-opioid receptor (KOR) pathway to increase food intake in rats. Pharmacological blockade of KOR decreases the acute orexigenic effect of ghrelin. Inhibition of KOR expression in the hypothalamic arcuate nucleus is sufficient to blunt ghrelin-induced food intake. By contrast, the specific inhibition of KOR expression in the ventral tegmental area does not affect central ghrelin-induced feeding. This new pathway is independent of ghrelin-induced AMP-activated protein kinase activation, but modulates the levels of the transcription factors and orexigenic neuropeptides triggered by ghrelin to finally stimulate feeding. Our novel data implicate hypothalamic KOR signaling in the orexigenic action of ghrelin