Regulation of hindbrain Pyy expression by acute food deprivation, prolonged caloric restriction, and weight loss surgery in mice.

PYY is a gut-derived putative satiety signal released in response to nutrient ingestion and is implicated in the regulation of energy homeostasis. Pyy-expressing neurons have been identified in the hindbrain of river lamprey, rodents, and primates. Despite this high evolutionary conservation, little is known about central PYY neurons. Using in situ hybridization, PYY-Cre;ROSA-EYFP mice, and immunohistochemistry, we identified PYY cell bodies in the gigantocellular reticular nucleus region of the hindbrain. PYY projections were present in the dorsal vagal complex and hypoglossal nucleus. In the hindbrain, Pyy mRNA was present at E9.5, and expression peaked at P2 and then decreased significantly by 70% at adulthood. We found that, in contrast to the circulation, PYY-(1-36) is the predominant isoform in mouse brainstem extracts in the ad libitum-fed state. However, following a 24-h fast, the relative amounts of PYY-(1-36) and PYY-(3-36) isoforms were similar. Interestingly, central Pyy expression showed nutritional regulation and decreased significantly by acute starvation, prolonged caloric restriction, and bariatric surgery (enterogastroanastomosis). Central Pyy expression correlated with body weight loss and circulating leptin and PYY concentrations. Central regulation of energy metabolism is not limited to the hypothalamus but also includes the midbrain and the brainstem. Our findings suggest a role for hindbrain PYY in the regulation of energy homeostasis and provide a starting point for further research on gigantocellular reticular nucleus PYY neurons, which will increase our understanding of the brain stem pathways in the integrated control of appetite and energy metabolism.

Chromosomal mapping of excessive physical activity in mice in response to a restricted feeding schedule.

Excessive physical activity plays an important role in the progression of anorexia nervosa (AN) by accelerating weight loss during dietary restriction. To search for mechanisms underlying this trait, a panel of mouse chromosome substitution strains derived from C57BL/6J and A/J strains was exposed to a scheduled feeding paradigm and to voluntary running wheel (RW) access. Here, we showed that A/J chromosomes 4, 12 and 13 contribute to the development of a disrupted RW activity in response to daily restricted feeding. This pattern is characterized by intense RW activity during the habitual rest phase and leads to accelerated body weight loss. Regions on mouse chromosomes 4, 12 and 13 display homology with regions on human chromosomes linked with anxiety and obsessionality in AN cohorts. Therefore, our data open new roads for interspecies genetic studies of AN and for unraveling novel mechanisms and potential effective treatment strategies for these neurobehavioral traits.

Dopaminergic and brain-derived neurotrophic factor signalling in inbred mice exposed to a restricted feeding schedule.

Increased physical activity and decreased motivation to eat are common features in anorexia nervosa. We investigated the development of these features and the potential implication of brain-derived neurotrophic factor (BDNF) and dopaminergic signalling in their development in C57BL/6J and A/J inbred mice, using the 'activity-based anorexia' model. In this model, mice on a restricted-feeding schedule are given unlimited access to running wheels. We measured dopamine receptor D2 and BDNF expression levels in the caudate putamen and the hippocampus, respectively, using in situ hybridization. We found that in response to scheduled feeding, C57BL/6J mice reduced their running wheel activity and displayed food anticipatory activity prior to food intake from day 2 of scheduled feeding as an indication of motivation to eat. In contrast, A/J mice increased running wheel activity during scheduled feeding and lacked food anticipatory activity. These were accompanied by increased dopamine receptor D2 expression in the caudate putamen and reduced BDNF expression in the hippocampus. Consistent with human linkage and association studies on BDNF and dopamine receptor D2 in anorexia nervosa, our study shows that dopaminergic and BDNF signalling are altered as a function of susceptibility to activity-based anorexia. Differences in gene expression and behaviour between A/J and C57BL/6J mice indicate that mouse genetic mapping populations based on these progenitor lines are valuable for identifying molecular determinants of anorexia-related traits.