Central control of energy balance by amylin and calcitonin receptor agonists and their potential for treatment of metabolic diseases

The prevalence of obesity and associated comorbidities such as type 2 diabetes and cardiovascular disease is increasing globally. Body-weight loss reduces the risk of morbidity and mortality in obese individuals, and thus, pharmacotherapies that induce weight loss can be of great value in improving the health and well-being of people living with obesity. Treatment with amylin and calcitonin receptor agonists reduces food intake and induces weight loss in several animal models, and a number of companies have started clinical testing for peptide analogues in the treatment of obesity and/or type 2 diabetes. Studies predominantly performed in rodent models show that amylin and the dual amylin/calcitonin receptor agonist salmon calcitonin achieve their metabolic effects by engaging areas in the brain associated with regulating homeostatic energy balance. In particular, signalling via neuronal circuits in the caudal hindbrain and the hypothalamus is implicated in mediating effects on food intake and energy expenditure. We review the current literature investigating the interaction of amylin/calcitonin receptor agonists with neurocircuits that induce the observed metabolic effects. Moreover, the status of drug development of amylin and calcitonin receptor agonists for the treatment of metabolic diseases is summarized

Reduced early life mucosal integrity decreases thymic cell counts and increases local, but not thymic regulatory, T cell recruitment: Gut mucosal integrity breach and thymic T cells

Early life immune gut microbiota contact is critical for regulatory T cell–mediated oral tolerance induction. We induced a mucosal integrity breach with low dextran sulfate sodium dose right after weaning in BALB/c mice along with a standard high dose to study the impact of increased gut microbiota lymphatic tissue contact on the thymus. Both doses increased gut permeability, which caused a short-term generalized thymic involution and regulatory T cell induction in the mesenteric lymph nodes, even in the absence of clinically apparent inflammation in the low-dose group. The thymic regulatory T cells resisted thymic involution. In the low-dose group, we found acutely altered gut mobilization patterns characterized by changed gut-homing marker CD103 expression on mesenteric lymph node CD4 + T cells as well as on mature CD8 + T cells and developing CD4 − /CD8 − thymocytes. Furthermore, CD218a (IL-18-receptor-a) expression was acutely decreased on both mature CD8 + T cells and regulatory T cells, while increased on the mesenteric lymph node CD8 + T cells, indicating a direct link between the thymus and the mesenteric lymph nodes with CD218a in a functional role in thymic involution. Acute and non-persisting regulatory responses in the mesenteric lymph nodes were induced in the form of a relative regulatory T cell increase. We saw no changes in total thymic regulatory T cells and thus the thymus does not seem to play a major role of in the regulatory immunity induced by increased gut microbiota lymphatic tissue contact around weaning, which in our study primarily was located to the gut

Salmon calcitonin distributes into the arcuate nucleus in mice to a subset of NPY neurons

The amylin receptor (AMY) and calcitonin receptor (CTR) agonists induce acute suppression of food intake in rodents by binding to receptors in the area postrema (AP) and potentially by targeting arcuate (ARC) neurons directly. Salmon calcitonin (sCT) induces more potent, longer lasting anorectic effects compared to amylin. We thus aimed to investigate whether AMY/CTR agonists target key neuronal populations in the ARC, and whether differing brain distribution patterns could mediate the observed differences in efficacy with sCT and amylin treatment. Brains were examined by whole brain 3D imaging and confocal microscopy following subcutaneous administration of fluorescently labelled peptides to male and female mice. We found that sCT, but not amylin, internalizes into a subset of ARC NPY neurons, along with an unknown subset of ARC, AP and dorsal vagal motor nucleus cells. ARC POMC neurons were not targeted. Furthermore, amylin and sCT displayed similar distribution patterns when binding to receptors in the AP, the organum vasculosum of the lamina terminalis (OVLT) and the ARC. Amylin was distributed within the median eminence with only specs of sCT being present in this region, however amylin was only detectable 10 min after injection while sCT displayed a residence time of up to 2 h post injection. We conclude that AMY/CTR agonists bind to receptors in a subset of ARC NPY neurons and in circumventricular organs. Furthermore, the more sustained and greater anorectic efficacy of sCT compared to rat amylin is not attributable to differences in brain distribution patterns but may more likely be explained by greater potency at both CTR and AMY3