Exocrine pancreas proteases regulate ß-cell proliferation in zebrafish ciliopathy models and in murine systems.

Pancreatic ß-cells are a critical cell type in the pathology of diabetes. Models of genetic syndromes featuring diabetes can provide novel mechanistic insights into regulation of ß-cells in the context of disease. We previously examined ß-cell mass in models of two ciliopathies, Alström Syndrome (AS) and Bardet-Biedl Syndrome (BBS), which are similar in the presence of metabolic phenotypes, including obesity, but exhibit strikingly different rates of diabetes. Zebrafish models of these disorders show deficient ß-cells with diabetes in AS models and an increased ß-cells absent diabetes in BBS models, indicating ß-cell generation or maintenance that correlates with disease prevalence. Using transcriptome analyses, differential expression of several exocrine pancreas proteases with directionality that was consistent with ß-cell numbers were identified. Based on these lines of evidence, we hypothesized that pancreatic proteases directly impact ß-cells. In the present study, we examined this possibility and found that pancreatic protease genes contribute to proper maintenance of normal ß-cell numbers, proliferation in larval zebrafish, and regulation of AS and BBS ß-cell phenotypes. Our data suggest that these proteins can be taken up directly by cultured ß-cells and ex vivo murine islets, inducing proliferation in both. Endogenous uptake of pancreatic proteases by ß-cells was confirmed in vivo using transgenic zebrafish and in intact murine pancreata. Taken together, these findings support a novel proliferative signaling role for exocrine pancreas proteases through interaction with endocrine ß-cells.

Seasonal patterns of melatonin alter aggressive phenotypes of female Siberian hamsters.

Many animal species exhibit year-round aggression, a behaviour that allows individuals to compete for limited resources in their environment (eg, food and mates). Interestingly, this high degree of territoriality persists during the non-breeding season, despite low levels of circulating gonadal steroids (ie, testosterone [T] and oestradiol [E2 ]). Our previous work suggests that the pineal hormone melatonin mediates a 'seasonal switch' from gonadal to adrenal regulation of aggression in Siberian hamsters (Phodopus sungorus); solitary, seasonally breeding mammals that display increased aggression during the short, 'winter-like' days (SDs) of the non-breeding season. To test the hypothesis that melatonin elevates non-breeding aggression by increasing circulating and neural steroid metabolism, we housed female hamsters in long days (LDs) or SDs, administered them timed or mis-timed melatonin injections (mimic or do not mimic a SD-like signal, respectively), and measured aggression, circulating hormone profiles and aromatase (ARO) immunoreactivity in brain regions associated with aggressive or reproductive behaviours (paraventricular hypothalamic nucleus [PVN], periaqueductal gray [PAG] and ventral tegmental area [VTA]). Females that were responsive to SD photoperiods (SD-R) and LD females given timed melatonin injections (Mel-T) exhibited gonadal regression and reduced circulating E2 , but increased aggression and circulating dehydroepiandrosterone (DHEA). Furthermore, aggressive challenges differentially altered circulating hormone profiles across seasonal phenotypes; reproductively inactive females (ie, SD-R and Mel-T females) reduced circulating DHEA and T, but increased E2 after an aggressive interaction, whereas reproductively active females (ie, LD females, SD non-responder females and LD females given mis-timed melatonin injections) solely increased circulating E2 . Although no differences in neural ARO abundance were observed, LD and SD-R females showed distinct associations between ARO cell density and aggressive behaviour in the PVN, PAG and VTA. Taken together, these results suggest that melatonin increases non-breeding aggression by elevating circulating steroid metabolism after an aggressive encounter and by regulating behaviourally relevant neural circuits in a region-specific manner.