Delineating the regulation of energy homeostasis using hypothalamic cell models.

Attesting to its intimate peripheral connections, hypothalamic neurons integrate nutritional and hormonal cues to effectively manage energy homeostasis according to the overall status of the system. Extensive progress in the identification of essential transcriptional and post-translational mechanisms regulating the controlled expression and actions of hypothalamic neuropeptides has been identified through the use of animal and cell models. This review will introduce the basic techniques of hypothalamic investigation both in vivo and in vitro and will briefly highlight the key advantages and challenges of their use. Further emphasis will be place on the use of immortalized models of hypothalamic neurons for in vitro study of feeding regulation, with a particular focus on cell lines proving themselves most fruitful in deciphering fundamental basics of NPY/AgRP, Proglucagon, and POMC neuropeptide function.

All in the Family: Barriers and Motivators to the Use of Cancer Family History Questionnaires and the Impact on Attendance Rates.

Data has demonstrated that family history questionnaires (FHQs) are an invaluable tool for assessing familial cancer risk and triaging patients for genetic counseling services. Despite their benefits, return rates of mailed FHQs from newly referred patients remain low, suggesting potential barriers to their use. To investigate this, a total of 461 participants, 239 who completed a FHQ (responders) and 222 who did not (non-responders), were surveyed at a subsequent appointment regarding potential barriers and motivators to using the FHQ. With respective rates of 51 and 56 %, there was no significant difference in the proportion of responders and non-responders who reported difficulty in completing the FHQ; however, for both groups factors related to family dynamics (large family size, lack of contact with relatives, and lack of knowledge of family history) were reported as major variables confounding completion of the FHQ. Responders were also significantly more likely to have a personal diagnosis of cancer (p = 0.02) and to report that their physician had discussed the reason for the appointment with them (p = 0.01). Overall, 19 % of non-responders returned their FHQ after being mailed an appointment letter and 67 % attended their scheduled genetic counseling appointment. These findings demonstrate that difficulty completing the FHQ is not inherent to its design but due to difficulty accessing one's family history, and that mailed appointment letters are a highly successful way to increase attendance rates in the non-responder population. Furthermore, these results demonstrate the important role that referring physicians play in the utilization of genetic counseling services.

The Screen Project: Guided Direct-To-Consumer Genetic Testing for Breast Cancer Susceptibility in Canada.

There is limited information of the outcomes of direct-to-consumer testing for BRCA1 and BRCA2 mutations. The Screen Project was initiated in 2017 to offer BRCA1 and BRCA2 genetic screening to all Canadians over the age of 18 who wish to know their mutation status. Patients enrolled in the study from 2017 to 2019 and were followed for one year after the receipt of a genetic test result. Study subjects registered online and were sent a saliva sample kit, which was shipped to the reference laboratory. Pre-test genetic counselling and counselling for mutation-negative subjects was optional and at the individual's discretion. There were 1269 tested individuals between March 2017 and January 2019. A total of 1157 (93%) were women and 87 (7%) were men. Sixty-six percent had a first- or second-degree relative with breast or ovarian cancer. Of the 1269 tested individuals, 30 (2.4%) had a pathogenic mutation in BRCA1 or BRCA2 (20 women and 10 men). Seventy-five percent of the female mutation carriers underwent a bilateral mastectomy and/or salpingo-oophorectomy within a year of receiving a positive result. Genetic counselling was available at no cost to all participants but was requested by only 5% of the non-carriers. The study subjects expressed a high degree of satisfaction with the process.

Glucocorticoid receptor-mediated regulation of Rfrp (GnIH) and Gpr147 (GnIH-R) synthesis in immortalized hypothalamic neurons.

A novel RFamide peptide, gonadotropin-inhibitory hormone (GnIH) has emerged as a modulator of avian reproduction. However, the functional role of the mammalian homologue, RFRP-3 remains poorly understood. The RFRP-3 neuronal circuit is influenced by the stress axis. However, whether the Rfrp gene is under direct glucocorticoid (GC)-mediated transcriptional regulation, in the presence and absence of the gonadal steroid, 17ß-estradiol, is unknown. We investigated the regulation of the Rfrp (GnIH) and Gpr147 (GnIH-R) transcripts by steroids in a novel hypothalamic Rfrp-expressing cell model, rHypoE-23. The GC agonist, dexamethasone increased Rfrp and Gpr147 mRNA levels. Dexamethasone acted directly on the nuclear GC receptor (GR) to mediate GC-dependent transcriptional changes, independently of de novo protein synthesis. 17ß-estradiol had no significant effect on Rfrp or Gpr147 biosynthesis in these neurons. This suggests that Rfrp-expressing neurons serve as potential upstream mediators of stress-induced effects through GR-dependent mechanisms.