Phoenixin knockout mice show no impairment in fertility or differences in metabolic response to a high-fat diet, but exhibit behavioral differences in an open field test.

Phoenixin (PNX) is a conserved secreted peptide that was identified 10 years ago with numerous studies published on its pleiotropic functions. PNX is associated with estrous cycle length, protection from a high-fat diet, and reduction of anxiety behavior. However, no study had yet evaluated the impact of deleting PNX in the whole animal. We sought to evaluate a mouse model lacking the PNX parent gene, small integral membrane protein 20 (Smim20), and the resulting effect on reproduction, energy homeostasis, and anxiety. We found that the Smim20 knockout mice had normal fertility and estrous cycle lengths. Consistent with normal fertility, the hypothalamii of the knockout mice showed no changes in the levels of reproduction-related genes, but the male mice had some changes in energy homeostasis-related genes, such as melanocortin receptor 4 (Mc4r). When placed on a high-fat diet, the wildtype and knockout mice responded similarly, but the male heterozygous mice gained slightly less weight. When placed in an open field test box, the female knockout mice traveled less distance in the outer zone, indicating alterations in anxiety or locomotor behavior. In summary, the homozygous knockout of PNX did not alter fertility and modestly alters a few neuroendocrine genes in response to a high-fat diet, especially in the female mice. However, it altered the behavior of mice in an open field test. PNX therefore may not be crucial for reproductive function or weight, however, we cannot rule out possible compensatory mechanisms in the knockout model. Understanding the role of PNX in physiology may ultimately lead to an enhanced understanding of neuroendocrine mechanisms involving this enigmatic peptide.

Bisphenol A Alters the Levels of miRNAs That Directly and/or Indirectly Target Neuropeptide Y in Murine Hypothalamic Neurons.

The hypothalamus is a vital regulator of energy homeostasis. Orexigenic neuropeptide Y (NPY) neurons within the hypothalamus can stimulate feeding and suppress energy expenditure, and dysregulation of these neurons may contribute to obesity. We previously reported that bisphenol A (BPA), an endocrine disruptor with obesogenic properties, alters Npy transcription in hypothalamic neurons by inducing oxidative stress. We hypothesized that hypothalamic microRNAs (miRNAs), a class of small non-coding RNAs, could directly regulate Npy gene expression by binding the 3' untranslated region (UTR). Five predicted Npy-targeting miRNA candidates were uncovered through TargetScan and were detected in Npy-expressing hypothalamic neuronal cell models and hypothalamic neuronal primary cultures. BPA dysregulated the expression of a number of these hypothalamic miRNAs. We examined the effects of putative Npy-targeting miRNAs using miRNA mimics, and we found that miR-143-3p, miR-140-5p, miR-29b-1-5p, and let-7b-3p altered Npy expression in the murine hypothalamic cell lines. Importantly, miR-143-3p targets the mouse Npy 3' UTR, as detected using a luciferase construct containing the potential 3' UTR binding sites. Overall, this study established the first hypothalamic miRNA that directly targets the 3' UTR of mouse Npy, emphasizing the involvement of miRNAs in the NPY system and providing an alternative target for control of NPY levels.

Neuroendocrine microRNAs linked to energy homeostasis: future therapeutic potential.

The brain orchestrates whole-body metabolism through an intricate system involving interneuronal crosstalk and communication. Specifically, a key player in this complex circuitry is the hypothalamus that controls feeding behaviour, energy expenditure, body weight and metabolism, whereby hypothalamic neurons sense and respond to circulating hormones, nutrients, and chemicals. Dysregulation of these neurons contributes to the development of metabolic disorders, such as obesity and type 2 diabetes. The involvement of hypothalamic microRNAs, post-transcriptional regulators of gene expression, in the central regulation of energy homeostasis has become increasingly apparent, although not completely delineated. This review summarizes current evidence demonstrating the regulation of feeding-related neuropeptides by brain-derived microRNAs as well as the regulation of specific miRNAs by nutrients and other peripheral signals. Moreover, the involvement of microRNAs in the central nervous system control of insulin, leptin, and estrogen signal transduction is examined. Finally, the therapeutic and diagnostic potential of microRNAs for metabolic disorders will be discussed and the regulation of brain-derived microRNAs by nutrients and other peripheral signals is considered. Demonstrating a critical role of microRNAs in hypothalamic regulation of energy homeostasis is an innovative route to uncover novel biomarkers and therapeutic candidates for metabolic disorders.

Disrupted and Elevated Circadian Secretion of Glucagon-Like Peptide-1 in a Murine Model of Type 2 Diabetes.

Metabolism and circadian rhythms are intimately linked, with circadian glucagon-like peptide-1 (GLP-1) secretion by the intestinal L-cell entraining rhythmic insulin release. GLP-1 secretion has been explored in the context of obesogenic diets, but never in a rodent model of type 2 diabetes (T2D). There is also considerable disagreement regarding GLP-1 levels in human T2D. Furthermore, recent evidence has demonstrated decreased expression of the ß-cell exocytotic protein secretagogin (SCGN) in T2D. To extend these findings to the L-cell, we administered oral glucose tolerance tests at 6 time points in 4-hour intervals to the high-fat diet/streptozotocin (HFD-STZ) mouse model of T2D. This revealed a 10-fold increase in peak GLP-1 secretion with a phase shift of the peak from the normal feeding period into the fasting-phase. This was accompanied by impairments in the rhythms of glucose, glucagon, mucosal clock genes (Arntl and Cry2), and Scgn. Immunostaining revealed that L-cell GLP-1 intensity was increased in the HFD-STZ model, as was the proportion of L-cells that expressed SCGN; however, this was not found in L-cells from humans with T2D, which exhibited decreased GLP-1 staining but maintained their SCGN expression. Gcg expression in isolated L-cells was increased along with pathways relating to GLP-1 secretion and electron transport chain activity in the HFD-STZ condition. Further investigation into the mechanisms responsible for this increase in GLP-1 secretion may give insights into therapies directed toward upregulating endogenous GLP-1 secretion.

The Effects of Video Instruction on Neuroscience Intensive Care Unit Nursing Skills in Case Presentations and Neurological Examinations.

ABSTRACT: BACKGROUND: The emergence of neuroscience intensive care units (NSICUs) for the past decades has led to growing interest in targeted training for NSICU nurses. We sought to evaluate the use of video instruction on NSICU nurses' skills in case presentations and neurological examinations, which has timely advantages as an asynchronous and distanced learning modality. METHODS: We enrolled NSICU and surgical intensive care unit nurses who took shifts in the NSICU at our institution. Participants were observed by a neurocritical care attending physician presenting the clinical details of an admitted patient and conducting a neurological examination, with both parties completing a 10-item evaluation on NSICU nursing presentation and examination skills. Participants randomized to an intervention group were given access to an instructional video on NSICU nursing skills. A median of 21 days later, participants were observed by a physician blinded to study randomization, with both parties recompleting the evaluation. Differences between day 1 and day 21 scores were analyzed using paired sample t tests. RESULTS: Fifteen NSICU and 55 surgical intensive care unit nurses were enrolled. Surgical intensive care unit nurses in both the intervention and control groups had statistically significant improvement between day 1 and day 21 physician-rated scores, with a greater increase in the intervention group; self-rated scores did not change. For NSICU nurses, there were no differences in physician-rated or self-rated scores for either group. CONCLUSIONS: Surgical intensive care unit nurses who underwent direct observation and self-evaluation had improvement in physician-rated NSICU nursing skills, likely as these activities allowed for reflective observation in Kolb's experiential learning cycle. Greater improvement in participants who viewed an instructional video highlights its value as a teaching modality for nurses.