Normal anterior pituitary function is essential for fertility. Release from the gland of the reproductive hormones LH and FSH is regulated primarily by hypothalamically-derived gonadotropin releasing hormone (GnRH), although other releasing factors have been postulated to exist. Using a bioinformatic approach, we have identified a novel peptide, phoenixin, that regulates pituitary gonadotropin secretion by modulating expression of the GnRH receptor, an action with physiologically relevant consequences. Compromise of phoenixin in vivo using siRNA resulted in the delayed appearance of oestrus and a reduction in GnRH receptor expression in the pituitary. Phoenixin may represent a new class of hypothalamically-derived pituitary priming factors (PFs) that sensitise the pituitary to the action of other RFs, rather than directly stimulating the fusion of secretory vesicles to pituitary membranes.

Somatostatin is important in the regulation of diverse neuroendocrine functions. Based on bioinformatic analyses of evolutionarily conserved sequences, we predicted another peptide hormone in pro-somatostatin and named it neuronostatin. Immuno-affinity purification allowed the sequencing of an amidated neuronostatin peptide of 13 residues from porcine tissues. In vivo treatment with neuronostatin induced c-Fos expression in gastrointestinal tissues, anterior pituitary, cerebellum, and hippocampus. In vitro treatment with neuronostatin promoted the migration of cerebellar granule cells and elicited direct depolarizing actions on paraventricular neurons in hypothalamic slices. In a gastric tumor cell line, neuronostatin induced c-Fos expression, stimulated SRE reporter activity, and promoted cell proliferation. Furthermore, intracerebroventricular treatment with neuronostatin increased blood pressure but suppressed food intake and water drinking. Our findings demonstrate diverse neuronal, neuroendocrine, and cardiovascular actions of a somatostatin gene-encoded hormone and provide the basis to investigate the physiological roles of this endogenously produced brain/gut peptide.Originally discovered in 1972 based on its ability to inhibit pituitary growth hormone release (1, 2), somatostatin is one of the most extensively studied peptide hormones (3, 4). Somatostatin is widely expressed in neuronal, neuroendocrine, gastrointestinal, inflammatory, immune, and cancer cells and plays important roles in the regulation of neuromodulation, hormone secretion, gastrointestinal functions, immune responses, cell growth, and exocrine secretion (5). Two somatostatin isoforms, somatostatin-14 and somatostatin-28, activate five related G protein-coupled receptors with different affinity (6 -8). Somatostatin receptors are also activated by two cortistatin isoforms secreted from different brain regions (9). Based on bioinformatic analysis of evolutionarily conserved sequences in the pro-somatostatin protein, we predicted the existence of another peptide hormone encoded by the somatostatin gene. We generated antibodies against the putative peptide, isolated the endogenous peptide, and found it to be an amidated peptide of 13 residues. This peptide hormone, named neuronostatin, induced c-Fos and c-Jun expression in diverse brain/gut tissues, regulated neuronal functions in vitro, and modulated blood pressure as well as food intake and drinking behavior in vivo. EXPERIMENTAL PROCEDURESPeptide Hormones-All peptides used were synthesized by Phoenix Pharmaceuticals Inc. (Burlingame, CA) or the PAN facility at Stanford University. Peptide purity was verified by analytical reverse phase HPLC and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) 4 mass spectrometry. Unless indicated otherwise, all functional tests utilized human amidated neuronostatin-13.Purification of Endogenous Neuronostatin-To purify endogenous neuronostatin, frozen porcine pancreas and spleen were obtained from Pel-Freez (Rogers, AK) and extracted ...

Irisin is a recently identified myokine secreted from the muscle in response to exercise. In the rats and mice, immunohistochemical studies with an antiserum against irisin peptide fragment (42–112), revealed that irisin-immunoreactivity (irIRN) was detected in three types of cells; namely, skeletal muscle cells, cardiomyocytes, and Purkinje cells of the cerebellum. Tissue sections processed with irisin antiserum pre-absorbed with the irisin peptide(42–112) (1 μg/ml) showed no immunoreactivity. Cerebellar Purkinje cells were also immunolabeled with an antiserum against fibronectin type II domain containing 5 (FNDC5), the precursor protein of irisin. Double-labeling of cerebellar sections with irisin antiserum and glutamate decarboxylase (GAD) antibody showed that nearly all irIRN Purkinje cells were GAD-positive. Injection of the fluorescence tracer Fluorogold into the vestibular nucleus of the rat medulla retrogradely labeled a population of Purkinje cells, some of which were also irIRN. Our results provide the first evidence of expression of irIRN in the rodent skeletal and cardiac muscle, and in the brain where it is present in GAD-positive Purkinje cells of the cerebellum. Our findings together with reports by others led us to hypothesize a novel neural pathway, which originates from cerebellum Purkinje cells, via several intermediary synapses in the medulla and spinal cord, and regulates adipocyte metabolism.

Tight control of glucose excursions has been a long-standing goal of treatment for patients with type 2 diabetes mellitus in order to ameliorate the morbidity and mortality associated with hyperglycemia. Fibroblast growth factor (FGF) 19 is a hormone-like enterokine released postprandially that emerged as a potential therapeutic agent for metabolic disorders, including diabetes and obesity. Remarkably, FGF19 treatment has hypoglycemic actions that remain potent in models of genetic and acquired insulin resistance. Here, we provided evidence that the central nervous system responds to FGF19 administered in the periphery. Then, in two mouse models of insulin resistance, leptin-deficiency and high-fat diet feeding, third intra-cerebro-ventricular infusions of FGF19 improved glycemic status, reduced insulin resistance and potentiated insulin signaling in the periphery. In addition, our study highlights a new mechanism of central FGF19 action, involving the suppression of AGRP/NPY neuronal activity. Overall, our work unveils novel regulatory pathways induced by FGF19 that will be useful in the design of novel strategies to control diabetes in obesity.

The regulation of acid secretion has been divided into cephalic and peripheral (gastric and intestinal) phases (1). The cephalic phase of gastric acid secretion originates in the central nervous system and impacts the hypothalamus; signals travel via the vagus nerve to the myenteric plexuses of the gastric mucosa. In the succeeding neural network, a variety of secondary neurons signal the gastric fundic and antral epithelia to influence gastric acid secretion by either primary or secondary action, namely, direct effects on parietal cells or gastric epithelial endocrine cells. The peripheral phase of acid secretion regulation involves local signaling within a variety of endocrine cells, transmitting regulatory information to the secretory cells of the gastric mucosa; the peripheral phase is more limited than the cephalic phase in terms of the possible mediators involved (2). Studies of isolated gastric endocrine cells have proved useful in defining the interactions of various signals in the regulation of gastric acid secretion, but such studies must be placed in context when considering their physiological implications. The isolated rabbit gastric gland is a more integrated model than that provided by isolated cells.With the isolation and purification (to between 85% and 95%) of functional enterochromaffin-like (ECL) cells from the rat gastric mucosa, a variety of receptors has been defined on this cell type. This has been done by measurement of calcium signals under superfusion conditions using video microscopy, and by histamine or pancreostatin release by radioimmunoassay under static conditions (3-5). When histamine release is measured in a static system, cross-talk is a problem. Superfusion of isolated, enriched ECL cells while measuring responses of intracellular calcium [Ca 2+ ] i eliminates cross-talk between possible contaminating gastric endocrine cells. Nevertheless, few (if any) inconsistencies have been found between the results of video-imaging and release measurements in this particular preparation. In this preparation, there are less than 2% D cells, and the addition of somatostatin antibody has not affected either calcium signaling or histamine release in response to a variety of agonists (3, 4).Histamine, released from ECL cells, is the most important direct stimulant of acid secretion, as shown by the broad efficacy of histamine-2 receptor antagonists as full inhibitors of gastrin and partial inhibitors of vagally stimulated acid secretion (6). The involvement of ECL cells in mediation of the cephalic (neural) phase of gastric acid secretion has been less clear. The atropine sensitivity of cephalic stimulation of acid secretion pointed