Peptide YY and neuropeptide Y: reciprocal control of digestion via modulation of the brain-gut axis

Peptide tyrosine-tyrosine (PYY) and neuropeptide tyrosine (NPY) are emerging as potent central nervous system regulators of digestive functions. There is, however, considerable debate concerning the mechanisms and even the direction of autonomic effects mediated by these peptides. PYY is thought to be the hormonal "enterogastrone" released by the ileum after feeding. This peptide acts on vagal reflex control circuits in the dorsal vagal complex (DVC) of the medulla oblongata to reduce gastric motility, i.e. the "ileal brake". However, equally convincing evidence is available to suggest that PYY and its close structural relative NPY may also act in the DVC to increase gastric motility through vagal mechanisms. This activation effect, particularly of NPY, has been linked to the increase in digestive functions seen at the onset of feeding behavior, i.e. Pavlov's "cephalic phase". We hypothesize that the confounding observations produced by these peptides are due to agonist effects on two different receptor types referred to as Y1 and Y2. Both receptors are present in the DVC but may be accessed differentially by peripheral humoral (PYY) versus central neurotransmitter (NPY) pathways. Our experiments show that the hormonal effect of PYY to suppress gastric functions such as the "ileal brake" is consistent with the activation of the Y2 receptor in the DVC, while NPY-ergic effects to increase gastric functions are mediated by the Y1 receptor. These results are corroborated by neurophysiological studies of the effects of Y1 and Y2 agonist peptides on single vagal efferent neurons. The seemingly paradoxical effects of PYY and NPY on the central neural control of gastric motility are reviewed in terms of the possible differential localization of Y1 versus Y2 receptors within the DVC. Specific reference is also made to recent observations that PYY is rapidly converted to a Y2 agonist by an ubiquitous dipeptidyl aminopeptidase.Biomedical Reviews 1997; 8: 55-69

IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB

© 2015 the American Physiological Society. Proinflammatory cytokines impact islet β-cell mass and function by altering the transcriptional activity within pancreatic β-cells, producing increases in intracellular nitric oxide abundance and the synthesis and secretion of immunomodulatory proteins such as chemokines. Herein, we report that IL-1β, a major mediator of inflammatory responses associated with diabetes development, coordinately and reciprocally regulates chemokine and insulin secretion. We discovered that NF-κB controls the increase in chemokine transcription and secretion as well as the decrease in both insulin secretion and proliferation in response to IL-1β. Nitric oxide production, which is markedly elevated in pancreatic β-cells exposed to IL-1β, is a negative regulator of both glucose-stimulated insulin secretion and glucose-induced increases in intracellular calcium levels. By contrast, the IL-1β-mediated production of the chemokines CCL2 and CCL20 was not influenced by either nitric oxide levels or glucose concentration. Instead, the synthesis and secretion of CCL2 and CCL20 in response to IL-1β were dependent on NF-κB transcriptional activity. We conclude that IL-1β-induced transcriptional reprogramming via NF-κB reciprocally regulates chemokine and insulin secretion while also negatively regulating β-cell proliferation. These findings are consistent with NF-κB as a major regulatory node controlling inflammation- associated alterations in islet β-cell function and mass

Astrocytes regulate GLP-1 receptor-mediated effects on energy balance

© 2016 the authors. Astrocytes are well established modulators of extracellular glutamate, but their direct influence on energy balance-relevant behaviors is largely understudied. As the anorectic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists are partly mediated by central modulation of glutamatergic signaling, we tested the hypothesis that astrocytic GLP-1R signaling regulates energy balance in rats. Central or peripheral administration of a fluorophore-labeled GLP-1R agonist, exendin-4, localizes within astrocytes and neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus critical for energy balance control. This effect is mediated by GLP-1R, as the uptake of systemically administered fluorophore-tagged exendin-4 was blocked by central pretreatment with the competitive GLP-1R antagonist exendin-(9–39). Ex vivo analyses show prolonged exendin-4-induced activation (live cell calcium signaling) of NTS astrocytes and neurons; these effects are also attenuated by exendin-(9–39), indicating mediation by the GLP-1R. In vitro analyses show that the application of GLP-1R agonists increases cAMP levels in astrocytes. Immunohistochemical analyses reveal that endogenous GLP-1 axons form close synaptic apposition with NTS astrocytes. Finally, pharmacological inhibition of NTS astrocytes attenuates the anorectic and body weight-suppressive effects of intra-NTS GLP-1R activation. Collectively, data demonstrate a role for NTS astrocytic GLP-1R signaling in energy balance control

Astrocytes in the nucleus of the solitary tract are activated by low glucose or glucoprivation: evidence for glial involvement in glucose homeostasis.

Glucose homeostasis is maintained through interplay between central and peripheral control mechanisms which are aimed at storing excess glucose following meals and mobilizing these same stores during periods of fasting. The nucleus of the solitary tract (NST) in the dorsal medulla has long been associated with the central detection of glucose availability and the control of glucose homeostasis. Recent evidence has emerged which supports the involvement of astrocytes in glucose homeostasis. The aim of the present study was to investigate whether NST-astrocytes respond to physiologically relevant decreases in glucose availability, in vitro, as well as to the presence of the glucoprivic compound 2-deoxy-D-Glucose. This report demonstrates that some NST-astrocytes are capable of responding to low glucose or glucoprivation by increasing cytoplasmic calcium; a change that reverses with restoration of normal glucose availability. While some NST-neurons also demonstrate an increase in calcium signaling during low glucose availability, this effect is smaller and somewhat delayed compared to those observed in adjacent astrocytes. TTX did not abolish these hypoglycemia mediated responses of astrocytes, suggesting that NST-astrocytes may be directly sensing low glucose levels as opposed to responding to neuronal detection of hypoglycemia. Thus, chemodetection of low glucose by NST-astrocytes may play an important role in the autonomic regulation of glucose homeostasis