Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.

The hormone leptin reduces food intake through actions in the peripheral and central nervous systems, including in the hindbrain nucleus of the solitary tract (NTS). The NTS receives viscerosensory information via vagal afferents, including information from the gastrointestinal tract, which is then relayed to other central nervous system (CNS) sites critical for control of food intake. Leptin receptors (lepRs) are expressed by a subpopulation of NTS neurons, and knockdown of these receptors increases both food intake and body weight. Recently, we demonstrated that leptin increases vagal activation of lepR-expressing neurons via increased NMDA receptor (NMDAR) currents, thereby potentiating vagally evoked firing. Furthermore, chemogenetic activation of these neurons was recently shown to inhibit food intake. However, the vagal inputs these neurons receive had not been characterized. Here we performed whole cell recordings in brain slices taken from lepRCre × floxedTdTomato mice and found that lepR neurons of the NTS are directly activated by monosynaptic inputs from C-type afferents sensitive to the transient receptor potential vanilloid type 1 (TRPV1) agonist capsaicin. CCK administered onto NTS slices stimulated spontaneous glutamate release onto lepR neurons and induced action potential firing, an effect mediated by CCKR 1 . Interestingly, NMDAR activation contributed to the current carried by spontaneous excitatory postsynaptic currents (EPSCs) and enhanced CCK-induced firing. Peripheral CCK also increased c-fos expression in these neurons, suggesting they are activated by CCK-sensitive vagal afferents in vivo. Our results indicate that the majority of NTS lepR neurons receive direct inputs from CCK-sensitive C vagal-type afferents, with both peripheral and central CCK capable of activating these neurons and NMDARs able to potentiate these effects.

The stomach, upper small intestine, lower small intestine, the liver and the colon, have all been suggested as exercising control over food intake. This chapter focuses on vagal participation in the control of food intake by the stomach and small intestine. Recordings from gastric mechanoresponsive fibers in the vagus were among the first data supporting the vagal role in gastrointestinal sensation. Clearly, gastrointestinal vagal innervation detects and responds to mechanical and chemical properties of ingesta during each meal. It would be surprising, however, if changes in food intake were mediated exclusively by signals from this innervation. In fact we can say with certainty that they are not. Nevertheless, sensory neurons of the vagus nerve respond to a variety of stimuli appropriate as putative satiety signals and it is probable that vagal sensory mechanisms make an important contribution to the process of satiation by relaying information to the brain on chemical and mechanical qualities of ingesta.

Neuropeptide Y (NPY), peptide YY (PYY), and their cognate receptors (YR) are expressed by subpopulations of central and peripheral nervous system neurons. Intracerebroventricular injections of NPY or PYY increase food intake, and intrahypothalamic NPY1 or NPY5 receptor agonist injections also increase food intake. In contrast, injection of PYY in the periphery reduces food intake, apparently by activating peripheral Y2R. The dorsal vagal complex (DVC) of the hindbrain is the site where vagal afferents relay gut satiation signals to the brain. While contributions of the DVC are increasingly investigated, a role for DVC YR in control of food intake has not been examined systematically. We used in situ hybridization to confirm expression of Y1R and Y2R, but not Y5R, in the DVC and vagal afferent neurons. We found that nanoinjections of a Y2R agonist, PYY-(3-36), into the DVC significantly increased food intake over a 4-h period in satiated male rats. PYY-(3-36)-evoked food intake was prevented by injection of a selective Y2R antagonist. Injection of a Y1R/Y5R-preferring agonist into the DVC failed to increase food intake at doses reported to increase food intake following hypothalamic injection. Finally, injection of PYY-(3-36) into the DVC prevented reduction of 30-min food intake following intraperitoneal injection of cholecystokinin (CCK). Our results indicate that activation of DVC Y2R, unlike hypothalamic or peripheral Y2R, increases food intake. Furthermore, in the context of available electrophysiological observations, our results are consistent with the hypothesis that DVC Y2R control food intake by dampening vagally mediated satiation signals in the DVC.

Release of endogenous cholecystokinin (CCK) from the small intestine by gastric loads was investigated in rats on postnatal days 9–12 (P9–P12). After 5–6 h of deprivation, pups received 5% b.wt. loads of water, 0.9% NaCl, 20% glucose, 20% maltose, 200 mg soybean trypsin inhibitor (SBTI) in 0.9% saline or sham load. Plasma was collected 15 min after the loads, and the concentration of bioactive CCK was measured by a specific and sensitive bioassay. Loads of SBTI and water significantly increased plasma CCK compared to sham loads, but loads of saline, glucose, and maltose did not. The efficacy of the water load was not demonstrated in adult rats. The results suggest that the previously reported reduction of intake during independent ingestion by hypertonic preloads of glucose and maltose was not mediated by the release of CCK sufficient to be detected in the plasma under these conditions.

Brenner, L. A. and R. C. Ritter. Intracerebroventricular cholecystokinin A-receptor antagonist does not reduce satiation by endogenous CCK. Physiol Behav 63(4) 711–716, 1998. Suppression of sham feeding by exogenous CCK-8 or intraintestinal oleate infusion is attenuated by peripheral administration of the CCK-A receptor antagonist, devazepide, but not by the CCK-B antagonist, L365260. Likewise, systemically administered devazepide increases food intake by real feeding rats. These results suggest that endogenous CCK participates in the reduction of food intake by intestinal oleate and ingested food. Although originally categorized as a “peripheral” receptor subtype, the CCK-A receptor is also present in the brain. In an effort to examine whether devazepide acts in the brain or in the periphery to attenuate suppression of food intake by intraintestinal oleate, we injected devazepide into the lateral or fourth cerebral ventricles of intraintestinally infused, sham-fed rats. We also compared the ability of intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) devazepide to elicit increased food intake in real feeding rats. Doses of devazepide that were sufficient to attenuate or abolish oleate-induced suppression of sham feeding, when administered i.p., failed to attenuate suppression of intake when administered i.c.v.. i.p. devazepide also was more effective than i.c.v. devazepide for attenuation of the suppression of sham feeding by i.p. injection of exogenous CCK-8. Finally, i.c.v. devazepide was ineffective for increasing real food intake, whereas the same dose administered i.p. significantly increased food intake. Our results do not support participation of brain CCK–A receptors in the suppression of food intake by exogenous CCK, or by endogenous CCK released after intraintestinal oleate infusion, or food intake.

An analogue of the C-terminal heptapeptide of cholecystokinin (CCK) t-Boc-Tyr(SO3-)-Nle-Gly-D-Trp-Nle-Asp-a-2-phenylethylester is a potent, specific CCK receptor antagonist. Intraperitoneal injection of the antagonist abolished suppression of real feeding and sham feeding by exogenous CCK-8 (1.8 nmol/kg), and significantly increased real feeding. Assuming an antagonist distribution like that of exogenous CCK-8, our results suggest that exogenous CCK-8 and endogenous CCK reduce food intake by acting at a site(s) accessible to peripherally administered peptides.

Cats have a dietary requirement for taurine as a re sult of a limited ability to synthesize taurine and ob ligate taurine conjugation to bile acids. Recent research indicates that increased taurocholic acid turnover may contribute to the taurine depletion that is observed in cats fed certain heat-processed canned diets or purified soy protein-containing diets (Hickman et al. 1992). The mechanism by which these diets increase bile se cretion and taurine loss is not known. Possibilities in clude increased loss of taurine-conjugated bile salts through binding to undigestible dietary components, increased bacterial degradation as a result of altered gut microflora, a direct increase in bile secretion and enterohepatic recycling due to diet-mediated eleva tions in cholecystokinin (CCK)7 release, or a combi

Annals of the New York Academy of SciencesVolume 713, Issue 1 p. 255-267 Endogenous CCK and the Peripheral Neural Substrates of Intestinal Satiety ROBERT C. RITTER, Corresponding Author ROBERT C. RITTER Department of V.C.A.P.P. College of Veterinary Medicine Washington State University Pullman, Washington 99164Dr. Robert C. Ritter, Dept. of VCAPP, Washington State University, Pullman, WA 99164-6520.Search for more papers by this authorLYNNE A. BRENNER, LYNNE A. BRENNER Department of V.C.A.P.P. College of Veterinary Medicine Washington State University Pullman, Washington 99164Search for more papers by this authorCONNIE S. TAMURA, CONNIE S. TAMURA Department of V.C.A.P.P. College of Veterinary Medicine Washington State University Pullman, Washington 99164Search for more papers by this author ROBERT C. RITTER, Corresponding Author ROBERT C. RITTER Department of V.C.A.P.P. College of Veterinary Medicine Washington State University Pullman, Washington 99164Dr. Robert C. Ritter, Dept. of VCAPP, Washington State University, Pullman, WA 99164-6520.Search for more papers by this authorLYNNE A. BRENNER, LYNNE A. BRENNER Department of V.C.A.P.P. College of Veterinary Medicine Washington State University Pullman, Washington 99164Search for more papers by this authorCONNIE S. TAMURA, CONNIE S. TAMURA Department of V.C.A.P.P. College of Veterinary Medicine Washington State University Pullman, Washington 99164Search for more papers by this author First published: March 1994 https://doi.org/10.1111/j.1749-6632.1994.tb44073.xCitations: 35AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES 1 Antin, J., J. Gibbs, J. Holt, R. C. Young & G. P. Smith. 1975. Cholecystokinin elicits complete behavioral satiety sequence in rats. J. Comp. Physiol. Psychol. 89: 784–790. 2 Gibbs, J., R. C. Young & G. P. Smith. 1973. 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Postgastric satiety in the sham feeding rat. Am. J. Physiol. 244: R872–R881. 39 Yox, D. P. & R. C. Ritter. 1988. Capsaicin attenuates suppression of sham feeding induced by intestinal nutrients. Am. J. Physiol. 255: R569–R574. 40 Gibbs, J., S. P. Maddison & E. T. Rolls. 1981. Satiety role of the small intestine examined in sham-feeding rhesus monkeys. J. Comp. Physiol. Psychol. 95: 1003–1015. 41 Welch, I. M., C. P. Sepple & N. W. Read. 1988. Comparisons of the effects on satiety and eating behavior of infusion of lipid into the different regions of the small intestine. Gut 29: 306–311. 42 Ritter, R. C. & E. Simon. 1989. Suppression of feeding by intraintestinal maltose is mediated by phloridzin-sensitive mechanism. Soc. Neurosci. Abstr. 16: 646. 43 Yox, D. P., H. Stokesberry & R. C. Ritter. 1991. Vagotomy attenuates suppression of sham feeding induced by intestinal nutrients. Am. J. Physiol. 260: R503–508. 44 Yox, D. P., H. Stokesberry & R. C. Ritter. 1991. 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To test the possibility that blood-borne cholecystokinin (CCK) participates in suppression of sham feeding by intestinal nutrients in rats, we examined the ability of oleate, maltose, L-phenylalanine (L-Phe), and casein to suppress sham ingestion of 15% sucrose solution. Plasma CCK concentrations were measured in parallel experiments in which the same intestinal nutrients were infused in rats that were not feeding. Intraintestinal oleate suppressed sham feeding and elevated plasma CCK concentrations. Casein infusion produced plasma CCK concentrations similar to those produced by oleate but did not suppress sham feeding. Both maltose and L-Phe suppressed sham feeding but failed to significantly elevate plasma CCK. Previously we demonstrated that CCK receptor antagonists attenuate suppression of sham feeding by intestinal infusion of either oleate or maltose, suggesting that endogenous CCK participates in suppression of sham feeding by some intestinal nutrients. The results of the study reported here suggest that plasma CCK levels after nutrient infusion are not correlated with suppression of sham feeding. Therefore, the mechanism of CCK's participation in nutrient-induced suppression of sham feeding may not depend on stimulus-induced elevation of plasma CCK.

Intragastric soybean trypsin inhibitor increased plasma CCK bioactivity by 87% in nondeprived, 9-12-day-old rat pups. Reunion with the dam for 1 h after overnight maternal deprivation also increased plasma CCK significantly. These results demonstrate that CCK can be released from the small intestine of rats as early as postnatal day 9.

To test the possibility that endogenous cholecystokinin (CCK) participates in suppression of sham feeding by intraintestinal nutrient infusions, we examined the effect of CCK-receptor antagonists on the suppression of sham feeding by intraintestinally infused oleic acid, maltose or L-phenylalanine (L-Phe). In addition, we monitored amylase activity in the intestinal lumen during some sham feeding experiments and measured plasma CCK in parallel experiments using intestinally infused animals that were not feeding. Suppression of sham feeding by oleic acid or maltose was attenuated by CCK-receptor antagonists, while suppression of sham feeding by L-Phe was not. Oleate infusion increased plasma CCK concentration and luminal amylase activity. Oleate-induced increase in luminal amylase activity was attenuated by a CCK-receptor antagonist. Intraintestinal maltose or L-Phe did not increase plasma CCK concentration or luminal amylase activity, suggesting that they did not release endocrine CCK. These results suggest 1) that endogenous CCK mediates suppression of sham feeding by oleate and maltose but not by L-Phe and 2) that CCK participating in suppression of feeding by intestinal stimuli might not be of endocrine origin.

Exogenous cholecystokinin (CCK) suppresses food intake by acting on vagal sensory neurons. However, CCK doses used in behavioral experiments are generally much larger than those necessary to produce electrophysiological changes in vagal afferents. We made automated measurements of liquid food intake before, during, and after infusion of low doses of CCK octapeptide (CCK-8) through a chronic aortic catheter with its tip seated just above the celiac juncture. In parallel experiments, we made similar infusions while collecting blood from the hepatic portal and jugular veins for CCK assay. Injection of 10, 30, 50, and 70 pmol of CCK-8 suppressed feeding in a dose-dependent manner beginning 1 min postinfusion. The lowest dose to produce statistically significant suppression of preinfusion intake was 30 pmol. Infusion of the same CCK-8 doses into the jugular vein did not suppress feeding. Near-celiac injection of 30 pmol of CCK-8 produced systemic plasma CCK concentrations averaging 6.5 +/- 1 pM compared with less than 1 pM after saline injection. These findings show that exogenous CCK, by acting on tissues perfused by the celiac artery, can suppress feeding at doses that 1) are similar to those producing effects on the firing of vagal neurons and 2) do not increase plasma CCK concentrations above postprandial levels.