Neurotrophin-4 Deficient Mice Have a Loss of Vagal Intraganglionic Mechanoreceptors from the Small Intestine and a Disruption of Short-Term Satiety

Fox, Edward A.; Phillips, Robert; Baronowsky, Elizabeth A.; Byerly, Mardi S.; Jones, Sarahlouise; Powley, Terry L.

doi:10.1523/jneurosci.21-21-08602.2001

Cited by 83 publications

(74 citation statements)

References 82 publications

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“…Distension of the stomach and small intestine has been proposed to contribute an inhibitory stimulus in the control of food intake when rodents consume liquid diet (12,22). Consistent with that hypothesis and of clear relevance to our present proposal, stretch receptors on the wall of the stomach and the proximal small intestine allow the detection of distension (18,34).…”

Section: Discussionsupporting

confidence: 89%

Inhibition of thirst when dehydrated rats drink water or saline

Hoffmann¹,

DenBleyker²,

Smith³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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The present experiments sought to identify the physiological signals that inhibit thirst when dehydrated rats drink water or NaCl solution. Rats were deprived of drinking fluid but not food overnight. When allowed to drink again, the dehydrated animals consumed water or saline (0.05 M, 0.10 M, 0.15 M, or 0.20 M NaCl solution) almost continuously for 5-8 min before stopping. The volumes consumed were similar regardless of which fluid they ingested, but blood analyses indicated that increased plasma osmolality and decreased plasma volume, or both, still remained when drinking terminated. These results suggest that the composition of the ingested fluid is less significant than its volume in providing an early signal that inhibits thirst and fluid consumption by dehydrated rats. Analyses of the gastrointestinal tracts revealed that the cumulative volume in the stomach and small intestine correlated highly with the amount consumed regardless of which fluid was ingested. These and other results suggest that the volume of fluid ingested by dehydrated rats is sensed by stretch receptors detecting distension of the stomach and small intestine, which provide an early inhibitory stimulus of thirst. dehydration; gastrointestinal distension; visceral osmoreceptors; water deprivation WATER DEPRIVATION ELICITS thirst and secretion of neurohypophyseal vasopressin (VP), the antidiuretic hormone, in rats and other animals (31). When dehydrated animals drink water, both responses are inhibited before systemic rehydration is evident. In dogs and human subjects, the early signal that inhibits thirst and VP secretion has been related to the volume of fluid consumed, apparently detected by oropharyngeal receptors that monitor the swallowing of liquids regardless of whether water, isotonic saline, or hypertonic saline solution is consumed (2,13,24,32). However, recent experiments indicate that early inhibition of VP secretion in rats is not mediated by oropharyngeal receptors (17, 29) because plasma VP levels (pVP) were not affected either when dehydrated rats ingested isotonic saline or when water was consumed but drained from the stomach through an open gastric fistula (29). In contrast, water ingested normally by thirsty rats initiated a rapid decline in pVP that began while systemic plasma Na ϩ concentrations (pNa) still were elevated (17, 29), suggesting that the inhibitory effect was not mediated by cerebral osmoreceptors but by a potent presystemic stimulus, related to the composition of ingested fluid, which might arise from osmoreceptors or Na ϩ receptors in the viscera (4, 19). Furthermore, the signal that terminated an initial bout of water consumption occurred a few minutes later, in association with a reduction of systemic pNa but continued plasma volume deficits (29). Because the intake of isotonic saline also ceased after similar volumes were consumed, without any associated change in pNa (29), these observations allow the hypothesis that thirst in rats is inhibited by signals related to the volume of ingested fluid rath...

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Section: Discussionsupporting

confidence: 89%

Inhibition of thirst when dehydrated rats drink water or saline

Hoffmann¹,

DenBleyker²,

Smith³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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“…A popular approach for revealing the functional significance of a given neuronal structure is to search for correlation of its absence with disturbed functions in knockout mice. This was first achieved in NT-4 Ϫ/Ϫ mutant mice that almost completely lacked IGLEs in the duodenum and showed disturbed satiety mechanisms (Fox et al 2001). In that study, the numerical deficiency of IGLEs was verified using anterograde tracing.…”

Section: Specific Markers For Iglesmentioning

confidence: 91%

Number and Distribution of Intraganglionic Laminar Endings in the Mouse Esophagus as Demonstrated with Two Different Immunohistochemical Markers

Raab

Neuhuber

2005

J Histochem Cytochem.

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S U M M A R YIntraganglionic laminar endings (IGLEs) represent the only vagal mechanosensory terminals in the tunica muscularis of the esophagus. Two specific markers for IGLEs were recently described in mouse: the purinergic P2 ϫ 2 receptor and the vesicular glutamate transporter 2 (VGLUT2). This study aimed at comparing both markers with respect to their suitability for quantitative analysis. We counted IGLEs immunostained for VGLUT2 and P2 ϫ 2 , respectively, and mapped their distribution in esophageal wholemounts of C57Bl/6 mice. Numbers and distribution of IGLEs were compared with those of myenteric ganglia as demonstrated by cuprolinic blue histochemistry. Whereas the distribution of VGLUT2-immunopositive IGLEs closely matched that of myenteric ganglia, P2 ϫ 2 -immunopositive IGLEs were rarely found in upper and middle esophagus but increasingly in its lower parts. P2 ϫ 2 stained only half the number of IGLEs found with VGLUT2 immunostaining. We also investigated the correlation between anterograde tracing and immunohistochemistry for identifying IGLEs. Confocal microscopy revealed colocalization of all three markers in ‫ف‬ 50% of IGLEs. The remaining IGLEs showed only tracer and VGLUT2 labeling but no P2 ϫ 2 immunoreactivity. Thus, VGLUT2 and P2 ϫ 2 represent two specific markers for qualitative demonstration of esophageal IGLEs. However, VGLUT2 may be superior to P2 ϫ 2 as a quantitative marker for IGLEs in the esophagus of C57Bl/6 mice.

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“…In general, of the two main classes of vagal afferent endings [intraganglionic laminar endings (IGLEs) and intramuscular arrays (IMAs)], IMAs have been shown to primarily mediate signals of stretch and length change within the stomach, whereas IGLEs function more in response to more direct muscular contraction (33). Of particular relevance to our findings is the recent report (9) showing that knockout animals lacking the neurotrophin (NT)-4 gene exhibit deficient intestinal IGLE innervation, which results in short-term satiation deficits. In contrast, NT-4 knockin mutants have been shown to be hypersensitive to CCK-induced satiation mediated through CCK-1 receptor activation (4).…”

Section: Discussionmentioning

confidence: 53%

Decreased gastric mechanodetection, but preserved gastric emptying, in CCK-1 receptor-deficient OLETF rats

Jonghe¹,

Hajnal²,

Covașă³

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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creased gastric mechanodetection, but preserved gastric emptying, in CCK-1 receptor-deficient OLETF rats. Am J Physiol Gastrointest Liver Physiol 291: G640 -G649, 2006. First published May 25, 2006 doi:10.1152/ajpgi.00109.2006.-Obese CCK-1 receptor-lacking Otsuka Long Evans Tokushima fatty (OLETF) rats are hyperphagic relative to control, nonmutant Long Evans Tokushima Otsuka (LETO) rats. This study sought to assess whether the overeating observed in OLETF rats is associated with changes in gastric emptying rates or detection of gastric volume. We performed experiments in both 12-and 29-wk-old OLETF and LETO rats to address possible alterations in gastric functions during the development of increased body weight and blood glucose abnormalities in OLETF rats. Gastric emptying of a 5-g solid chow test meal was not significantly different between strains at either 1, 2, or 4 h postmeal. When rats with ad libitum access to chow were tested, there were no significant differences in gastric emptying between strains at any time period despite OLETF rats consuming significantly more chow than LETO rats. Similar to solid food, 5-min gastric emptying of a 5-ml isosmotic and hyperosmotic saline or glucose load was not significantly different between strains. When the stomach was distended with a 15-ml semisolid chow load, there was no significance difference in emptying at either 1 or 2 h. No significant differences in gastric emptying were detected between 12-and 29-wk-old rats under any conditions. Both young and old OLETF rats, however, reduced sham intake significantly less compared with LETO rats during a brief period of gastric distension by 5-or 10-ml balloon inflation. Finally, OLETF rats showed decreased Fos expression in the nucleus of the solitary tract relative to LETO rats after an 8-ml gastric distension. These findings demonstrate that OLETF rats do not express deficits in controlling gastric emptying rates; however, they exhibit decreased behavioral and vagal responsiveness to gastric distension that may contribute to the increased meal size in these animals.cholecystokinin; hyperphagia; cholecystokinin-1 receptor; c-Fos; gastric distension; sucrose; sham feeding THE OTSUKA LONG-EVANS TOKUSHIMA FATTY (OLETF) rat is an outbred mutant strain of the Long Evans Tokushima Otsuka (LETO) rat that lacks CCK-1 receptor expression entirely due to a spontaneous 6.8-kb mutation spanning the promoter and first two exon regions of the CCK-1 receptor gene (46). In addition to the use of these animals as a model of insulin resistance, due to their natural manifestation of hyperglycemia and non-insulin-dependent diabetes mellitus relative to agematched LETO rats (16), OLETF rats are also currently under investigation as a model of obesity. OLETF rats exhibit an increased rate of weight gain relative to controls across their lifespan, with a marked elevation in body weight seen as early as 2-4 postnatal days (2, 27, 43). It is also known that OLETF rats are hyperphagic via increased meal size. This behavior has been attribu...

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Neurotrophin-4 Deficient Mice Have a Loss of Vagal Intraganglionic Mechanoreceptors from the Small Intestine and a Disruption of Short-Term Satiety

Cited by 83 publications

References 82 publications

Inhibition of thirst when dehydrated rats drink water or saline

Inhibition of thirst when dehydrated rats drink water or saline

Number and Distribution of Intraganglionic Laminar Endings in the Mouse Esophagus as Demonstrated with Two Different Immunohistochemical Markers

Decreased gastric mechanodetection, but preserved gastric emptying, in CCK-1 receptor-deficient OLETF rats

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