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. 2012 Sep 1;303(5):E659-68.
doi: 10.1152/ajpendo.00033.2012. Epub 2012 Jul 3.

Regulation of hindbrain Pyy expression by acute food deprivation, prolonged caloric restriction, and weight loss surgery in mice

C Gelegen  1 , K Chandarana, A I Choudhury, H Al-Qassab, I M Evans, E E Irvine, C B Hyde, M Claret, F Andreelli, S E Sloan, A B Leiter, D J Withers, R L Batterham
Affiliations

Regulation of hindbrain Pyy expression by acute food deprivation, prolonged caloric restriction, and weight loss surgery in mice

C Gelegen et al. Am J Physiol Endocrinol Metab. .

Abstract

PYY is a gut-derived putative satiety signal released in response to nutrient ingestion and is implicated in the regulation of energy homeostasis. Pyy-expressing neurons have been identified in the hindbrain of river lamprey, rodents, and primates. Despite this high evolutionary conservation, little is known about central PYY neurons. Using in situ hybridization, PYY-Cre;ROSA-EYFP mice, and immunohistochemistry, we identified PYY cell bodies in the gigantocellular reticular nucleus region of the hindbrain. PYY projections were present in the dorsal vagal complex and hypoglossal nucleus. In the hindbrain, Pyy mRNA was present at E9.5, and expression peaked at P2 and then decreased significantly by 70% at adulthood. We found that, in contrast to the circulation, PYY-(1-36) is the predominant isoform in mouse brainstem extracts in the ad libitum-fed state. However, following a 24-h fast, the relative amounts of PYY-(1-36) and PYY-(3-36) isoforms were similar. Interestingly, central Pyy expression showed nutritional regulation and decreased significantly by acute starvation, prolonged caloric restriction, and bariatric surgery (enterogastroanastomosis). Central Pyy expression correlated with body weight loss and circulating leptin and PYY concentrations. Central regulation of energy metabolism is not limited to the hypothalamus but also includes the midbrain and the brainstem. Our findings suggest a role for hindbrain PYY in the regulation of energy homeostasis and provide a starting point for further research on gigantocellular reticular nucleus PYY neurons, which will increase our understanding of the brain stem pathways in the integrated control of appetite and energy metabolism.

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Figures

Fig. 1.
Fig. 1.
Peptide YY (PYY) neurons are localized in the gigantocellular reticular nucleus (Gi) region of the hindbrain. A: coronal section of mouse hindbrain containing Gi region (24). B: representative in situ hybridization (ISH) image in brain slices from control mice showing Pyy expression in neurons located in the Gi region. C: representative immunofluorescence image in hindbrain slices from PYY-Cre;ROSA-EYFP mice. D: representative immunohistochemistry (IHC) image using PYY antibody on EYFP-positive cells in C. E: high magnification confocal image showing merge of C and D. Red, PYY immunostaining; green, EYFP; yellow: colocalization.
Fig. 2.
Fig. 2.
Brain stem Pyy expression reaches a peak at postnatal day 2 (P2) and decreases by 70% at 10 wk of age. A: real-time PCR assay using a predesigned assay for Pyy showed that Pyy mRNA is already present in the hindbrain at embryonic day (E)9.5, expression reaches peak at P2 and decreases to its E9.5 level by 10 wk of age. B: presence of PYY in the brain stem was confirmed with IHC on brain stem sections prepared from neuropeptide Y knockout (NpyKO) P2 pups. C: representative ISH image on brain stem sections from P2 pups, confirming the presence of Pyy mRNA. Bregma, 6.36 mm.
Fig. 3.
Fig. 3.
PYY-immunoreactive (ir) fibers are present in NTS, 10N, and 12N regions of the hindbrain. DVC, dorsal vagal complex; NTS, nucleus of the solitary tract; 10N, dorsal motor nucleus of the vagus; 12N, hypoglossal nucleus; Bregma, 7.08–7.64 mm. A and B: representative IHC images using PYY antibody showing the presence of PYY-ir projections in DVC and 12N regions. C and D: high magnification images of squared areas in A and B, respectively. E and F: high magnification confocal images of squared areas in C and D, respectively.
Fig. 4.
Fig. 4.
Serotonergic neurons are in close proximity to PYY cell bodies. RMg, Raphe magnus; Rob, Raphe obscures; RPa, raphe pallidus. A: representative IHC image using serotonin (5-HT) antibody on brain stem sections prepared from PYY-Cre;ROSA-EYFP mice, showing close proximity of two neuron groups. Bregma, 6.36 mm. B: high magnification confocal image of the section in A showing close apposition between 5-HT and PYY cell bodies. C: high magnification confocal image of the section in A showing close apposition between 5-HT-ir projections and PYY cell bodies. D: representative confocal image of an EYFP-positive neuron in the Rob nuclei costained with 5-HT antibody. Red, 5-HT immunostaining; green, EYFP; yellow, colocalization.
Fig. 5.
Fig. 5.
Brain stem Pyy mRNA expression is reduced significantly in response to 24-h fasting, prolonged calorie restriction (CR), and following enterogastroanastomosis (EGA) procedure. A: change in brain stem Pyy mRNA expression in mice in response to 24-h fasting. B and C: changes in body weight and circulating leptin levels, respectively, in mice subjected to prolonged CR. D and E: changes in Pyy and Y1, Y2, and Y5 receptor mRNA expression levels in mice subjected to prolonged CR and in mice that underwent EGA procedure, respectively.
Fig. 6.
Fig. 6.
PYY-(1–36) is the predominant form under ad libitum feeding, and the level of both isoforms is similar following 24-h fasting. A and B: representative chromatograms from one fed and one 24-h-fasted mouse, respectively. C: changes in PYY-like immunoreactivity corresponding to PYY-(1–36) and PYY-(3–36) isoforms in response to 24-h fasting.
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