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Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239-3098
Address all correspondence and requests for reprints to: Roger D. Cone, Ph.D, Vollum Institute, Center for the Study of Weight Regulation and Associated Disorders, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239-3098. E-mail: cone{at}ohsu.edu.
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Introduction |
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The PYY3–36 form appears to be anorexigenic when given peripherally (11, 12). In a recent study Batterham and co-workers (11) showed that ip injections of PYY3–36, acting through Y2 receptors, can suppress fast-induced feeding in rats and mice. Additionally, PYY3–36 was shown to activate proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) when bath-applied to hypothalamic slices in vitro (11). However, a number of laboratories (13) have had difficulty reliably and reproducibly repeating the anorexigenic effect of PYY3–36 in the rodent.
One model for the anorexigenic action of PYY3–36 proposes activation of ARC POMC neurons of the central melanocortin system (11), and indeed, PYY3–36 administration has been demonstrated to elevate hypothalamic POMC mRNA levels (12); however, we were concerned by the very low percentage (20% with PYY3–36 vs. 8% with saline) of POMC ARC neurons activated by PYY3–36, as assessed by c-Fos immunohistochemistry. In this study we demonstrate a reproducible protocol for assessing the anorexigenic activity of PYY3–36 utilizing a long acclimatization of animals, and that the peptide retains full activity in the melanocortin-4 receptor knockout (MC4-R–/–) mouse.
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Materials and Methods |
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4.5% fat). Wild-type (WT) controls of the C57BL/6J strain were purchased to be age, sex, and weight matched (The Jackson Laboratory, Bar Harbor, ME). Upon arrival WT mice were allowed to acclimate for 1 wk under the conditions stated above. All studies were conducted according to the NIH Guide for the Care and Use of Laboratory Animals and were approved by the animal care and use committee of Oregon Health and Science University.
Source of reagents/peptides
All experiments, unless stated otherwise, were performed with human PYY3–36 purchased from American Peptides (Sunnyvale, CA; first batch: lot Q08111T1). A second human PYY3–36 batch and the synthetic MC3-R/MC4-R antagonist SHU9119 were purchased form Bachem (Torrance, CA; lot 0558311), and a second independent batch of human PYY3–36 was purchased from American Peptides (lot R05026T1). All peptides were certified by the manufacturer and came with HPLC data showing a single peak with the correct molecular weight from mass spectrograms and a purity greater than 97%. Peptides were dissolved in sterile isotonic saline and injected ip in a total volume of 500 µl/injection. Fresh human PYY3–36 and SHU9119 concentrations were prepared on the day of injection from frozen stock solutions.
Feeding protocols
Response of unacclimated animals to a 16-h fast.
Age-matched WT (The Jackson Laboratory) male mice (8 wk old) were used for unacclimated feeding studies. Mice were individually housed the day before a nocturnal fast (1800–1000 h). Injections and food consumption measurements were performed in a double-blinded experiment. Animals were injected ip at 1000 h with either saline or PYY3–36 at a dose of 0.3, 3, or 10 µg/100 g. Food intake was measured hourly for the first 4 h and at 12 h, by placing two pellets of chow in petri dishes at the bottom of the cage at the time of ip injection. To minimize error attributable to loss of food particles, all bedding was screened before and after the experiment to capture any spilled food. Food in petri dishes was also screened to remove any bedding or other debris.
Response of acclimated animals to a 16-h fast.
Age-matched WT (The Jackson Laboratory) male mice (8 wk) were used for the feeding study. Mice were individually housed for 1 wk. In the following week they were acclimated to daily ip saline injections at 1000 h with two pellets of food being placed in a petri dish on the floor of the cage and weighed hourly for 4 h. Animals were fasted for 16 h the night before the experiment (1800–1000 h). Food intake was measured by placing two pellets of chow in petri dishes on the floor of the cage at the time of ip injection (double-blinded) of either saline or PYY3–36 at a dose of 0.3, 3, or 10 µg/100 g, and cumulative food intake was measured hourly for 4 h post injection. As before, to minimize error attributable to loss of food particles, all bedding and petri dishes were screened.
Response of acclimated animals in a nighttime feeding protocol.
Age-matched MC4-R–/– and WT (The Jackson Laboratory) male mice (8 wk old) were used for the nocturnal feeding study. For habituation, mice were individually housed for 1 wk and injected with daily (500 µl) saline immediately before lights out (1900 h). Two pellets of food were placed in a petri dish on the floor of the cage immediately after injection, and food intake was measured hourly for 4 h. Animals were habituated until their food intake stabilized for at least 4 consecutive days before experimental treatment. Animals were randomly injected with either saline or 0.3 µg/100 g PYY3–36 on the first experimental day, with 3 µg/100 g on the second day, and with 10 µg/100 g on the last experimental day. On nonexperimental days animals were injected with saline to measure deviation from previous habituation baseline. Measurement error was minimized with careful screening of petri dishes for debris and cage bedding for spilled food.
c-Fos immunohistochemistry
POMC-EGFP mice (23–27 g), a transgenic strain in which EGFP is expressed under the control of the POMC promoter (14), were handled and received 100 µl sterile saline, ip, at 0900 h for 5 d before the experiment to minimize background c-Fos immunoreactivity caused by stress. Animals received an ip injection of PYY3–36 (5 µg/100 g) or sterile saline 90 min before being deeply anesthetized and undergoing transcardial perfusion with 0.9% heparinized saline, followed by 4% paraformaldehyde in 0.01 M PBS. Sections were cut at 30 µm from perfused brains and stored free-floating in 0.01 M PBS containing 0.03% sodium azide. The sections were incubated for 1 h at room temperature in blocking reagent (5% normal donkey serum in 0.01 M PBS and 0.3% Triton X-100). After the initial blocking step, the sections were incubated in rabbit anti-c-Fos antibody (sc-052, Santa Cruz Biotechnology, Inc., Santa Cruz, CA) diluted 1:6000 in blocking reagent for 24 h at 4 C, followed by incubation in 1:500 donkey antirabbit Alexa 594 (Molecular Probes, Inc., Eugene, OR) for 1 h at room temperature. In the nucleus tractus solitarius (NTS) sections, the POMC-EGFP cells were detected using a 1:4000 dilution of rabbit anti-GFP antibody directly conjugated to Alexa 488 (Molecular Probes, Inc.). Between each stage the sections were washed thoroughly with 0.01 M PBS. At the end of the incubations the sections were mounted onto gelatin-coated slides, coverslipped using gel-based fluorescence mounting medium (Biomeda Corp., Foster City, CA), and viewed under a fluorescence microscope (Axioplan 2, Zeiss, Inc., Thornwood, NY). The number of c-Fos-immunoreactive cells was counted on sections that also contained POMC-EGFP cells by a person blinded to the individual treatments.
Statistics
Statistical analyses were performed using PRISM (GraphPad, San Diego, CA). Data are expressed as the mean ± SEM. One-way ANOVA with Dunnett’s test post hoc test was used to determine significance in Fig. 1
. Significance was determined using an unpaired (two-tailed) t test in Figs. 2 and 3. Significance was taken as P < 0.05.
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). Unacclimated WT saline controls (Fig. 1A) ate 32.0% (Fig. 1B) and 53.5% (Fig. 1, C and D) less than acclimated WT saline controls in the first hour of measurement [unacclimated, 0.48 ± 0.13 g (Fig. 1A); acclimated, 0.71 ± 0.04 g (Fig. 1B); acclimated, 1.04 ± 0.08 g (Fig. 1, C and D)].
PYY3–36 reduces food intake in a dose-dependent manner after a single ip injection after 16-h fast in acclimated mice
Due to our previous experience we tested PYY3–36 action after a week-long acclimatization protocol that we have shown to reduce stress due to handling (16). In this study WT animals were individually housed for 1 wk and treated daily with ip saline injections, and food was weighed at the appropriate times for acclimation. The animals were fasted for 16 h before ip injection of PYY3–36 at varying doses of 0.3, 3, and 10 µg/100 g, and cumulative food intake was measured at 1-h intervals for 4 h. Compound administration and food intake measurements were performed using a double-blind procedure to prevent any handling artifacts or experimental bias. PYY3–36 reduced food intake in a dose-dependent matter in the first 4 h after administration (Fig. 1B). PYY3–36 significantly reduced food intake in the 3 and 10 µg/100 g treatment groups compared with the saline-treated animals at both 1 and 2 h (Fig. 1B). Although there was a trend toward a reduction in food intake by PYY3–36 with the 0.3 µg/100 g dose, statistical significance was not reached (Fig. 1B). Four hours after the ip injections, only the 10 µg/100 g dose retained its ability to significantly reduce food consumption (Fig. 1B). At 12 h post injection, no difference in food intake was measured at any concentrations (Fig. 1B, inset).
PYY3–36 from different batches and companies reliably reduces food intake after a 16-h fast in acclimated WT mice in a dose-dependent manner
Given the small degree of anorexia caused by PYY3–36 and the limited duration of its action, we postulated that negative results might be due to batch to batch differences in the peptide. We next tested the effects of two different batches of PYY3–36 obtained from two separate manufacturers on reducing food intake by a double-blinded experiment in 16-h fasted WT mice acclimated to handling. Peptides from both companies reduced food intake in habituated animals in a dose-dependent fashion (Fig. 1, C and D) Bachem PYY3–36 showed a dose-response curve with increasing doses of peptide (Fig. 1D), whereas American Peptides PYY3–36 showed a saturation of its effects past the 3 µg/100 g dose (Fig. 1C). Additionally, PYY3–36 from Bachem also acted in a short-term manner, where it reduced food intake significantly only for the first 2 h after injection (Fig. 1D) like American Peptides PYY3–36 in Fig. 1B. As before (Fig. 1B), both new batches of peptides were unable to reduce food intake at the lowest dose (0.3 µg/100 g) at any time point measured, and, in fact, at the single time point of 3 h American Peptides PYY3–36 stimulated feeding (Fig. 1C). At 10 µg/100 g, peptides from both companies significantly reduced food intake for the duration of the experiment (Fig. 1, C and D).
It is possible that the reduction in food intake that was observed in the previous experiments could have simply been due to ip injection of any peptide or from a nonspecific compound that the particular company uses for its peptide storage. To test this hypothesis we obtained the MC3/4R antagonist SHU9119 from Bachem simultaneously with PYY3–36. The ip injections of SHU9119 (3 and 10 µg/100 g) in a double-blinded experiment performed in 16-h fasted WT acclimated mice had no effect on food intake at any time point that PYY3–36 dose-dependently reduced food intake (data not shown).
MC4-R is not required for inhibition of feeding by PYY3–36
PYY3–36 increases POMC neuronal firing in hypothalamic slices (11) and POMC mRNA expression acutely after peripheral PYY3–36 administration (12). However, ip injection of PYY3–36 only increases the expression of c-Fos, an indirect marker of neuronal activation, in approximately 12% of ARC POMC neurons (11). These results suggested that the role of the melanocortin system in the action of PYY3–36 needed to be examined more carefully. To test the role of the melanocortin system in the action of PYY3–36, we evaluated the ability of MC4-R–/– mice to show an anorexigenic response after ip administration of PYY3–36. We chose a nocturnal feeding response to PYY3–36 because it is most physiologically relevant. WT and MC4-R–/– feeding ad libitum were injected with either saline or PYY3–36 at increasing doses immediately before lights out (1900 h), and cumulative food intake was measured hourly for 4 h. The freely night-feeding WT animals showed a similar response to increasing doses of PYY3–36 as fasted animals (Fig. 1). At the lowest dose, PYY3–36 (0.3 µg/100 g) did not significantly reduce nocturnal food intake in WT mice over the 4 h of measurement (Fig. 2A). At the 3 µg/100 g dose, PYY3–36 reduced food intake significantly in WT over the first 3 h (Fig. 2B). At the highest dose of 10 µg/100 g, PYY3–36 significantly reduced food intake in WT for the 4 h of measurements (Fig. 2C).
MC4-R–/– mice injected with PYY3–36 exhibited a similar dose-dependent decrease in ad libitum nocturnal food intake as WT animals (Fig. 2). Like WT animals, the lowest dose of PYY3–36 (0.3 µg/100 g) did not induce a significant decrease in food intake in MC4-R–/– mice at any of the time points measured (Fig. 2A). The intermediate dose of PYY3–36 (3 µg/100 g) transiently reduced food intake in MC4-R–/– mice to a similar degree and over the same time course as in WT mice (Fig. 2B). At the highest dose of 10 µg/100 g PYY3–36, MC4-R–/– animals responded in the same way as WT mice (Fig. 2C).
Daytime peripheral PYY3–36 administration induces c-Fos expression in POMC neurons in the ARC
To further examine the possible role of POMC neurons in mediating the effects of PYY3–36, we performed a preliminary experiment to examine the activation of POMC neurons in both the ARC and NTS using c-Fos immunohistochemistry. Immunohistochemical experiments were performed using a previously characterized transgenic mouse in which EGFP is expressed under the control of the POMC promoter (14); thus, EGFP immunoreactivity was used to visualize POMC-positive cells. Daytime ip injection at 0900 h of PYY3–36 at 5 µg/100 g significantly increased c-Fos expression in POMC neurons in the ARC from 9% to 22% (Fig. 3A) similar to data reported previously (11). No increase was seen in c-Fos-positive POMC neurons in the NTS; however, this analysis involved a small sample (three animals) examined under a single condition (Fig. 3C). In this preliminary experiment there was a trend upward, but no significant increase in total c-Fos expression in the ARC (Fig. 3B) or NTS (Fig. 3D) was found compared with saline-treated animals.
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Discussion |
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Recently, there have been reports that PYY3–36 is incapable of reliably reducing food intake (13). Here we showed that without proper habituation of the WT mice, the satiating effect of PYY3–36 was not evident. This loss of efficacy may be due to the effects of stress caused by handling and ip injection, as evident by the 32% decrease in food intake in unacclimated WT mice compared with acclimated WT mice (16). Therefore, as PYY3–36 has a modest anorexigenic efficacy and a short time window of action, its effects may be insignificant relative to the prominent reduction in food intake due to stress. Alternatively, if PYY3–36 and stress activate common anorexigenic circuits, stress-induced anorexia could mask the effects of PYY3–36. The PYY3–36-induced reduction in food intake is small even at high doses, and the effect is very short-lived. Thus, the action of PYY3–36 could also be easily missed if food intake is not measured within the first 4 h after injection or if the peptide is administered sc vs. ip. For example, a study by Challis et al. (12) showed that PYY3–36 (10 µg/100 g) reduced food intake after a 24-h fast, but did not measurably reduce nocturnal food intake in nonfasted, freely feeding mice when food intake was measured 6 h post injection. The lack of response seen with this paradigm may be due to the fact that food intake was not measured until 6 h after peptide administration. In our study the effect of PYY3–36 on food intake was largely absent by this time point. Furthermore, it is not clear whether these animals were acclimated to handling before the procedure, but this may be a contributing factor to the lack of response seen.
Additionally, different batches of peptide from American Peptides and Bachem both similarly and reliably reduced fast-induced food intake in the first 4 h of measurement in a double-blinded experiment, which was used to prevent any handling artifacts.
In this study we further tested the hypothesis that PYY3–36 acts via the central melanocortin system. The original report by Batterham and colleagues (11) showing that PYY3–36 has anorexigenic effects in mice also proposed that these effects might be mediated by the central melanocortin system. They observed an increase in POMC neuron firing with PYY3–36 in an electrophysiological slice preparation and an increase in c-Fos expression in POMC neurons of the ARC. We wanted to further examine this model in two ways: 1) by examining whether the MC4-R is essential for the anorexigenic action of PYY3–36, and 2) by addressing whether POMC neurons in the ARC are activated by PYY3–36 and whether a potent activation of brain stem neurons by PYY3–36 is seen, as is the case with CCK or gastric distention (20, 21, 22, 23). Here we show that MC4-R–/– mice are just as responsive to the anorexigenic effects PYY3–36 as WT mice in a nocturnal feeding paradigm. This result argues that the MC4-R is not essential for the anorexigenic action of PYY3–36. Therefore, although the increase in the POMC neuron firing rate in slice preparations (11) and the induction of POMC mRNA (12) by PYY3–36 may indeed lead to an increase in melanocortin signaling though the MC4-R, this does not appear to be essential for the anorexigenic effects of the peptide.
In our preliminary immunohistochemical study, a small, but significant, increase in of c-Fos was seen in ARC POMC neurons after daytime administration of PYY3–36, consistent with previously published results (11). Surprisingly, only a small nonsignificant increase in c-Fos immunoreactivitypositive cells was observed in total NTS neurons and NTS POMC neurons. The relatively small increase in c-Fos expression in the ARC and the lack of a significant increase in NTS may be due to a number of factors. First, the actions of PYY3–36 via the autoinhibitory Y2 receptor may indirectly modulate anorexigenic neurons and thus may not be potent enough to activate c-Fos; for example, in the ARC PYY3–36 appears to stimulate POMC neurons by indirectly decreasing the inhibitory 
-aminobutyric acid-ergic drive onto POMC neurons. Alternatively, PYY3–36 may inhibit feeding via a mechanism quite distinct from other gut-derived satiety factors. The lack of significant c-Fos expression in the NTS after PYY3–36 administration is in contrast to other GI peptides such as CCK and bombesin (24, 25), which also have short-term satiety-like actions yet induce c-Fos immunoreactivity in a great number of NTS neurons (24, 25). We have recently demonstrated that ip CCK routinely activates greater than 30% of POMC NTS neurons under similar experimental conditions, and furthermore, that the anorexic actions of CCK are blocked by either genetic or pharmacologic MC4-R blockade (26). Regardless of the causes behind the limited up-regulation of c-Fos in NTS and ARC after inhibition of feeding by PYY3–36, the data presented here argue that PYY3–36 inhibits food intake via a strikingly different mechanism than that of either the long-term adipostatic factor leptin, which can potently activate ARC POMC neurons (27), or satiety signals, such as CCK, bombesin, or gastric distension, which potently activate c-Fos in NTS neurons.
In summary, we have presented data indicating that the satiating effect of PYY3–36 is complex, atypical, and does not require the presence of the MC4-R. If the MC4-R is not essential, other mechanisms must be involved. They may include atypical mechanisms of action of PYY3–36 on POMC neurons, other sites of action of PYY3–36 in the central nervous system, or, finally, a possible peripheral mode of action.
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Acknowledgments |
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Footnotes |
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Abbreviations: ARC, Arcuate nucleus of the hypothalamus; CCK, cholecystokinin; EGFP, enhanced green fluorescent protein; GI, gastrointestinal; MC4-R, melanocortin-4 receptor; NTS, nucleus tractus solitarius; POMC, proopiomelanocortin; WT, wild-type.
Received December 26, 2003.
Accepted for publication March 1, 2004.
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 C. Acuna-Goycolea and A. N. van den Pol Peptide YY3-36 Inhibits Both Anorexigenic Proopiomelanocortin and Orexigenic Neuropeptide Y Neurons: Implications for Hypothalamic Regulation of Energy Homeostasis J. Neurosci., November 9, 2005; 25(45): 10510 - 10519. [Abstract] [Full Text] |
