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Attenuated Peptide YY Release in Obese Subjects Is Associated with Reduced Satiety

Departments of Metabolic Medicine (C.W.l.R., M.P., C.M.B., K.J.W., A.K., R.P.V., J.G., M.A.G., S.R.B.), Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom; Department of Endocrinology (R.L.B.), University College London, London WC1E 6BT, United Kingdom; and Department of Endocrinology (S.J.B.A.), King’s College Hospital, London SE5 9RS, United Kingdom

Address all correspondence and requests for reprints to: Prof. S. R. Bloom, Department of Metabolic Medicine, 6th Floor Commonwealth Building, Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk.

	Abstract

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The responses of the gut hormone peptide YY (PYY) to food were investigated in 20 normal-weight and 20 obese humans in response to six test meals of varying calorie content. Human volunteers had a graded rise in plasma PYY (R² = 0.96; P < 0.001) during increasing calorific meals, but the obese subjects had a lower endogenous PYY response at each meal size (P < 0.05 at all levels). The ratio of plasma PYY_1–36 to PYY_3–36 was similar in normal-weight and obese subjects. The effect on food intake and satiety of graded doses of exogenous PYY_3–36 was also evaluated in 12 human volunteers. Stepwise increasing doses of exogenous PYY_3–36 in humans caused a graded reduction in food intake (R² = 0.38; P < 0.001). In high-fat-fed (HF) mice that became obese and low-fat-fed mice that remained normal weight, we measured plasma PYY, tissue PYY, and PYY mRNA levels and assessed the effect of exogenous administered PYY_3–36 on food intake in HF mice. HF mice remained sensitive to the anorectic effects of exogenous ip PYY_3–36. Compared with low-fat-fed fed mice, the HF mice had lower endogenous plasma PYY and higher tissue PYY but similar PYY mRNA levels, suggesting a possible reduction of PYY release. Thus, fasting and postprandial endogenous plasma PYY levels were attenuated in obese humans and rodents. The PYY_3–36 infusion study showed that the degree of plasma PYY reduction in obese subjects were likely associated with decreased satiety and relatively increased food intake. We conclude that obese subjects have a PYY deficiency that would reduce satiety and could thus reinforce their obesity.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
PEPTIDE YY (PYY) is present throughout the intestinal tract, with the highest concentrations in distal segments (1). Two forms are released postprandially: PYY_1–36 and PYY_3–36 (1, 2, 3). Postprandial plasma PYY concentrations have been reported to be proportional to meal size (1), with levels peaking 2 h after food intake (4, 5). Elevated fasting levels of PYY have been described in several gastrointestinal diseases associated with loss of appetite (6, 7). Batterham et al. (4, 5) demonstrated that PYY_3–36 reduced food intake in both humans and rodents, although a recent publication reported a failure of PYY to inhibit food intake in rodents (8). More recently, however, the effect of PYY as an inhibitor of food intake in rodents has been replicated in a number of studies, and it has become clear that the habituation of laboratory animals to handling and injection is required to demonstrate the effect of PYY_3–36 (4, 9, 10, 11, 12, 13, 14). PYY may thus be an important factor influencing postprandial satiety (15, 16). Fasting endogenous PYY concentrations have been shown to be lower in obese individuals (5). Differences in fasting PYY levels are controversial (17); however, it is apparent that the duration of a fast before a study critically affects plasma PYY concentrations (18). Attenuated postprandial PYY responses in obese subjects have been more consistently reported (5, 17, 19).

In this study, we sought to determine whether obese individuals have lower endogenous PYY levels and whether PYY release could be achieved by sufficient caloric stimulus. We also aimed to determine whether the lower observed postprandial levels of PYY among the obese could be expected to have an effect on food intake. Furthermore, we explored possible mechanisms for the observed relative PYY deficiency among the obese. We thus investigated 1) the endogenous postprandial PYY response, 2) the effect of varied exogenous PYY_3–36 doses on satiety and food intake, and 3) high-fat-fed (HF) and low-fat-fed (LF) mice for plasma and tissue PYY and PYY mRNA.

	Materials and Methods

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All human studies were performed according to the principles of the Declaration of Helsinki. The Local Research and Ethics committee at the Hammersmith Hospital approved the postprandial PYY response (03/6499) and multiple PYY infusion (03/6616) studies. Written informed consent was obtained, and exclusion criteria included chronic medical or psychiatric illness, pregnancy, substance abuse, more than two alcoholic drinks per day, and aerobic exercise for more than 30 min three times per week. All animal studies were performed under project licenses issued by the Home Office, United Kingdom (PL/70/5516).

Endogenous postprandial PYY responses
We evaluated the postprandial PYY response to a series of six standard meals in 20 obese and 20 normal-weight subjects (Table 1). The body mass index of all subjects had been stable for 3 months and was 40.3 ± 1.1 kg/m² (mean ± SEM) in the obese group and 21.7 ± 0.4 kg/m² in the normal-weight group. Both groups consisted of 14 females and six males. The ages were 29.0 ± 2.0 and 28.6 ± 1.6 yr for the obese and normal-weight group, respectively. Subjects attended on three occasions after a 12-h overnight fast and received in random order either a 500-ml liquid meal (250, 500, or 1000 kcal) or a 900-ml meal (1000, 2000, or 3000 kcal). All the subjects were required to drink the entire volume, and after consumption of the drink, no liquid was left in the glass. The 1000-kcal meals given as 500 ml or 900 ml allowed investigation of a possible volume effect on plasma PYY response. Visual analog scales (VAS) were completed and venous blood collected every 30 min for 3 h after each meal. Blood samples were centrifuged and plasma was immediately separated and stored at –70 C before analysis. The VAS were used to assess hunger, fullness, and malaise. Subjects indicated their opinion on a 100-mm VAS with text expressing the most positive and most negative ratings anchored at each end (20).

Rodent studies to test possible mechanisms of lower endogenous plasma PYY
Eighty-eight C57B6 mice (Charles River Laboratories, Wilmington, MA) were randomized to 16 wk of diets containing either 2.6% (n = 24) or 60% (n = 64) of calories from fat (Research Diets, New Brunswick, NJ). Using an established protocol, 40 of the HF mice were acclimatized to ip injections (9). Mice were randomly allocated to ip injections with 0.9% saline or 5 µg/100 g PYY_3–36 (Bachem) after an overnight fast (4). Food intake was measured 1, 2, 4, 8, 12, 24, and 48 h later. The remaining 48 mice were killed after a 12-h fast (n = 24) or 120 min after a 0.5-g high-fat meal (n = 24). A constant section of tissue was dissected from the cecum to the end of the ascending colon in the fasted mice. The tissue was longitudinally separated in equal halves. The samples were weighed and snap frozen in liquid nitrogen.

Peptide extraction and assays for plasma and mRNA
Tissue samples were placed into preheated polypropylene tubes containing 0.5% acetic acid. The wet tissues were weighed at autopsy, and the volume of the acetic acid was adjusted accordingly (10 ml/g). The samples were boiled for 15 min. After another 30 min at room temperature, the supernatant was used to measure PYY immunoreactivity.

All plasma and tissue extracted samples were assayed in duplicate. PYY-like immunoreactivity was measured with a specific and sensitive RIA (5, 22). The assay measured the biologically active components, both the full-length PYY_1–36 and the fragment PYY_3–36. The antiserum (Y21) was produced in a rabbit against synthetic porcine PYY (Bachem) coupled to BSA glutaraldehyde and used at a final dilution of 1:50,000. Similar to all current PYY assays, our antibody cross-reacts fully with PYY_1–36 and PYY_3–36 but not with pancreatic polypeptide, neuropeptide Y, or any other gastrointestinal hormone. ¹²⁵I-labeled PYY was prepared by the iodogen method and purified by HPLC. The specific activity of the ¹²⁵I-labeled PYY was 54 Bq/fmol. The assay was performed in a total volume of 700 µl of 0.06 M phosphate buffer (pH 7.26) containing 0.3% BSA. The samples were incubated for 3 d at 4 C before separation of free and antibody-bound label by sheep antirabbit antibody. Two hundred microliters of unextracted plasma were assayed, whereas 200 µl of PYY-free colloid fluid, Hemacel, was added to standards and other reference tubes to negate any effects of nonspecific assay interference. The assay detected changes of 2 pmol/liter, with intra- and interassay coefficients of variation of 5.8 and 9.8%, respectively.

Before reverse-phase fast protein liquid chromatography, 10 ml of plasma pooled from 10 subjects was pretreated using Sep-Pak C18 cartridges (Waters, Milford, CT) as previously described (23). Recovered plasma samples were resuspended in 0.7 ml water plus trifluoroacetic acid (0.1% vol/vol) and filtered through 0.2-µm hydrophilic membranes (Satorius, Gottingen, Germany). Then, 0.5 ml of the filtrate was fractionated by fast protein liquid chromatography on a high-resolution reverse-phase (Pep RPC HR) C-18 column (Pharmacia, Uppsala, Sweden). The column was eluted with an initial gradient of 0–23.5% (vol/vol) acetonitrile/water/0.1% (vol/vol) trifluoroacetic acid over the first 15 min followed by a gradient of 23.5–24.5% acetonitrile/water/0.1% (vol/vol) trifluoroacetic acid gradient over the next 60 min. The 1.0-ml fractions were collected and dried by vacuum centrifugation (Savant, Greenbush, NY) and reconstituted in assay buffer, and PYY-like immunoreactivity was determined by RIA.

Fasting PYY mRNA levels were measured by Northern blot analysis (n = 6). Total RNA was extracted using Tri-reagent (Helena Biosciences, Sunderland, UK) according to the manufacturer’s protocol. A 50-µg amount of total RNA from each tissue was size separated on a denaturing MOPS [3-(n-morpholino) propane-sulfonic acid]/formaldehyde gel (1% agarose) and transferred to a Hybond-N membrane (Amersham International, Little Chalfont, UK). The RNA was fixed by baking at 80 C for 2 h before probing with a random primer labeled corresponding to nucleotides 121–450 of rat PYY (accession number M17523). The probe was synthesized using [-³²P]dATP (Amersham) using Klenow DNA polymerase (Promega, Southampton, UK). Hybridization was carried out overnight at 55 C in 5x standard saline citrate (SSC) (1x SSC contains 0.15 M sodium chloride, 15 mM sodium citrate), 5x Denhardt’s, 50% (wt/vol) deionized formamide, 100 µg/ml denatured sonicated herring sperm DNA, and 100 µg/ml yeast tRNA. Nonspecific hybridization was removed by increasingly stringent washes, the final one being in 0.1x SSC/0.1% (wt/vol) SDS at 70 C for 30 min.

The Northern blot was exposed to a phosphoimager screen and quantified using ImageQuant 5.2 (Molecular Dynamics, Sunnyvale, CA). The Northern blot was normalized using oligo-dT as a probe (24).

Statistical analysis
Data are expressed as means ± SEM. Values for the area under the curve were calculated with the use of the trapezoidal rule. End points were compared with the use of two-tailed, unpaired Student’s t tests or ANOVA. For Fig. 1, C and D, the Wilcoxon two-sample test was used. For Fig. 2, one-way ANOVA with 6 degrees of freedom was used with Student-Newman-Keuls method as post hoc analysis. For Fig. 3B, one-way ANOVA with Kruskal-Wallis statistic and Dunn’s multiple comparison test was used. Correlations were determined by univariate linear regression (GraphPad Prism).

View larger version (26K): [in this window] [in a new window]   FIG. 1. A and B, Isoforms PYY1–36 and PYY3–36 in normal-weight (A) and obese (B) patients 90 min after a 2000-kcal meal; C, peak PYY levels in obese () and normal-weight () subjects at 90 min after the meal; D, fullness scores at 180 min after the meal, measured by VAS in the obese () and normal-weight () subjects. *, P < 0.05 (unpaired t test).

View larger version (16K): [in this window] [in a new window]   FIG. 2. A, PYY levels achieved after infusion of increasing doses in normal-weight subjects; B, effect for each infusion rate of PYY3–36 on calories consumed when normalized for consumption on saline infusion day; C, VAS shows change (in millimeters) in level of fullness at end of the infusion. *, P < 0.05 compared with saline (one-way ANOVA).

View larger version (19K): [in this window] [in a new window]   FIG. 3. A, Food intake at 1, 2, 4, 8, and 24 h in diet-induced obese mice after ip PYY3–36 (striped bars) compared with saline (solid bars); B, plasma PYY fasting and after 0.5 g chow in normal-weight and obese mice; C, ascending colon tissue levels of PYY in obese and normal-weight mice; D, mRNA levels from ascending colon tissue in normal-weight (N) and obese (O) mice. *, P < 0.05 (t test between groups indicated by lines).

	Results

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The effect of varied doses of exogenous PYY_3–36
In the human multiple-dose infusion study there was a strong correlation between infused PYY_3–36 doses and measured plasma PYY levels (R² = 0.73; P < 0.001) (Fig. 2A). No difference in VAS-rated malaise, desire to eat, or hunger was detected when the meal was served (P > 0.1). There was a strong negative correlation between infused doses of PYY_3–36 and food intake (R² = 0.3; P < 0.001) with a significant reduction in calorie intake observed at doses of 0.7 and 0.8 pmol/kg·min (Fig. 2B). In contrast to the graded reduction in calorie intake across the infusion doses, a significant rise in fullness scores was observed with an apparent threshold at an infusion dose of 0.5 pmol/kg·min, corresponding to a plasma PYY level of 40 pmol/liter (Fig. 2C). Moreover, no additional increase in fullness scores was observed with PYY_3–36 doses above 0.5 pmol/kg·min.

Rodent studies to test possible mechanisms of lower endogenous plasma PYY
The 64 mice fed the high-fat diet (HF) weighed significantly more than the 24 fed a low-fat diet (LF) (42.6 ± 1.3 g for HF vs. 30.1 ± 0.8 g for LF; P < 0.001). The ip administration of PYY_3–36 to 40 HF mice resulted in a reduced food intake for up to 8 h (Fig. 3A) compared with saline controls. The group of HF mice (n = 24) had lower plasma PYY levels than the group of LF mice (n = 24), both fasting (35.7 ± 3.8 pmol/liter for HF vs. 47.2 ± 3.1 pmol/liter for LF; P = 0.048) and postprandially (46.3 ± 2.9 pmol/liter for HF vs. 56.6 ± 4.2 pmol/liter for LF; P = 0.03) (Fig. 3B). The tissue PYY levels in the ascending colon were higher in the HF mice (340.2 ± 56 pmol/g for HF vs. 148.0 ± 23 pmol/g for LF; P < 0.05; n = 24) (Fig. 3C). PYY mRNA levels in the ascending colon, however, was similar between the two groups (Fig. 3D).

	Discussion

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Termination of a meal depends on the balance between hunger before and fullness or satiety subsequent to the consumption of food (25, 26). A number of hormonal signals, including PYY, are generated during a meal, and it has been suggested that several of these signals may contribute to satiety (15). The etiology of obesity is still unclear, but it has been suggested that decreased satiety is one factor in its initiation and maintenance. For example, it has been reported that overweight and obese individuals required approximately 225 kcal more than normal-weight individuals to reach maximum satiety (27), whereas as little as 100 kcal in excess of daily requirements is enough to lead to weight gain (28). Obese subjects have delayed onset of satiety after consuming an ad libitum meal, and it has been speculated that this is related to alterations in hormone responses to food intake (27). We therefore investigated whether there are abnormalities in the PYY system at the level of synthesis, secretion, or sensitivity. The study reported here suggests that the contribution of PYY_1–36 and PYY_3–36 is similar in lean and obese subjects. The study supports the previous finding that obese subjects have reduced plasma PYY levels (5, 17, 19). In addition, we found that obese subjects have an attenuated PYY response across a range of meals with different calorie content. Greater meal calorie content was required to increase plasma PYY concentrations in obese to similar levels seen in normal-weight subjects. Infusions of exogenous PYY_3–36 at increasing doses produced an increased fullness and decreased food intake in normal-weight individuals. Taken together, these findings suggest that lower endogenous postprandial PYY levels may relate to reduced satiety and that obese subjects may have a weaker PYY-induced satiety signal for an equivalent meal.

Similar to human subjects (5), HF mice remain sensitive to the anorectic effects of exogenous PYY_3–36. In HF mice, the reduced plasma PYY levels were associated with elevated colon PYY levels, whereas the PYY mRNA levels were similar in the LF and HF groups. Our findings are consistent with a report in HF mice of reduced plasma levels and increased tissue levels for another L-cell-produced hormone, glucagon-like peptide 1 (29). These findings suggest that the plasma PYY deficiency may result from impaired PYY release rather than decreased synthesis, although we cannot exclude the possibility of an enhanced clearance rate or reduction in mRNA translation. PYY cell density was not measured in our study but may be important in future work to evaluate the discrepancy between low plasma levels and high tissue levels.

Obesity does not seem to cause a peripheral resistance to PYY, unlike the marked resistance observed for leptin and insulin (30, 31). The HF mice appear to be sensitive to the effects of PYY_3–36. This is consistent with previous reports (13) and the sensitivity to PYY_3–36 observed in obese humans (5). The definitive role of PYY in the pathogenesis of obesity and the mechanisms that contribute to the reduced plasma levels of PYY in obese humans and rodents remains to be determined. Models with genetic mutations may prove helpful in future as was recently shown when a mutation in PYY was demonstrated to be associated with the development of type 2 diabetes mellitus (32). Our study also addresses the question as to whether low plasma PYY is a cause or consequence of obesity. We observed that after randomization of mice into HF or LF groups, plasma PYY was lower in the diet-induced obese mice. We would therefore conclude that low plasma PYY is more likely to be a consequence rather than a cause of obesity. The apparent reduction in PYY release may have a potential maintenance effect rather than a causative effect on obesity.

Taken together, these studies suggest that the observed lower postprandial PYY levels in obese individuals may result in an increase in food intake to achieve the same level of satiety as seen in normal-weight subjects. PYY release from the intestinal tract may be inhibited in the obese, thus leaving obese subjects with a functional deficiency in PYY-induced satiety. Low plasma PYY may therefore reinforce obesity.

	Footnotes

 
C.L.R. and K.J.W. are supported by a Wellcome Clinical Fellowship, R.L.B. by a Medical Research Council Intermediate Fellowship. The research was supported by EU FP6 funding (contract no. LSHM-CT-2003-503041). This publication reflects the authors’ views and not necessarily those of the European Union. The information in this document is provided as is, and no guarantee or warranty is given that the information is fit for any particular purpose. The user thereof uses the information at its sole risk and liability.

First Published Online September 15, 2005

Abbreviations: HF, High-fat-fed; LF, low-fat-fed; PYY, peptide YY; SSC, standard saline citrate; VAS, visual analog scale.

Received August 1, 2005.

Accepted for publication September 10, 2005.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

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