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Endocrinology Vol. 145, No. 1 304-310
Copyright © 2004 by The Endocrine Society

Chronic Neuropeptide Y Infusion into the Lateral Ventricle Induces Sustained Feeding and Obesity in Mice Lacking Either Npy1r or Npy5r Expression

Paula D. Raposinho, Thierry Pedrazzini, Richard B. White, Richard D. Palmiter and Michel L. Aubert

Division of Pediatric Endocrinology and Diabetology, University of Geneva School of Medicine (P.D.R., R.B.W., M.L.A.), 1211 Geneva 14, Switzerland; Instituto Tecnológico e Nuclear (P.D.R.), 2685 Sacavém, Portugal; Division of Hypertension, University of Lausanne Medical School (T.P.), 1011 Lausanne, Switzerland; and Department of Biochemistry, Howard Hughes Medical Institute (R.D.P.), Seattle, Washington 98195

Address all correspondence and requests for reprints to: Dr. M. L. Aubert, Hôpital des Enfants, HUGs, 6 rue Willy-Donzé, 1211 Geneva 14, Switzerland. E-mail: michel.aubert{at}medecine.unige.ch.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Neuropeptide Y (NPY) is a powerful orexigenic neurotransmitter. The NPY Y1 and Y5 receptors have been implicated in mediating the appetite-stimulating activity of NPY. To further investigate the importance of these two receptors in NPY-induced hyperphagia after chronic central administration, we used mice lacking either Npy1r or Npy5r expression. NPY infusion into the lateral ventricle of wild-type mice stimulated food intake and induced obesity over a 7-d period. Fat pad weight as well as plasma insulin, leptin, and corticosterone levels were strongly increased in NPY-treated mice. In addition, NPY infusion resulted in a significant decrease in hypothalamic NPY and proopiomelanocortin expression. Interestingly, the lack of either Npy1r or Npy5r expression in knockout mice did not affect such feeding response to chronic NPY infusion. Moreover, the obesity syndrome that developed in these animals was similar to that in wild-type animals. Taken together, these data strongly suggest biological redundancies between Y1 and Y5 receptor signaling in the NPY-mediated control of food intake.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
NEUROPEPTIDE Y (NPY) is a 36-amino acid peptide (1) with strong orexigenic effects in vivo. NPY-expressing neurons in the hypothalamic arcuate nucleus (ARC) project into the paraventricular (PVN), the dorsomedial, and the ventromedial hypothalamic nuclei, areas implicated in the control of food intake (2). Therefore, a bolus injection of NPY into the cerebral ventricles (3) or the PVN (4, 5) induces a robust feeding response. Furthermore, when chronically infused, NPY provokes unabated hyperphagia and an obese phenotype characterized by insulin resistance and hypogonadism (6, 7, 8, 9). Six different NPY receptor subtypes (Yx) have been identified, among them five were cloned and characterized (10, 11). The Y1 and Y5 receptor subtypes have been linked to the orexigenic action of NPY (11). Based on pharmacological studies, the Y1 receptor was initially suggested to be unique for the control of feeding (11). However, the cloned Y5 receptor displays binding affinity for a series of semiselective agonists known for their capacity to stimulate food intake (12, 13). In addition, both Y1 and Y5 receptors are expressed in hypothalamic areas that control feeding (14, 15, 16), and coexpression of these two receptors is even observed in the same neurons (17).

Npy1r-deficient mice demonstrate only a marginal decrease in daily food intake (18). However, the refeeding response following starvation is strongly reduced in these animals. In contrast, mice lacking Npy5r have been reported to be paradoxically hyperphagic (19). Nevertheless, food intake in Npy5r knockout animals after acute NPY injection was shown to be decreased compared with that in wild-type mice. In addition, the residual NPY-induced feeding response in Npy5r-/- mice can be blunted by the administration of a Y1 receptor antagonist (18, 19, 20). Surprisingly, both types of knockout mice eventually developed late-onset obesity (18, 19). However, whereas it is likely that this obesity developed secondary to hyperphagia in Npy5r knockout animals, increased body weight gain appeared to result from decreased energy expenditure in mice lacking Npy1r (18).

Leptin, a hormone produced by adipocytes, plays a pivotal role in the regulation of food intake and energy homeostasis (21). Leptin suppresses feeding and decreases adiposity in part by inhibiting hypothalamic NPY synthesis and secretion (22, 23), but also by stimulating proopiomelanocortin (POMC) mRNA expression and {alpha}-melanocortin-stimulating hormone ({alpha}MSH) release (24, 25). A role for Y1R in conditions of leptin deficiency has been suggested. Indeed, the leptin-deficient ob/ob mice that were made deficient for Npy1r expression by cross-breeding exhibited reduced hyperphagia and a partial correction of the obese syndrome (26). On the contrary, ob/ob mice lacking Npy5r are undistinguishable from ob/ob mice carrying a functional Npy5r gene (19). Taken together, these findings suggest that both Y1 and Y5 receptor subtypes can contribute to the acute feeding response to NPY injection. The present study evaluated the respective roles of these two receptor subtypes using knockout mice in a situation of chronic NPY administration. When NPY is infused centrally, it is believed that activation of NPY receptors is the primary cause of hyperphagia, not a plethora of other physiological reactions that would result from fasting-induced hyperphagia, another way to stimulate feeding.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Mice lacking the NPY Y1 or Y5 receptors were described previously (18, 19). Male Npy1r knockout mice were backcrossed for seven generations into a C57BL/6J background, and male Npy5r knockouts were generated into a pure 129/J background. Mice were used at 6–7 months of age. C57BL/6J (Iffa Credo, L’Arbresle, France) and 129/J mice (The Jackson Laboratory, Bar Harbor, ME) were used as wild-type controls for Npy1r-/- and Npy5r-/- mice, respectively. Mice were housed in individual cages and provided with water and a standard chow (catalogue no. 3200, Provimi Kliba, Kaiseraugst, Switzerland) ad libitum. Animals were kept in a 14-h light, 10-h dark cycle.

Chronic NPY infusion in intact male mice
A cannula (Alzet brain infusion kit II, Iffa Credo, L’Arbresle, France) was implanted into the right lateral ventricle (0.5 mm posterior and 1.0 lateral to the bregma, 2.2-mm depth) under ketalar/xylazine anesthesia (8.5:1 mg/ml·kg). The cannula was fixed onto the skull with instant adhesive (Loctite 454, Loctite Corp. Hartford, CT) and dental cement (Paladur, Heraeus Kulzer GmbH & Co., Wehrheim, Germany). An Alzet osmotic minipump (model 2001, Iffa Credo) was attached to the cannula and implanted sc during the same surgical session. NPY (porcine, Neosystem, Strasbourg, France) was dissolved in sterile 0.04 M phosphate buffer (pH 7.4) containing 0.15 M NaCl, 0.01% ascorbic acid, and 0.2% BSA. Concentrations were adjusted to deliver 2 nmol/d. NPY was infused for 7 d. Body weight, food intake, and water intake were monitored daily. Mice were then killed by decapitation, and trunk blood was collected in EDTA tubes. Plasma samples were snap-frozen and stored until used. The retroperitoneal fat pad was dissected out and weighed. Hypothalami were snap-frozen and stored at -80 C for RNA extraction.

Hormone assays
Plasma leptin and insulin were determined using kits ML-82K and RI-13K (Linco Research, Inc., St. Charles, MO). Plasma corticosterone levels were determined as previously described (27).

Hypothalamic mRNA expression analysis using competitive quantitative RT-PCR
Hypothalamic NPY and POMC mRNA expression was determined by competitive RT-PCR as previously described (9). Briefly, sample RNA was reverse transcribed together with known amounts of competitor RNA and coamplified by PCR.

Statistical analysis
Statistical analysis was performed by ANOVA using Dunnett’s t test and the Student-Newman-Keuls test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Food and water intake and body weight gain
Figure 1Go depicts food intake in Npy1r and Npy5r knockout mice as well as in their respective controls in response to chronic NPY infusion. After recovering from surgery, vehicle-infused wild-type mice of either strain ate about 4 g daily. In these mice, NPY infusion induced a strong stimulation of food intake (Fig. 1Go and Table 1Go), which resulted in a doubling of the daily amount of food ingested after 1 wk of treatment. Interestingly, central NPY administration stimulated feeding in both Npy1r and Npy5r knockout mice to an extent similar to that seen in wild-type animals. In addition, daily water intake was strongly stimulated by NPY infusion in all groups (Table 1Go). In both strains of wild-type mice, NPY treatment resulted in a significant body weight gain compared with that in vehicle-infused mice (Fig. 2Go). Because experiments were performed in 6- to 7-month-old animals, knockout mice from both strains already had a significantly higher body weight at the initiation of the experiment than their wild-type counterparts (Table 1Go). Despite this higher initial body weight, both Npy1r- and Npy5r-deficient mice still increased their body weight after NPY-induced stimulation of food intake (Fig. 2Go and Table 1Go). Initial loss of weight reflects the stress of surgery/anesthesia. This effect of surgery and anesthesia was more apparent in the knockout animals, but in all situations, NPY infusion stimulated feeding and body weight gain.



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  		FIG. 1. Effects of a 7-d chronic infusion into the lateral ventricle of porcine NPY (2 nmol/d) on food intake in Npy1r- and Npy5r-deficient mice and their respective wild-type controls. The intracerebroventricular cannula were placed on d 0, and peptide infusion was started immediately. Data are the mean ± SE (n = 5–10 mice/group). *, P < 0.01 vs. vehicle-infused mice, first time point different from vehicle animals.

 

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  		TABLE 1. Effects of chronic 7-d central infusion of pNPY (2 nmol/d) on metabolic parameters

 


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  		FIG. 2. Effects of a 7-d chronic infusion into the lateral ventricle of porcine NPY (2 nmol/d) on cumulative body weight gain in Npy1r- and Npy5r-deficient mice and their respective wild-type controls. Data are the mean ± SE (n = 5–10 mice/group). *, P < 0.01 vs. vehicle-infused mice, first time point different from vehicle animals.

 
Fat pad mass and plasma leptin, insulin, and corticosterone levels
NPY-induced feeding produced obesity in wild-type animals, characterized by a highly significant increase in the retroperitoneal fat pad mass of mice receiving NPY compared with those infused with vehicle (Fig. 3Go). Plasma insulin and leptin levels were also elevated in these animals. In accordance with previous observations, at 6 months of age, vehicle-infused knockout mice demonstrated an increase in fad pad mass as well as in plasma insulin and leptin levels. However, NPY infusion resulted in a further increase in these parameters to levels even higher than those measured in wild-type mice treated with NPY. Interestingly, NPY infusion also increased plasma corticosterone levels in wild-type and knockout mice (Table 1Go).



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  		FIG. 3. Effects of a 7-d chronic infusion into the lateral ventricle of porcine NPY (2 nmol/d) on plasma levels of insulin and leptin and on the weight of the retroperitoneal fat pad in Npy1r- and Npy5r-deficient mice and their respective wild-type controls as seen at the time the mice were killed (d 7). Data are the mean ± SE (n = 5–10 mice/group). *, P < 0.05; **, P < 0.01 (NPY- infused mice vs. vehicle-infused mice). °, P < 0.05; °°, P < 0.01 (untreated knockout mice vs. untreated wild-type mice).

 
NPY and POMC mRNA expression
To evaluate the impact of NPY infusion on orexigenic and anorexigenic pathways in the hypothalamus, we determined hypothalamic NPY and POMC mRNA expression in mice chronically treated with NPY. Hypothalamic NPY mRNA expression was significantly reduced by NPY infusion in wild-type mice from both strains (Fig. 4Go). Interestingly, in vehicle-infused animals, NPY mRNA expression was already decreased in knockouts compared with wild-type animals. However, NPY infusion still significantly reduced NPY mRNA expression in Npy5r knockout mice, but had only a modest effect in Npy1r-deficient mice. In addition, NPY reduced hypothalamic POMC mRNA expression in wild-type mice as well as in both knockout animals. In this case, however, basal POMC mRNA expression was not different from that in wild-type mice lacking Npy1r and was even increased in Npy5r knockout mice compared with their wild-type controls (Fig. 4Go).



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  		FIG. 4. Effects of a 7-d chronic infusion into the lateral ventricle of porcine NPY (2 nmol/d) on hypothalamic mRNA expression for NPY and POMC in Npy1r- and Npy5r-deficient mice and their respective wild-type controls. mRNAs for these hypothalamic peptides were measured by quantitative RT-PCR techniques using total RNA extracts from mice hypothalami collected at the time the mice were killed (d 7). Data are the mean ± SE (n = 5–10 mice/group). *, P < 0.05; **, P < 0.01 (NPY-infused mice vs. vehicle-infused mice). °, P < 0.05; °°, P < 0.01 (untreated KO mice vs. untreated wild-type mice).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The effects of central administration of NPY on the control of feeding and energy homeostasis are well documented (28, 29). NPY infusion into the lateral ventricle in rats or mice results in hyperphagia; increased adiposity; elevated plasma leptin, insulin, and corticosterone levels; as well as hypogonadism (8, 9). Both Y1 and Y5 receptors are implicated in the control of feeding, but their relative importance is still a matter of controversy. The availability of Npy1r and Npy5r knockout mice has not fully clarified this issue (18, 19, 30). Here we present the first study directly comparing the response to chronic NPY infusion in Npy1r-/- and Npy5r-/- mice. We show that in both knockout mice, intracerebroventricular NPY infusion produces hyperphagia and the immediate development of an obesity syndrome similar to that observed in wild-type mice, suggesting biological redundancies between Y1 and Y5 receptor signaling in the control of food intake.

Several studies have indicated that both the Y1 and Y5 receptors mediate the orexigenic actions of NPY. In fact, these two receptors could participate concurrently in the NPY-induced feeding. The roles of Y1 and Y5 receptor subtypes are supported by pharmacological studies using bolus injections of semiselective NPY receptor agonists (12, 13, 31, 32, 33, 34, 35, 36, 37) and antagonists (38, 39, 40, 41, 42, 43, 44). For instance, a selective Y5 antagonist (CGP71683A) (38) or a selective Y1 antagonist (1229U91) (45) suppressed only about half of the NPY- induced food intake and the c-Fos-like immunoreactivity in the magnocellular PVN, in which both Y1 and Y5 receptors are expressed (46, 47). Moreover, 4-d treatment with a combination of suboptimal doses of these two antagonists given twice daily led to a reduction in food intake and body weight gain in normal rats, fa/fa rats, and ob/ob mice (39). A possible synergistic effect is also supported by the observation that Y1 and Y5 receptors are often expressed in the same neurons (17), probably reflecting a common transcriptional control (12). Moreover, the fact that both Npy1r-/- and Npy5r-/- mice demonstrated a blunted, but still significant, feeding response to acute NPY injections supports a dual participation of these two receptors (18, 19). In addition, the observations made in the present study demonstrating that chronic NPY infusion rapidly and strongly stimulated food intake in both Npy1r- and Npy5r-deficient mice to a similar extent indicate that neither of these two receptor subtypes is mandatory for maintaining a feeding response and suggest biological redundancy between the Y1 and Y5 systems. Interestingly, the NPY-induced pathways mediating an acute feeding response were previously shown to be significantly blunted in both Y1 and Y5 knockout animals. The fact that in the present study no difference could be observed in the obesity syndrome that develops upon chronic NPY infusion suggests that either distinct pathways operated in short- vs. long-term responses to NPY or that strong compensatory mechanisms are progressively activated. Another interesting approach to evaluate the relative importance of Y1 and Y5 receptors in the control of feeding would have been to chronically treat Npy1r and Npy5r transgenic mice with powerful antagonists against either Y1 or Y5. Unfortunately, the frequent occurrence of behavioral side-effects, such as tremor or rolling, when administering NPY antagonists at effective doses prevented meaningful long-term studies with repeated central injections or infusion (39).

The involvement of a different type of NPY receptor in the control of feeding is still possible. The Y2 receptor, a putative inhibitory presynaptic receptor, is highly expressed in ARC NPY and POMC neurons, which are accessible to peripheral hormones, and could be implicated in the basal control of feeding (48). Indeed, a recent study demonstrated that peptide YY3–36 given peripherally in postprandial concentrations or directly in the ARC decreased, rather than increased, feeding via the Y2 receptor (48). Nevertheless, studies using Npy2r-/- mice suggest that the Y2 receptor is probably not involved in either fasting- or NPY-induced hyperphagia (49). There is little evidence for Y4R involvement, since rat pancreatic polypeptide, a selective Y4R agonist, does not induce feeding in mice (13, 30). In addition, Npy4r-/- knockout mice display normal or lower feeding pattern and body weight gain, and when Npy4r-/- mice are crossed with ob/ob mice, the absence of Y4R does not significantly modify obesity in ob/ob mice (50). In addition, an unknown NPY receptor might be involved in NPY-induced feeding (30). Along these lines, human pancreatic polypeptide (a Y4/Y5 receptor mixed agonist) as well as peptide YY3–36 (a Y2/Y5 receptor mixed agonist) both induced an obesity syndrome similar to that induced by NPY in rats and mice (9) while stimulating feeding in Npy5r-/- mice (19, 30). Clearly more work is needed to resolve these discrepancies.

At the age of 6–7 months, both Npy1r-/- and Npy5r-/- mice were significantly overweight compared with their respective wild-type littermates and demonstrated an increase in fat pad size as well as elevated plasma leptin and insulin levels, in accord with previously published data (18, 19). Whereas obesity in Npy5r-/- mice probably developed secondary to hyperphagia, the obesity observed in adult Npy1r-/- mice most likely resulted from low energy expenditure, including decreased expression of uncoupling protein-2 in white adipose tissue and impaired control of insulin secretion (51). In both Npy1r-/- and Npy5r-/- mice, central NPY infusion further exacerbated the obesity syndrome, thus demonstrating that they remained exquisitely sensitive to NPY.

Corticosterone secretion was generally increased in Y5 compared with Y1 knockout mice and their wild-type controls. This difference may reflect a background difference between the two strains of mice used. However, most importantly, NPY infusion raised plasma corticosterone in all situations regardless of basal levels.

Compensatory mechanisms in diet-induced obese mice have been shown to include decreased NPY and increased POMC mRNA expression (52, 53, 54). Interestingly, some background differences were observed in the POMC response, as C57BL/6 mice demonstrated a stronger compensatory increase in POMC gene expression than A/J mice (52). We also observed that in untreated Npy1r-/- and Npy5r-/- mice, hypothalamic mRNA expression for NPY was significantly decreased, probably secondary to the high plasma leptin and/or insulin levels (55). This suggests that the leptin- regulated NPY pathways are not affected by the lack of Npy1r or Npy5r expression. This is in agreement with previous observations demonstrating that the sensitivity to leptin in both Npy1r and Npy5r knockout mice is preserved (19, 26). In contrast, hypothalamic POMC mRNA expression was unchanged in untreated Npy1r-/- mice and was increased in untreated Npy5r-/-, a difference reminiscent of that seen between C57BL/6 and A/J mice subjected to diet-induced obesity (52). As plasma leptin levels were similarly elevated in both knockout groups, it is unlikely that leptin concentrations are responsible for the observed difference. The lack of up-regulation of POMC mRNA expression in Npy1r-/- mice could be related to their decrease in energy expenditure. This would be consistent with inappropriate {alpha}MSH production and release secondary to a lack of compensatory POMC expression. In contrast, mice lacking Npy5r were shown to be hyperphagic and demonstrated the expected increase in POMC expression.

Chronic NPY infusion strongly reduced hypothalamic NPY mRNA levels in both wild-type groups and fully decreased the already partially reduced NPY mRNA expression in knockout animals. These further decreases are consistent with the elevated leptin levels observed. NPY infusion also strongly and significantly reduced hypothalamic POMC mRNA expression in wild-type animals as well as in knockout mice, as previously observed in rats (56) and mice (9), despite the maximally increased plasma leptin levels, which would have been expected to stimulate POMC expression (57). These data strongly suggest that NPY induces hyperphagia by acting on its own receptors, as well as by inhibiting synthesis and the anorexic action of {alpha}MSH. This is consistent with a recent study demonstrating local action of NPY on POMC neurons (58), which are known to express the Y1 receptor (59, 60). In fact, it was suggested that NPY could inhibit the anorectic melanocortin pathways in part by activating inhibitory Y1 receptor located on POMC-expressing cells (59, 60, 61). Here we show that even in the absence of Y1 receptor, NPY strongly inhibits POMC mRNA expression, and thus another pathway may exist.

Whereas this study clearly demonstrated biological redundancies between the Y1 and Y5 receptors, it would be interesting to repeat such a study with double Npy1r and Npy5r knockout mice. However, the two genes are adjacent to each other, and this double knockout cannot be generated by breeding. Other less obvious experimental approaches are needed for this purpose. As Y1 and Y5 receptor subtypes appeared interchangeable in this study, disruption of both genes, with elimination of the possibility of one receptor rescuing the other one, may result in more significant changes in feeding behavior. Finally, the finding that mice lacking either of the NPY receptor subtypes concerned with feeding maintain near-normal energy homeostasis and an appropriate response to NPY stimulation may be interpreted to indicate that by virtue of presumed evolutionary pressure, the anabolic pathway involving NPY action exhibits plasticity and redundancy, further confirming that energy homeostasis is inherently biased toward weight gain (62).


   Acknowledgments
 
We acknowledge the excellent technical assistance of Veronica Rivero, Brigitte Delavy, Christiane Rey, and Anne Scherrer. The skillful technical assistance of Jean-Jacques Goy and Ramon Junco in our animal quarter is gratefully acknowledged.


   Footnotes
 
This work was supported by grants from the Swiss National Research Science Foundation [31-55732-98 and 31-67164.01 (to M.L.A.) and 32-61524-00 (to T.P.)] and in part by the Ferring Research Institute.

Abbreviations: ARC, Arcuate nucleus; {alpha}MSH, {alpha}-melanocortin-stimulating hormone; NPY, neuropeptide Y; POMC, proopiomelanocortin; PVN, paraventricular hypothalamic nucleus.

Received July 21, 2003.

Accepted for publication September 26, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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