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Endocrinology Vol. 143, No. 8 2995-3000
Copyright © 2002 by The Endocrine Society

ARTICLE

Eating Elicited by Orexin-A, But Not Melanin-Concentrating Hormone, Is Opioid Mediated

Deborah J. Clegg, Ellen L. Air, Stephen C. Woods and Randy J. Seeley

Department of Psychiatry, University of Cincinnati Medical Center (D.J.C., S.C.W., R.J.S.), Cincinnati, Ohio 45267-0559; and Departments of Biomedical Sciences and Cell Biology, Neurobiology, and Anatomy, University of Cincinnati Medical Center (E.L.A.), Cincinnati, Ohio 45267-0559

Address all correspondence and requests for reprints to: Deborah J. Clegg, Ph.D., Department of Psychiatry, University of Cincinnati Medical Center, P.O. Box 670559, Cincinnati, Ohio 45267-0559. E-mail: . debbie.clegg{at}uc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Melanin-concentrating hormone (MCH) and orexin-A are orexigenic peptidergic neurotransmitters produced primarily in the lateral hypothalamus. Because two other hypothalamic peptides, neuropeptide Y and agouti-related peptide, increase food intake by a mechanism that depends on activation of opioid receptors, we assessed whether MCH or orexin-A also elicits food intake via opioid receptor activation. A dose of naloxone (0.3 mg/kg, ip) that had no effect on its own reduced the acute orexigenic effect of third ventricular (i3vt) orexin-A (3 ng/rat). However, this same dose of naloxone had no effect on i3vt MCH (5 µg/rat)-induced hyperphagia. Because the opioid system has also been linked to food selection, we investigated whether MCH or orexin-A alters food choice when rats have simultaneous access to two diets differing in the relative amounts of fat and carbohydrate. Whereas i3vt MCH stimulated intake of both diets and did not alter food choice, i3vt orexin-A stimulated intake of only the high fat diet. These data indicate that despite several similarities between MCH and orexin-A, these two lateral hypothalamic area peptides stimulate food intake by recruiting different neural circuits and exert different effects on food choice.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN MAMMALS, neurons located in the lateral hypothalamic area (LHA) are important controllers of both feeding and behavioral arousal. Animals with lesions of the LHA exhibit hypophagia, increased metabolic rate, decreased arousal, and extreme weight loss (1, 2, 3, 4, 5). They also fail to respond with appropriate adaptive behavioral and physiological responses to homeostatic challenges such as fasting (6). Because electrical stimulation of the LHA results in a vigorous feeding response as well (see review in Ref. 2), the LHA was historically regarded as the hypothalamic feeding center and was considered to be an important integrating site for the somatic and autonomic controls over ingestion. Related to these functional observations, the LHA has extensive anatomical projections within the hypothalamus as well as throughout the entire neuroaxis, facilitating its coordination of metabolic, motivational, motor, autonomic, and arousal processes important in energy homeostasis (6).

Neurons in the LHA synthesize peptidergic transmitters that stimulate feeding behavior, specifically melanin-concentrating hormone (MCH) (7) and the orexins (A and B), which are also termed hypocretins (8, 9). MCH is expressed predominately in the LHA (10, 11), and several lines of investigation implicate it as a key regulator of food intake and body weight (7, 12, 13, 14). First, MCH gene expression is influenced by changes in energy balance. The adipocyte hormone leptin inhibits MCH gene expression, and food restriction increases MCH gene expression (15). Second, intracerebroventricular administration of exogenous MCH stimulates food intake (7, 13, 14), and mice that overexpress MCH are obese and insulin resistant (13). Finally, mice with targeted disruption of the MCH gene have reduced food intake and body weight accompanied by increased metabolic rate, resulting in little or no body fat (15).

The orexin or hypocretin system (8, 9) is comprised of two peptides, termed orexin-A and orexin-B, and two associated receptors. Intraventricular administration of a neutralizing antiorexin antibody suppresses spontaneous feeding in fasted rats (16), and intraventricular administration of orexin-A dose-dependently stimulates food consumption (9, 16, 17, 18). Changes in feeding after the administration of orexin-B have been inconsistent (9, 17, 18), such that a stronger case can be made for a role of orexin-A in energy homeostasis.

Although orexin- and MCH-expressing neurons are made within different neurons in the LHA (19, 20), both peptides increase energy intake. In this regard they are similar to agouti-related protein (AgRP) and neuropeptide Y (NPY), peptides made in the same population of neurons within the arcuate nucleus. Both NPY and AgRP, when administered exogenously, increase food intake (21, 22, 23, 24, 25, 26). As axons from the LHA project to the medial hypothalamus, including the arcuate, and as the AgRP/NPY neurons in the arcuate project to the LHA (27, 28, 29), understanding the functional interactions among these peptides is important. NPY- and AgRP-induced increases in food intake are dependent on opioid receptor activation, as this action is blocked by the nonspecific opioid receptor antagonist, naloxone (30, 31). Activation of the opioid system, in turn, has been associated with increased intake of preferred, high fat-containing diets (32). Consistent with this, we found that AgRP selectively increases the intake of a high fat diet when rats have simultaneous access to two diets differing in their relative amounts of carbohydrate and fat (31). On the other hand, administration of NPY reportedly increases the consumption of high carbohydrate diets (33, 34), although this has been attributed to a stimulation of whichever diet an individual rat prefers (35, 36). The purpose of the present experiments was to determine whether the orexigenic action of MCH and orexin-A depends upon activity at opioid receptors, and whether these peptides influence diet selection.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Male Long-Evans rats (Harlan Sprague Dawley, Indianapolis, IN), weighing 380–440 g at the onset of the experiments, were individually housed in Plexiglas tubs and maintained on a 12-h light, 12-h dark cycle in a temperature-controlled, American Association for Accedidation of Laboratory Animal Care-accredited vivarium, and all procedures were approved by the internal animal care and use committee at University of Cincinnati. The rats were maintained on ad libitum pelleted food and tap water unless otherwise noted. Each rat was implanted with a cannula aimed at the third cerebral ventricle (i3vt). Coordinates for cannula placement were on the midline, 2.2 mm posterior to bregma, and 7.5 mm ventral to dura, with bregma and {lambda} at the same vertical coordinate (37). After 10 d of recovery, accuracy of cannula placement was verified by i3vt infusion of 10 ng angiotensin II in 1 µl physiological saline. Only animals that drank at least 5 ml water within 1 h were used in the experiments.

Drugs
AgRP-(83–132), orexin-A, and MCH were purchased from Phoenix Pharmaceuticals, Inc. (Mountain View, CA). Naloxone hydrochloride (NALX) was purchased from Sigma (St. Louis, MO). All substances were dissolved in physiological saline, which also served as the control solution. AgRP-(83–132), orexin-A, MCH, and saline were administered i3vt in a 2-µl volume; NALX and control saline were injected ip in a volume of 0.3 ml/kg.

Diets
Animals were maintained on pelleted rat chow (Harlan-Teklad, Indianapolis, IN) in experiments 1–4. High fat (HF) and low fat (LF) pelleted diets prepared by Dyets (Bethlehem, PA) were used in experiments 5 and 6. The macronutrient compositions of these diets are given in Table 1Go.


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  		Table 1. Macronutrient composition of low fat, high fat, and regular chow diets by kilocalories per gram and by percentage of total kilocalories

 
Experiment 1.
We had previously determined that 0.3 mg/kg NALX, ip, has no effect of its own on food intake; i.e. this dose is subthreshold (31). However, the same dose when administered in conjunction with i3vt AgRP reliably reduced the increase in food intake elicited by AgRP (31). Experiment 1 was a replication of that experiment to confirm that 0.3 mg/kg NALX, ip, is, in fact, subthreshold in this cohort of rats and to reconfirm that it attenuates AgRP-induced overeating. Rats were assigned to one of four treatment groups (n = 8 or 9/group) matched by preexperimental body weight and food intake. On the test day, food was removed 2 h before lights off. Thirty minutes before lights off, rats in two groups received an ip injection of 0.3 mg/kg NALX, and rats in the other two groups received an equal volume of saline. Ten minutes later, one naloxone and one saline group received an i3vt injection of 1 nmol AgRP/2 µl, and the other two groups received saline (2 µl). This dose of AgRP elicits a reliable and long-lasting increase in food intake (25, 26, 38). Five minutes before lights off, food was returned to the cages, and intake was measured after 1, 2, 3, 4, and 24 h. Water was available at all times.

Experiment 2.
This experiment paralleled experiment 1, except that MCH was used instead of AgRP. Body weight-matched rats were assigned to one of four treatment groups (n = 8 or 9/group). On the test day, half the rats received an ip injection of 0.3 mg/kg NALX, and half received saline; 10 min later half of each group received an i3vt injection of MCH or saline (5 µg in a 2-µl vol or saline in a 2-µl vol.

Experiment 3.
Because it has been observed that MCH is more effective at increasing food intake during the light than during the dark period (14), experiment 2 was repeated in the same animals 10 d later, except that the first injection occurred 7 h into the light phase. The animals were counterbalanced for their previous treatment and reassigned to one of four new groups: ip NALX or saline, and i3vt MCH or saline.

Experiment 4.
Because orexin-A is more effective at increasing food intake during the light than during the dark period (18), this experiment paralleled experiment 2 in every way, except that orexin-A (3 ng/2 µl/rat) was substituted for MCH. There were 10 rats/group.

Experiment 5.
A group of rats (n = 20) was adapted to having two diets (HF and LF) simultaneously available ad libitum in separate food hoppers on their cages for 1 month. They were then matched by average daily food intake and body weight and assigned to one of two groups, receiving either saline or 5 µg MCH i3vt in a 2-µl injection volume following the same paradigm as that described above for experiment 3.

Experiment 6.
This experiment paralleled experiment 5, except that rats received either saline or 3 ng orexin-A i3vt in 2 µl. On the test day, a procedure identical to that described in experiment 5 was followed. Intake of each diet was recorded after 30, 60, 90, and 120 min.

Data analysis
The data were analyzed by parametric statistics (repeated measures ANOVA with time as the repeated measure, followed by Tukey’s HSD post hoc tests). Significance was set at P < 0.05 (two-tailed test).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Experiment 1
As depicted in Fig. 1Go, 0.3 mg/kg NALX, ip, did not by itself alter food intake. As we and others have observed, i3vt AgRP increased food intake by 85% relative to saline, and this trend continued after 24 h (data not depicted). NALX significantly reduced AgRP-induced eating beginning at the first hour. Two-way repeated measures ANOVA yielded a reliable interaction of drug and time [F(1,3) = 12.52; P < 0.05]. Tukey’s post hoc tests confirmed that food intake after AgRP plus NALX and that after AgRP plus saline were significantly different from each other, and that both were higher than intake after saline plus saline or saline plus NALX (P < 0.05; Fig. 1Go). The anorectic effect of NALX on AgRP-induced eating was gone by 4 h (data not shown).



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  		Figure 1. Effect of 0.3 mg/kg NALX, ip, or saline when injected in association with i3vt injection of saline or 1 nmol AgRP on chow intake over 1 h. *, Different from saline plus saline, P < 0.05; #, different from AgRP plus saline, P < 0.05.

 
Experiment 2
MCH (5 µg) potently stimulated food intake to a level 70% greater than that produced by saline during the dark. As depicted in Fig. 2Go, 0.3 mg/kg NALX did not by itself affect food intake. Further, NALX did not reduce MCH-induced eating. Two-way repeated measures ANOVA yielded a reliable main effect of drug [F(3,3) = 36.3; P < 0.05]. Tukey’s post hoc tests confirmed that food intake after MCH plus NALX and that after MCH alone were significantly higher than that after saline or saline plus NALX (P < 0.05; Fig. 2Go).



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  		Figure 2. Effect of 0.3 mg/kg NALX, ip, or saline when administered in association with the i3vt injection of saline or 5 µg MCH on chow intake over 1 h. Injections were given 30 min before the onset of the dark phase. *, Different from saline plus saline, P < 0.05.

 
Experiment 3
During the light period, MCH stimulated food intake to a level 85% greater than that with saline. As occurred at the beginning of the dark phase, NALX neither suppressed food intake on its own nor reduced MCH-induced hyperphagia (Fig. 3Go). Two-way repeated measures ANOVA yielded a reliable interaction of drug and time [F(3,9) = 5.95; P < 0.01]. Tukey’s post hoc tests confirmed that food intakes after MCH plus NALX and after MCH alone were significantly higher than intake after saline or saline plus NALX (P < 0.05; Fig. 3Go).



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  		Figure 3. Effect of 0.3 mg/kg NALX, ip, or saline when administered in association with i3vt injection of saline or 5 µg MCH on chow intake over 1 h. Injections were given during the light phase. *, Different from saline plus saline, P < 0.05.

 
Experiment 4
Orexin-A increased intake by 85% relative to saline, and NALX significantly reduced orexin-A-induced eating by the second hour (P < 0.05; Fig. 4Go). Two-way repeated measures ANOVA yielded a reliable interaction of drug and time [F(3,9) = 4.865; P < 0.05]. Tukey’s post hoc tests confirmed that food intake after orexin-A plus saline and orexin-A plus NALX were different and significantly higher than intake after saline and saline plus NALX (P < 0.05; Fig. 4Go).



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  		Figure 4. Effect of 0.3 mg/kg NALX, ip, or saline when administered in association with i3vt injection of saline or 3 ng orexin-A on chow intake over 1 h. Injections were given during the light phase. *, Different from saline plus saline, P < 0.05; #, different from orexin-A plus saline, P < 0.05.

 
Experiment 5
On the day before the test day, all of the animals preferred the HF diet to the LF diet, consuming an average 84% of their intake (by weight) from the HF diet. As depicted in Fig. 5Go, MCH increased total food intake as well as total caloric intake, and this was manifest as a significant increase in both diets. Hence, food intake, but not food choice, was altered by i3vt MCH.



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  		Figure 5. Intake of the HF and LF diets over 1 h during the light phase after 5 µg MCH i3vt or saline. *, P < 0.01; #, P < 0.01.

 
Experiment 6
On the day before the test day, all of the animals preferred the HF diet to the LF diet, consuming an average of 90% HF diet. As depicted in Fig. 6Go, orexin-A stimulated intake of the HF diet (to a level 176% of the saline control intake) to a significantly greater extent than it did intake of the LF diet (P < 0.05). Therefore, total caloric intake increased as well as the proportion of calories derived from the HF diet.



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  		Figure 6. Intake of the HF and LF diets over 1 h during the light phase after 3 ng orexin-A i3vt or saline. *, P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The current results indicate that although a subthreshold dose of naloxone, a nonselective opioid antagonist, can attenuate the potent effects of AgRP and orexin-A to increase food intake, the same dose does not alter the effect of MCH to stimulate food intake. These data are consistent with the hypothesis that the orexigenic effect of orexin-A critically depends on activation of opioid receptors downstream of its receptor, whereas the orexigenic action of MCH does not. The data also indicate that although both orexin-A and MCH can increase food intake, their effects on food choice are quite distinct. Although orexin-A selectively stimulates consumption of a HF diet, MCH stimulates intake of each diet comparably. Thus MCH increases caloric intake without altering the source of those calories, whereas orexin-A alters both caloric intake and diet selection.

These results are consistent with the hypothesis that with regard to energy homeostasis, AgRP and orexin-A share a common underlying mechanism, whereas MCH acts through a different mechanism. The opioid system has long been implicated in the regulation of food intake, with increased opioid activity in the brain leading to increased caloric consumption (30, 39, 40, 41). In particular, opioids modulate the incentive value of food, with opioid agonists increasing and opioid antagonists decreasing it (30, 40, 42). Consistent with this, opioids alter the relative selection of, or preference for, specific foods. ß-Endorphin, for example, increases intake of a preferred HF diet (43, 44). Likewise, in the present experiments orexin-A selectively increased consumption of a preferred HF diet, and orexin-A-stimulated intake of pelleted chow was attenuated by the prior administration of naloxone. Hence, we conclude that orexin-A, like AgRP, uses opioid-mediated circuits for its orexigenic action. In contrast, a comparably orexigenic dose of MCH did not alter diet selection, and an MCH-elicited increase in pelleted chow was not influenced by naloxone. We therefore conclude that the opioid system is not a downstream mediator of MCH’s orexigenic action.

Considerable controversy surrounds the contention that macronutrient intake is selectively regulated by different central nervous system systems (45), including the opioids (42, 46, 47). As an example, when a drug or other treatment is given, it cannot easily be ascertained whether an increase (or decrease) in one particular food choice relative to another reflects a preference (aversion) for a specific macronutrient (e.g. fat vs. carbohydrate) or whether it reflects a magnified (minimized) preexisting preference based upon palatability (48). Regardless of the actual mechanism, the critical observation is that orexin-A and MCH influence food intake via distinct mechanisms that can be dissociated by use of opioid antagonists and/or by considering food selection. Because AgRP’s orexigenic action is also reduced by naloxone, and because AgRP selectively increases intake of the preferred HF diet (31), we conclude that orexin-A and AgRP act through a common mechanism. Recent data from our laboratory (49, 50) and others (51) indicate that an orexigenic dose of AgRP increases Fos activity in the LHA, and dual label immunohistochemistry indicates that the increased activity is in orexin-A-producing neurons. Importantly, AgRP does not increase Fos activity in MCH-producing neurons (50, 51). Hence, functional anatomical data are consistent with the pharmacological and behavioral data.

AgRP is an endogenous antagonist of melanocortin 3 and 4 receptors (27), and these are found in the LHA as well as other projection sites of the NPY/AgRP neurons in the arcuate nucleus (20, 29). The present data do not allow determination of whether AgRP stimulates orexin-A neurons, and these, in turn, stimulate food intake by acting via opioid receptors. Additionally, these data do not determine whether the pathway is orexin-A to AgRP to opioid circuits, or whether other relay sites are involved that integrate information from both AgRP and orexin-A inputs. Added to this are the facts that AgRP neurons in the arcuate cosynthesize NPY, and NPY-elicited food intake is also naloxone dependent. Hence, NPY, AgRP, and orexin-A all appear to share a common circuit at some point.

Over the last several years, the number of identified peptides that are involved in the control of food intake and energy balance has grown enormously. Much of this growth has been fueled by the application of sophisticated molecular biological approaches and the pressing clinical need to treat the exponential growth in obesity. To develop appropriate therapeutic strategies, however, this "alphabet soup" of peptides and transmitters will need to be organized into functional circuits. The identification of such functional circuits will depend on intensive efforts to delineate both the neuroanatomical relationship among these systems as well as their functional interactions. The present results demonstrate that two peptides located within a single hypothalamic subarea, peptides that appear to be regulated similarly by energy balance and that each stimulate food intake, act via distinct behavioral and neural mechanisms. Such results point to the complexity of a homeostatic system that was designed to do much more than regulate the intake of a rat with ad libitum access to a single caloric source. Rather, the existence of two LHA subsystems that influence food intake in different ways emphasizes a system with great flexibility to respond to a myriad of environmental and physiological challenges.


   Acknowledgments
 


   Footnotes
 
This work was supported by NIH Grants DK-17844, DK-56863, and DK-54080 and the American Diabetes Association (Physician Scientist Training Award to E.L.A.). The Obesity Research Center at the University of Cincinnati is supported in part by the Procter & Gamble Co.

Abbreviations: AgRP, Agouti-related peptide; HF, high fat; i3vt, administered by third ventricular; LF, low fat; LHA, lateral hypothalamic area; MCH, melanin-concentrating hormone; NALX, naloxone hydrochloride; NPY, neuropeptide Y.

Received January 16, 2002.

Accepted for publication April 23, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Anand BK, Brobeck JR 1951 Hypothalamic control of food intake in rats and cats. Yale J Biol Med 24:123–140[Medline]
  2. Smith OAJ 1961 Food intake and hypothalamic stimulation. In: Sheer DE, ed. Electrical stimulation of the brain. Austin: University of Texas Press; 367–370
  3. Teitelbaum P, Epstein AN 1962 The lateral hypothalamic syndrome: recovery of feeding and drinking after hypothalamic lesions. Psychol Rev 69:74–90
  4. Teitelbaum P, Cheng MF, Rozin P 1969 Stages of recovery and development of lateral hypothalamic control of food and water intake. Ann NY Acad Sci 157:849–860[Medline]
  5. Teitelbaum P, Stellar E 1954 Recovery from the failure to eat, produced by hypothalamic lesions. Science 120:894–895[Free Full Text]
  6. Bernardis LL, Bellinger LL 1996 The lateral hypothalamic area revisited: ingestive behavior. Neurosci Biobehav Rev 20:189–287[CrossRef][Medline]
  7. Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek R, Kanarek R, Maratos-Flier E 1996 A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380:243–247[CrossRef][Medline]
  8. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG 1998 The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95:322–327[Abstract/Free Full Text]
  9. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M 1998 Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585[CrossRef][Medline]
  10. Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL, Vale W, Sawchenko PE 1992 The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. J Comp Neurol 319:218–245[CrossRef][Medline]
  11. Skofitsch G, Jacobowitz DM 1985 Immunohistochemical mapping of galanin-like neurons in the rat central nervous system. Peptides 6:509–546[CrossRef][Medline]
  12. Tritos NA, Maratos-Flier E 1999 Two important systems in energy homeostasis: melanocortins and melanin-concentrating hormone. Neuropeptides 33:339–349[CrossRef][Medline]
  13. Ludwig D, Mountjoy K, Tatro J, Gillette J, Frederich R, Flier J, Maratos-Flier E 1998 Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus. Am J Physiol 274:E627–E633
  14. Rossi M, Choi SJ, O’Shea D, Miyoshi T, Ghatei MA, Bloom SR 1997 Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology 138:351–355[Abstract/Free Full Text]
  15. Shimada M, Tritos N, Lowell B, Flier J, Maratos-Flier E 1998 Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396:670–674[CrossRef][Medline]
  16. Yamanaka A, Kunii K, Nambu T, Tsujino N, Sakai A, Matsuzaki I, Miwa Y, Goto K, Sakurai T 2000 Orexin-induced food intake involves neuropeptide Y pathway. Brain Res 859:404–409[CrossRef][Medline]
  17. Edwards CM, Abusnana S, Sunter D, Murphy KG, Ghatei MA, Bloom SR 1999 The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. J Endocrinol 160:R7–R12
  18. Haynes AC, Jackson B, Overend P, Buckingham RE, Wilson S, Tadayyon M, Arch JR 1999 Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat. Peptides 20:1099–1105[CrossRef][Medline]
  19. Broberger C, De Lecea L, Sutcliffe JG, Hokfelt T 1998 Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol 402:460–474[CrossRef][Medline]
  20. Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee C, Kelly J, Tatro JB, Hoffman GE, Ollmann MM, Barsh GS, Sakurai T, Yanagisawa M, Elmquist JK 1998 Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol 402:442–459[CrossRef][Medline]
  21. Stanley BG, Leibowitz SF 1984 Neuropeptide Y injected into the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc Natl Acad Sci USA 82:3940–3943
  22. Stanley BG 1993 Neuropeptide Y in multiple hypothalamic sites controls eating behavior, endocrine, and autonomic systems for energy balance. In: Colmers WF, Wahlestedt C, eds. The biology of neuropeptide Y and related peptides. Totowa: Humana Press; 457–509
  23. Clark JT, Kalra PS, Crowley WR, Kalra SP 1984 Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115:427–429[Abstract]
  24. Billington CJ, Briggs JE, Grace M, Levine AS 1991 Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism. Am J Physiol 260:R321–R327
  25. Rossi M, Kim M, Morgan D, Small C, Edwards C, Sunter D, Abusnana S, Goldstone A, Russell S, Stanley S, Smith D, Yagaloff K, Ghatei M, Bloom S 1998 A C-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of {alpha}-melanocyte stimulating hormone in vivo. Endocrinology 139:4428–4431[Abstract/Free Full Text]
  26. Hagan MM, Rushing PA, Pritchard LM, Schwartz MW, Strack AM, Van der Ploeg HT, Woods SC, Seeley RJ 2000 Long-term orexigenic effects of AgRP-(83–132) involve mechanisms other than melanocortin receptor blockade. Am J Physiol 279:R47–R52
  27. Ollmann M, Wilson B, Yang Y, Kerns J, Chen Y, Gantz I, Barsh G 1997 Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278:135–138[Abstract/Free Full Text]
  28. Hahn TM, Breininger JF, Baskin DG, Schwartz MW 1998 Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1:271–272[CrossRef][Medline]
  29. Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF, Cone RD 1999 Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24:155–163[CrossRef][Medline]
  30. Kotz CM, Grace MK, Briggs J, Levine AS, Billington CJ 1995 Effects of opioid antagonists naloxone and naltrexone on neuropeptide Y-induced feeding and brown fat thermogenesis in the rat. Neural site of action. J Clin Invest 96:163–170
  31. Hagan MM, Rushing PA, Benoit SC, Woods SC, Seeley RJ 2001 Opioid receptor involvement in the effect of AgRP-(83–132) on food intake and food selection. Am J Physiol 280:R814–R821
  32. Zhang M, Gosnell BA, Kelley AE 1998 Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus accumbens. J Pharmacol Exp Ther 285:908–914[Abstract/Free Full Text]
  33. Wang J, Akabayashi A, Dourmashkin J, Yu HJ, Alexander JT, Chae HJ, Leibowitz SF 1998 Neuropeptide Y in relation to carbohydrate intake, corticosterone and dietary obesity. Brain Res 802:75–88[CrossRef][Medline]
  34. Stanley BG, Daniel DR, Chin AS, Leibowitz SF 1985 Paraventricular nucleus injections of peptide YY and neuropeptide Y preferentially enhance carbohydrate ingestion. Peptides 6:1205–1211[CrossRef][Medline]
  35. Morley JE, Levine AS, Gosnell BA, Kneip J, Grace M 1987 Effect of neuropeptide Y on ingestive behaviors in the rat. Am J Physiol 252:R599–R609
  36. Brown CM, Coscina DV, Fletcher PJ 2000 The rewarding properties of neuropeptide Y in perifornical hypothalamus versus nucleus accumbens. Peptides 21:1279–1287[CrossRef][Medline]
  37. Chavez M, Kaiyala K, Madden LJ, Schwartz MW, Woods SC 1995 Intraventricular insulin and the level of maintained body weight in rats. Behav Neurosci 109:528–531[CrossRef][Medline]
  38. Wirth MM, Giraudo SQ 2001 Effect of agouti-related protein delivered to the dorsomedial nucleus of the hypothalamus on intake of a preferred versus a non-preferred diet. Brain Res 897:169–174[CrossRef][Medline]
  39. Rudski JM, Grace M, Kuskowski MA, Billington CJ, Levine AS 1996 Behavioral effects of naloxone on neuropeptide Y-induced feeding. Pharmacol Biochem Behav 54:771–777[CrossRef][Medline]
  40. Kotz CM, Billington CJ, Levine AS 1997 Opioids in the nucleus of the solitary tract are involved in feeding in the rat. Am J Physiol 272:R1028–R1032
  41. Levine AS, Grace M, Billington CJ 1990 The effect of centrally administered naloxone on deprivation and drug-induced feeding. Pharmacol Biochem Behav 36:409–412[CrossRef][Medline]
  42. Glass MJ, Billington CJ, Levine AS 1999 Opioids and food intake: distributed functional neuronal pathways? Neuropeptides 33:360–368[CrossRef][Medline]
  43. Silva RM, Hadjimarkou MM, Rossi GC, Pasternak GW, Bodnar RJ 2001 ß-Endorphin-induced feeding: pharmacological characterization using selective opioid antagonists and antisense probes in rats. J Pharmacol Exp Ther 297:590–596[Abstract/Free Full Text]
  44. McKay LD, Kenney NJ, Edens NK, Williams RH, Woods SC 1981 Intracerebroventricular ß-endorphin increases food intake of rats. Life Sci 29:1429–1434[CrossRef][Medline]
  45. Seeley RJ, Berthoud HR 2000 Neural control of macronutrient selection: consensus and controversy. In: Neural and metabolic control of macronutrient selection. Boca Raton, FL; CRC Press; 489–496
  46. Islam AK, Bodnar RJ 1990 Selective opioid receptor antagonist effects upon intake of a high-fat diet in rats. Brain Res 508:293–296[CrossRef][Medline]
  47. Ookuma K, Barton C, York DA, Bray GA 1997 Effect of enterostatin and {kappa}-opioids on macronutrient selection and consumption. Peptides 18:785–791[CrossRef][Medline]
  48. Glass MJ, Billington, CJ, Levine, AS 2000 Opioids, food reward, and macronutrient selection. In: Berthoud HR, Seeley RJ, eds. Neural and metabolic control of macronutrient intake. Danvers: CRC Press; vol 1:407–423
  49. Hagan MM, Benoit SC, Rushing PA, Pritchard LM, Woods SC, Seeley RJ 2001 Immediate and prolonged patterns of agouti-related peptide-(83–132)-induced c-Fos activation in hypothalamic and extrahypothalamic sites. Endocrinology 142:1050–1056[Abstract/Free Full Text]
  50. Jackman A, Reed, JA, Clegg, DJ, Woods, SC, Seeley, RJ, Interactions between melanin concentrating hormone (MCH) and c-fos after agouti-related protein (AgRP) administration. Society of the Study of Ingestive Behaviors, Philadelphia, PA, 2001, p 60 (Abstract)
  51. Zheng H, Corkern MM, Crousillac SM, Patterson LM, Phifer CB, Berthoud HR 2002 Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP. Am J Physiol Regul Integr Comp Physiol 282:R1773–R1781



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