β-Endorphin Is Associated with Overeating in Genetically Obese Mice (
 ob
 /
 ob
 ) and Rats (
 fa
 /
 fa
 )

Margules, David L.; Moisset, Beatriz; Lewis, Michael J.; Shibuya, Haruo; Pert, Candace B.

doi:10.1126/science.715455

Cited by 468 publications

(83 citation statements)

References 15 publications

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“…Pituitary f-endorphin is also elevated in ob/ob mice and obese (Zucker) rats (6). Furthermore, hypothalamic injections of f-endorphin result in overeating by nonobese rats (7,8), whereas injections of naloxone, an opiate antagonist, result in decreased food intake in rats (9) and mice (6,10).…”

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“…The latter effect has been found to be more pronounced for ob/ob mice than for ob/? heterozygous controls (6). These data have led to recent speculation that the obesity of ob/ob mice is caused by abnormal opioid metabolism and that f3-endorphin may play a role in the regulation of food intake through interactions with central, gastrointestinal, or pancreatic opiate receptors (6).…”

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confidence: 99%

“…Furthermore, hypothalamic injections of f-endorphin result in overeating by nonobese rats (7,8), whereas injections of naloxone, an opiate antagonist, result in decreased food intake in rats (9) and mice (6,10). The latter effect has been found to be more pronounced for ob/ob mice than for ob/?…”

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Opioid peptides and alpha-melanocyte-stimulating hormone in genetically obese (ob/ob) mice during development.

Rossier¹,

Rogers²,

Shibasaki³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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Compared to littermate controls (C57BL/6J ob! ?), body weights of genetically obese (ob/ob) mice are sig- The genetically obese (ob/ob) mouse was discovered in 1950 at the Jackson Laboratory (1). Since then the obesity gene, a recessive single mutation located on chromosome 6, has been extensively studied in the congenic inbred strain C57BL/6J (2, 3). The mutation produces hyperphagia, obesity, increased lipogenesis, decreased lipolysis, hypogonadism, hyperinsulinemia, and other alterations of the endocrine pancreas (2, 4, 5). Pituitary f-endorphin is also elevated in ob/ob mice and obese (Zucker) rats (6). Furthermore, hypothalamic injections of f-endorphin result in overeating by nonobese rats (7,8), whereas injections of naloxone, an opiate antagonist, result in decreased food intake in rats (9) and mice (6, 10). The latter effect has been found to be more pronounced for ob/ob mice than for ob/? heterozygous controls (6). These data have led to recent speculation that the obesity of ob/ob mice is caused by abnormal opioid metabolism and that f3-endorphin may play a role in the regulation of food intake through interactions with central, gastrointestinal, or pancreatic opiate receptors (6).In order to evaluate this hypothesis, we have examined hypothalamic and hypophyseal levels of immunoreactive (IR) f-endorphin, a-melanocyte-stimulating hormone (MSH), and Leu5-enkephalin in ob/ob mice and ob/? littermates at 1-6 months of age. A physiological or pharmacological anomaly causing obesity would be expected to occur before or, at the least, simultaneously with the onset of obesity. Previous studies (6) have pooled data from several age groups making such a cause-effect relationship difficult to determine. MATERIALS AND METHODSThe experiment employed a two-way factorial design. The first factor, genotype, had two levels representing mice which were either homozygous (ob/ob) or heterozygous (ob/?) for the obesity gene. The second factor, age, had five levels representing subjects born 1, 2, 3, 4, or 6 months prior to the experiment. A number of variables were examined, including body weight, hypothalamus weight, and levels of IR f-endorphin, IR a-MSH, and IR Leu5-enkephalin. A second experiment compared body, brain, and pituitary weights of 7-month-old ob/ob and ob/? mice.One-month-old C57BL/6J ob/ob mice and littermate ob/? controls were obtained from Jackson Laboratory and housed here until they were killed. Both groups were fed and watered ad lib throughout. Mice were killed by cervical dislocation and subsequent decapitation. Brains were rapidly removed and hypothalami were dissected out according to the procedure of Glowinski and Iversen (11). Tissue was kept frozen on dry ice. Under a dissecting lens, the pars nervosa and the pars distalis were teased apart and removed. The former was surrounded by most of the lobules of the pars intermedia and is referred to hereafter as the posterior lobe; anterior lobe designates the pars distalis (including any remaining pars intermedia fragments). For extracti...

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Opioid peptides and alpha-melanocyte-stimulating hormone in genetically obese (ob/ob) mice during development.

Rossier¹,

Rogers²,

Shibasaki³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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“…How ingestion of palatable food is regulated is of great interest to those studying ingestive behavior as well as those studying basic mechanisms of motivation and reward. One of the first neurochemical systems implicated in the hedonics of feeding and obesity was the endogenous opioid system (Belluzzi and Stein, 1977;Mandenoff, et al, 1982;Margules, et al, 1978). In general, opioid antagonists are anorexigenic while opioid agonists are orexigenic [reviewed in (Bodnar, 2004;Glass, et al, 1999)].…”

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Differential involvement of endogenous opioids in sucrose consumption and food reinforcement

Hayward

Schaich-Borg

Pintar

et al. 2006

Pharmacology Biochemistry and Behavior

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Endogenous opioids within the central nervous system are postulated to mediate hedonic aspects of feeding behavior. To identify the relevant endogenous opioid receptor ligands, mice lacking one or two of the opioid peptide families β-endorphin, enkephalins or dynorphins were tested for sucrose preference in a two-bottle free-choice drinking paradigm under drug-naïve conditions and following treatment with an opioid antagonist (1 mg/kg naloxone i.p.) or saline. Basal sucrose consumption was unaltered in all of the knockout genotypes compared to their congenic wild-type C57BL/6 littermates during 0.5 and 6 h access to a bottle containing 2, 4, 8, or 16% sucrose and a second bottle containing water. Moreover, all mutant genotypes and wildtype mice exhibited a similar compensatory decrease in overnight food intake following the extra caloric load from 6 h sucrose access. Although these basal responses to sucrose were unaffected by the knockout genotypes, naloxone reduced sucrose consumption by 50% compared to saline treatment during the first 0.5 h in wild-type and β-endorphin knockout mice, but had no effect in enkephalin knockouts, β-endorphin and enkephalin double knockouts, or dynorphin knockouts. These data suggest that naloxone reduces sucrose consumption in wild-type mice by blocking endogenous enkephalin and/or dynorphin signaling, but not β-endorphin. Dynorphin knockouts in the current study had bar-pressing responses for a palatable food reinforcer in an operant procedure under free-feeding conditions similar to wildtype mice while we found in a previous study that β-endorphin and enkephalin knockout mice had reduced motivation to respond (Hayward, et al., 2002). We conclude from these studies directly comparing three strains of opioid peptide knockout mice that enkephalin and dynorphin can modulate sucrose preference but are not necessary to support sucrose consumption. However, dynorphin was not necessary to support wildtype levels of operant responding suggesting that only enkephalin and β-endorphin modulate conditioned food reinforcement. KeywordsOperant behavior; β-endorphin; enkephalin; dynorphin; knockout mice; ingestive behavior * Corresponding author phone: 609-235-1430 fax: 609-235-1498 e-mail: Michael.Hayward@Xenogen.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe plentiful access to calorically dense and highly palatable food choices is a likely contributor to the current obesity epidemic. How ingestion of palatable food is regulated is of great i...

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“…To date, the direct effects of endogenous opioids on myocardial contractility have not been investigated. Thus, the purpose of the present study was to determine if enkephalins ([Met] (Margules et al, 1978), have been shown to have a reduced inotropic response to secretin and (± )-isoprenaline, compared to lean controls (Chatelain et al, 1981;Robberecht et al, 1983).…”

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No inotropic action of enkephalins or enkephalin derivatives on electrically‐stimulated atria isolated from lean and obese rats

Saunders¹,

Thornhill²

1985

British J Pharmacology

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3 NA and isoprenaline (l0-7 to 10-6M) caused significant, dose-related increases in atrial tension in each of the three strains of rats tested with the Fa/fa group showing the greatest change and fastest rate of tension development.[Met] enkephalin, [Leu] enkephalin, DAMEA or DALEA (4 x 10-6M) infused concurrently with NA or isoprenaline (10-6M) evoked atrial tension changes within each group that were not different from those observed when NA or isoprenaline was administered alone. 4 Carbachol (l0-9 and 10-8M) caused a dose-related decrease (10% and 30-40%, respectively, from pre-injection control values) in atrial tension in auricles excised from all three groups. Again, infusion of [Met] enkephalin, [Leu] enkephalin, DAMEA or DALEA (4 x 10-6M) together with carbachol (10-8M) did not affect atrial tension changes of auricles isolated from any group compared to when carbachol was given alone. 5 The results indicate that the endogenous pentapeptides, ([Met] or [Leu] enkephalin), or derivatives (DAMEA and DALEA) do not affect atrial tension of electrically-stimulated auricles isolated from Sprague-Dawley, fa/fa or Fa/fa rats. In addition, these pentapeptides do not modify the positive inotropic actions of NA or isoprenaline or the negative inotropic effects of carbachol. It is suggested that in vivo, the enkephalins or enkephalin derivatives do not have a direct action on the heart to alter myocardial contractility.

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β-Endorphin Is Associated with Overeating in Genetically Obese Mice ( ob / ob ) and Rats ( fa / fa )

Cited by 468 publications

References 15 publications

Opioid peptides and alpha-melanocyte-stimulating hormone in genetically obese (ob/ob) mice during development.

Opioid peptides and alpha-melanocyte-stimulating hormone in genetically obese (ob/ob) mice during development.

Differential involvement of endogenous opioids in sucrose consumption and food reinforcement

No inotropic action of enkephalins or enkephalin derivatives on electrically‐stimulated atria isolated from lean and obese rats

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