Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36)

B G Challis, A P Coll, G S H Yeo, S B Pinnock, S L Dickson, R R Thresher, J Dixon, D Zahn, J J Rochford, A White, R L Oliver, G Millington, S A Aparicio, W H Colledge, A P Russ, M B Carlton, S O'Rahilly

    Research output: Contribution to journalArticle

    273 Citations (Scopus)

    Abstract

    Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis, we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model, Pomc(-/-) mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc(-/-) mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus, but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc(-/-) and Pomc(+/-) mice. The effects of leptin on food intake and body weight were blunted in obese Pomc(-/-) mice whereas nonobese Pomc(-/-) mice were sensitive to leptin. Surprisingly, we found that Pomc(-/-) mice maintained their acute anorectic response to peptide-YY(3-36) (PYY(3-36)). However, 7 days of PYY(3-36) administration had no effect on cumulative food intake or body weight in wild-type or Pomc(-/-) mice. Thus, POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding, but not for the acute anorectic effect of PYY(3-36) or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.
    Original languageEnglish
    Pages (from-to)4695-700
    Number of pages6
    JournalPNAS
    Volume101
    Issue number13
    DOIs
    Publication statusPublished - 30 Mar 2004

    Fingerprint

    Appetite Depressants
    Pro-Opiomelanocortin
    Fats
    Leptin
    Obese Mice
    Body Weight
    Obesity
    Eating
    Lateral Hypothalamic Area
    Gene-Environment Interaction
    Hyperphagia
    Messenger RNA
    Arcuate Nucleus of Hypothalamus
    Peptides
    peptide YY (3-36)
    Neuropeptide Y
    Energy Intake
    Thyroxine
    Oxygen Consumption
    Genes

    Keywords

    • Animals
    • Appetite Depressants
    • Base Sequence
    • Body Weight
    • DNA Primers
    • Dietary Fats
    • Energy Intake
    • Hypothalamic Hormones
    • Hypothalamus
    • Kinetics
    • Leptin
    • Melanins
    • Mice
    • Mice, Knockout
    • Mutagenesis, Site-Directed
    • Neuropeptide Y
    • Obesity
    • Peptide YY
    • Phenotype
    • Pituitary Hormones
    • Polymerase Chain Reaction
    • Pro-Opiomelanocortin
    • Transcription, Genetic

    Cite this

    Challis, B. G., Coll, A. P., Yeo, G. S. H., Pinnock, S. B., Dickson, S. L., Thresher, R. R., ... O'Rahilly, S. (2004). Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36). PNAS, 101(13), 4695-700. https://doi.org/10.1073/pnas.0306931101

    Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36). / Challis, B G; Coll, A P; Yeo, G S H; Pinnock, S B; Dickson, S L; Thresher, R R; Dixon, J; Zahn, D; Rochford, J J; White, A; Oliver, R L; Millington, G; Aparicio, S A; Colledge, W H; Russ, A P; Carlton, M B; O'Rahilly, S.

    In: PNAS, Vol. 101, No. 13, 30.03.2004, p. 4695-700.

    Research output: Contribution to journalArticle

    Challis, BG, Coll, AP, Yeo, GSH, Pinnock, SB, Dickson, SL, Thresher, RR, Dixon, J, Zahn, D, Rochford, JJ, White, A, Oliver, RL, Millington, G, Aparicio, SA, Colledge, WH, Russ, AP, Carlton, MB & O'Rahilly, S 2004, 'Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36)', PNAS, vol. 101, no. 13, pp. 4695-700. https://doi.org/10.1073/pnas.0306931101
    Challis, B G ; Coll, A P ; Yeo, G S H ; Pinnock, S B ; Dickson, S L ; Thresher, R R ; Dixon, J ; Zahn, D ; Rochford, J J ; White, A ; Oliver, R L ; Millington, G ; Aparicio, S A ; Colledge, W H ; Russ, A P ; Carlton, M B ; O'Rahilly, S. / Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36). In: PNAS. 2004 ; Vol. 101, No. 13. pp. 4695-700.
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    AU - Challis, B G

    AU - Coll, A P

    AU - Yeo, G S H

    AU - Pinnock, S B

    AU - Dickson, S L

    AU - Thresher, R R

    AU - Dixon, J

    AU - Zahn, D

    AU - Rochford, J J

    AU - White, A

    AU - Oliver, R L

    AU - Millington, G

    AU - Aparicio, S A

    AU - Colledge, W H

    AU - Russ, A P

    AU - Carlton, M B

    AU - O'Rahilly, S

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    N2 - Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis, we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model, Pomc(-/-) mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc(-/-) mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus, but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc(-/-) and Pomc(+/-) mice. The effects of leptin on food intake and body weight were blunted in obese Pomc(-/-) mice whereas nonobese Pomc(-/-) mice were sensitive to leptin. Surprisingly, we found that Pomc(-/-) mice maintained their acute anorectic response to peptide-YY(3-36) (PYY(3-36)). However, 7 days of PYY(3-36) administration had no effect on cumulative food intake or body weight in wild-type or Pomc(-/-) mice. Thus, POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding, but not for the acute anorectic effect of PYY(3-36) or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.

    AB - Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis, we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model, Pomc(-/-) mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc(-/-) mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus, but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc(-/-) and Pomc(+/-) mice. The effects of leptin on food intake and body weight were blunted in obese Pomc(-/-) mice whereas nonobese Pomc(-/-) mice were sensitive to leptin. Surprisingly, we found that Pomc(-/-) mice maintained their acute anorectic response to peptide-YY(3-36) (PYY(3-36)). However, 7 days of PYY(3-36) administration had no effect on cumulative food intake or body weight in wild-type or Pomc(-/-) mice. Thus, POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding, but not for the acute anorectic effect of PYY(3-36) or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.

    KW - Animals

    KW - Appetite Depressants

    KW - Base Sequence

    KW - Body Weight

    KW - DNA Primers

    KW - Dietary Fats

    KW - Energy Intake

    KW - Hypothalamic Hormones

    KW - Hypothalamus

    KW - Kinetics

    KW - Leptin

    KW - Melanins

    KW - Mice

    KW - Mice, Knockout

    KW - Mutagenesis, Site-Directed

    KW - Neuropeptide Y

    KW - Obesity

    KW - Peptide YY

    KW - Phenotype

    KW - Pituitary Hormones

    KW - Polymerase Chain Reaction

    KW - Pro-Opiomelanocortin

    KW - Transcription, Genetic

    U2 - 10.1073/pnas.0306931101

    DO - 10.1073/pnas.0306931101

    M3 - Article

    VL - 101

    SP - 4695

    EP - 4700

    JO - PNAS

    JF - PNAS

    SN - 0027-8424

    IS - 13

    ER -