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Published on: September 7, 2013
Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides
D J Marsh1, G Hollopeter, D Huszar
1Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle 98195, USA.
Abstract:
Mutations reducing the functional activity of leptin, the leptin receptor, alpha-melanocyte stimulating hormones (alpha-MSH) and the melanocortin-4 receptor (Mc4r) all lead to obesity in mammals. Moreover, mutant mice that ectopically express either agouti (Ay/a mice) or agouti-related protein (Agrp), antagonists of melanocortin signalling, become obese. These data suggest that alpha-MSH signalling transduced by Mc4r tonically inhibits feeding; however, it is not known to what extent this pathway mediates leptin signalling. We show here that Mc4r-deficient (Mc4r-/-) mice do not respond to the anorectic actions of MTII, an MSH-like agonist, suggesting that alpha-MSH inhibits feeding primarily by activating Mc4r. Obese Mc4r-/-mice do not respond significantly to the inhibitory effects of leptin on feeding, whereas non-obese Mc4r-/- mice do. These data demonstrate that melanocortin signalling transduced by Mc4r is not an exclusive target of leptin action and that factors resulting from obesity contribute to leptin resistance. Leptin resistance of obese Mc4r-/- mice does not prevent their response to the anorectic actions of ciliary neurotrophic factor (CNTF), corticotropin releasing factor (CRF), or urocortin; or the orexigenic actions of neuropeptide Y (NPY) or peptide YY (PYY), indicating that these neuromodulators act independently or downstream of Mc4r signalling.
Insights
Leptin resistance in obese mice is linked to melanocortin-4 receptor (Mc4r) signaling. Mc4r-deficient mice show obesity and altered responses to leptin, indicating Mc4r
Area of Science:
- Neuroendocrinology
- Obesity Research
- Molecular Biology
Background:
- Mutations in leptin, leptin receptor, alpha-melanocyte stimulating hormone (alpha-MSH), and melanocortin-4 receptor (Mc4r) are linked to obesity.
- Agouti and agouti-related protein (Agrp) antagonists of melanocortin signaling cause obesity in mice.
- The role of Mc4r signaling in mediating leptin's effects on feeding is not fully understood.
Purpose of the Study:
- To investigate the extent to which melanocortin signaling, mediated by Mc4r, is involved in leptin's anorectic effects.
- To determine if Mc4r signaling is essential for leptin's action.
- To explore the mechanisms underlying leptin resistance in the context of Mc4r deficiency.
Main Methods:
- Utilized Mc4r-deficient (Mc4r-/-) mice to assess responses to anorectic agents.
- Administered MTII, an MSH-like agonist, to Mc4r-/- mice to evaluate Mc4r dependency.
- Compared leptin's effects on feeding in obese versus non-obese Mc4r-/- mice.
- Tested responses to other neuromodulators like CNTF, CRF, urocortin, NPY, and PYY in Mc4r-/- mice.
Main Results:
- Mc4r-/- mice did not respond to MTII, confirming alpha-MSH primarily acts via Mc4r to inhibit feeding.
- Obese Mc4r-/- mice exhibited leptin resistance, while non-obese Mc4r-/- mice responded to leptin.
- Leptin resistance in obese Mc4r-/- mice did not affect responses to CNTF, CRF, urocortin, NPY, or PYY.
Conclusions:
- Melanocortin signaling through Mc4r is crucial for leptin's anorectic effects but is not the sole mediator.
- Obesity itself contributes to leptin resistance, independent of Mc4r signaling status.
- Other feeding regulatory pathways involving CNTF, CRF, urocortin, NPY, and PYY operate independently or downstream of Mc4r.
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