Leptin resistance and enhancement of feeding facilitation by melanin-concentrating hormone in mice lacking bombesin receptor subtype-3.
Mice lacking either bombesin receptor subtype (BRS)-3 or gastrin-releasing peptide receptor (GRP-R) exhibit feeding abnormalities. However, it is unclear how these receptors are associated with feeding regulation. In BRS-3-deficient mice, we found hyperphagia, subsequent hyperleptinemia, and brain leptin resistance that occurred after the onset of obesity. To explore the cause of this phenomenon, we examined changes in feeding responses to appetite-related neuropeptides in BRS-3-deficient, GRP-R-deficient, and wild-type littermate mice. Among orexigenic neuropeptides, the hyperphagic response to melanin-concentrating hormone (MCH) was significantly enhanced in BRS-3-deficient mice but not in GRP-R-deficient mice. In addition, the levels of MCH-R and prepro-MCH mRNAs in the hypothalamus of BRS-3-deficient mice were significantly more elevated than those of wild-type littermates. There was no significant difference in feeding between BRS-3-deficient and wild-type littermate mice after treatment with bombesin (BN), although the hypophagic response to low-dose BN was significantly suppressed in the GRP-R-deficient mice. These results suggest that upregulation of MCH-R and MCH triggers hyperphagia in BRS-3-deficient mice. From these results, we assume that the BRS-3 gene deletion upsets the mechanism by which leptin decreases the expression of MCH-R and that this effect may be mediated through neural networks independent of BN-related peptides such as GRP-R.
Maekawa
Fumihiko
F
Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Quah
Hun-Meng A
HM
Tanaka
Kohichi
K
Ohki-Hamazaki
Hiroko
H
D000818:Animals; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D001839:Bombesin / Q000494:pharmacology; D017931:DNA Primers; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005260:Female; D007028:Hypothalamic Hormones / Q000235:genetics / Q000502:physiology*; D007035:Hypothermia; D020738:Leptin / Q000097:blood / Q000502:physiology*; D008297:Male; D008543:Melanins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010907:Pituitary Hormones / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D018004:Receptors, Bombesin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D054411:Receptors, Leptin; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D007028:Hypothalamic Hormones; D020738:Leptin; D008543:Melanins; D010907:Pituitary Hormones; D012333:RNA, Messenger; D018004:Receptors, Bombesin; D054411:Receptors, Leptin; C107120:bombesin receptor subtype 3; C515447:leptin receptor, mouse; C019463:melanin-concentrating hormone; D001839:Bombesin