Increased hypothalamic melanin concentrating hormone gene expression during energy restriction involves a melanocortin-independent, estrogen-sensitive mechanism.
Increased expression of melanin concentrating hormone (MCH), an orexigenic neuropeptide produced by neurons in the lateral hypothalamic area (LHA), is implicated in the effect of energy restriction to increase food intake. Since melanocortins inhibit Mch gene expression, this effect of energy restriction to increase Mch signaling may involve reduced hypothalamic melanocortin signaling. Consistent with this hypothesis, we detected increased hypothalamic Mch mRNA levels in agouti (Ay) mice (by 102%; P < 0.05), a model of genetic obesity resulting from impaired melanocortin signaling, compared to wild-type controls. If reduced melanocortin signaling mediates the effect of energy restriction, hypothalamic Mch gene expression in Ay mice should not be increased further by energy restriction, since melanocortin signaling is impaired in these animals regardless of nutritional state. We therefore investigated the effects of energy restriction on hypothalamic Mch gene expression in both Ay mice and in wild-type mice with diet-induced obesity (DIO). Responses in these mice were compared to those induced by administration of 17beta-estradiol (E2) at a dose previously shown to reduce food intake and Mch expression in rats. In both Ay and DIO mice, energy restriction increased hypothalamic Mch mRNA levels (P < 0.05 for each) via a mechanism that was fully blocked by E2. However, E2 did not lower levels of Mch mRNA below basal values in Ay mice, whereas it did so in DIO mice. Thus, the effect of energy restriction to increase hypothalamic Mch gene expression involves an E2-sensitive mechanism that is not altered by impaired melanocortin signaling. By comparison, impaired melanocortin signaling increases hypothalamic Mch gene expression via a mechanism that is insensitive to E2. These findings suggest that while both energy restriction and reduced melanocortin signaling stimulate hypothalamic Mch gene expression, they do so via distinct mechanisms.
Morton
Gregory J
GJ
Department of Medicine, Harborview Medical Center, University of Washington, 325 Ninth Avenue, Box 359757, Seattle, WA 98104, USA.
Mystkowski
Paul
P
Matsumoto
Alvin M
AM
Schwartz
Michael W
MW
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage*; D004967:Estrogens / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects; D007026:Hypothalamic Area, Lateral / Q000378:metabolism*; D007028:Hypothalamic Hormones / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008543:Melanins / Q000096:biosynthesis* / Q000235:genetics; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010907:Pituitary Hormones / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects
D004967:Estrogens; D007028:Hypothalamic Hormones; D008543:Melanins; D010907:Pituitary Hormones; D012333:RNA, Messenger; D004958:Estradiol; C019463:melanin-concentrating hormone; D009074:Melanocyte-Stimulating Hormones