Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice.
Leptin-deficient obese mice (ob/ob) have decreased circulating growth hormone (GH) and pituitary GH and ghrelin receptor (GHS-R) mRNA levels, whereas hypothalamic GH-releasing hormone (GHRH) and somatostatin (SST) expression do not differ from lean controls. Given the fact that GH is suppressed in diet-induced obesity (a state of hyperleptinemia), it remains to be determined whether the absence of leptin contributes to changes in the GH axis of ob/ob mice. Therefore, to study the impact of leptin replacement on the hypothalamic-pituitary GH axis of ob/ob mice, leptin was infused for 7 days (sc), resulting in circulating leptin levels that were similar to wild-type controls (approximately 1 ng/ml). Leptin treatment reduced food intake, body weight, and circulating insulin while elevating circulating n-octanoyl ghrelin concentrations. Leptin treatment did not alter hypothalamic GHRH, SST, or GHS-R mRNA levels compared with vehicle-treated controls. However, leptin significantly increased pituitary GH and GHRH-R expression and tended to enhance circulating GH levels, but this latter effect did not reach statistical significance. In vitro, leptin (1 ng/ml, 24 h) did not affect pituitary GH, GHRH-R, or GHS-R mRNA but did enhance GH release. The in vivo effects of leptin on circulating hormone and pituitary mRNA levels were not replicated by pair feeding ob/ob mice to match the food intake of leptin-treated mice. However, leptin did prevent the fall in hypothalamic GHRH mRNA and circulating IGF-I levels observed in pair-fed mice. These results demonstrate that leptin replacement has positive effects on multiple levels of GH axis function in ob/ob mice.
Luque
Raul M
RM
Department of Medicine, University of Illinois at Chicago, and Jesse Brown VA Medical Center, Research and Development Division, M. P. 151, West Side, Suite no. 6215, 820 South Damen Ave., Chicago, IL 60612, USA.
Huang
Zhi H
ZH
Shah
Bhumik
B
Mazzone
Theodore
T
Kineman
Rhonda D
RD
D000818:Animals; D002478:Cells, Cultured; D054439:Ghrelin; D013006:Growth Hormone / Q000378:metabolism / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D036361:Peptide Hormones / Q000032:analysis / Q000097:blood*; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D054440:Receptors, Ghrelin; D054411:Receptors, Leptin; D018013:Receptors, Neuropeptide / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000378:metabolism; D013270:Stomach / Q000737:chemistry
D054439:Ghrelin; D020738:Leptin; D036361:Peptide Hormones; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D054411:Receptors, Leptin; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; C515447:leptin receptor, mouse; D013006:Growth Hormone; C048250:somatotropin releasing hormone receptor