Clinical and in vitro data suggest a link between the elevation of the melanocortin peptide, ACTH, and longitudinal growth. Overproduction of ACTH in familial glucocorticoid deficiency (FGD) is associated with increased growth and ACTH increases the differentiation of chondrocytes along the endochondral pathway in vitro. Using the leptin-deficient obese (ob/ob) mouse along with lean control littermates (n = 9–10), we investigated the effects of adrenalectomy (ADX)-induced elevated ACTH with and without peripheral administration of the MC3-R-specific agonist, γ2-melanocyte stimulating hormone (γ2-MSH), on longitudinal growth. Naso-anal and tibial growth were measured together with growth plate parameters; both total and zonal heights together with the proliferative index. Data were analyzed using two-way ANOVA with post hoc comparisons made using the Bonferroni correction. ADX significantly increased naso-anal length in lean mice and ADX plus γ2-MSH administration significantly increased naso-anal length above ADX alone in ob/ob mice. γ2-MSH administration to ADX lean and ob/ob mice significantly increased tibial length. In ob/ob mice, these changes occurred in the context of reduced food intake. Analysis of total and zonal growth plate heights suggest an increase in hypertrophic differentiation and an overall increase in growth plate turnover in ADX lean and ob/ob mice. These in vivo data show that ADX enhances linear growth and the results of γ2-MSH treatment suggest that the melanocortin system plays a role in linear growth.
James K Yeh, Jodi F Evans, Qing-Tian Niu and John F Aloia
Jodi F Evans, Shahidul Islam, Yoshihiro Urade, Naomi Eguchi and Louis Ragolia
Obesity and diabetes are closely associated with hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis. In this study, the diet-induced obese C57BL/6 mouse was used to test the hypothesis that chronically elevated metabolic parameters associated with the development of obesity such as cholesterol and glucose can aggravate basal HPA axis activity. Because the lipocalin-type prostaglandin D2 synthase (L-PGDS) knockout (KO) mouse is a model of accelerated insulin resistance, glucose intolerance, and obesity, it was further hypothesized that HPA activity would be greater in this model. Starting at 8 weeks of age, the L-PGDS KO and C57BL/6 mice were maintained on a low-fat or high-fat diet. After 20 or 37 weeks, fasting metabolic parameters and basal HPA axis hormones were measured and compared between genotypes. Correlation analyses were performed to identify associations between obesity-related chronic metabolic changes and changes in the basal activity of the HPA axis. Our results have identified strong positive correlations between total cholesterol, LDL-cholesterol, glucose, and HPA axis hormones that increase with age in the C57BL/6 mice. These data confirm that obesity-related elevations in cholesterol and glucose can heighten basal HPA activity. Additionally, the L-PGDS KO mice show early elevations in HPA activity with no age-related changes relative to the C57BL/6 mice.