Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice

Abstract

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.

Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice

“…It is somewhat surprising that IGF-1 levels were increased in this study because caloric restriction is known to suppress IGF-1 levels. However, Luque and colleagues (36) found that peripheral administration of leptin to ob/ob mice prevented the reduction of IGF-1 levels that occurred in pair-fed controls, and Chan and colleagues (37) found that r-metHuleptin administration to women under chronic energydeficit conditions increased IGF-1 levels. Thus leptin administration may act independent of energy intake to increase IGF-1 levels under certain conditions, for example, when endogenous leptin levels are chronically reduced.…”

Pituitary Leptin-A Paracrine Regulator of Gonadotropes: A Review

“…78], and GH and GHRH receptor expression in leptindeficient ob/ob mice [80]. Leptin increased LH levels in ovariectomized, estrogen-primed rats [72,73].…”

“…Luque et al [80] reported that leptin restored GH secretion in ob/ob mice that were infused with exogenous leptin for 7 days. In addition, leptin caused an increase in GHRH receptors.…”

“…Interestingly, no changes were noted in hypothalamic GHRH levels themselves, which suggested that GHRH did not mediate the restoration. In addition, several in vitro studies showed that leptin directly stimulated LH secretion [70][71][72][73][74] and may stimulate or inhibit GH [23,68,76,77,79,80,88,114,[179][180][181][182][183][184], depending on experimental conditions. In light of these findings, we hypothesized that, if it was a paracrine regulator, pituitary leptin might itself be regulated by the nutrient status.…”

“…Leptin stimulates GH secretion mediated by GH releasing peptide (GHRP [77,79] and restores GH pulses in fasted rats [76,78]. Luque et al [80] reported that leptin restored GH secretion in ob/ob mice that were infused with exogenous leptin for 7 days. In addition, leptin caused an increase in Growth hormone releasing hormone (GHRH) receptors.…”