Leptin Reverses the Inhibitory Effect of Caloric Restriction on Longitudinal Growth

Abstract

Caloric imbalance, particularly in critical periods of growth and development, is often the underlying cause of growth abnormalities. Serum levels of leptin are elevated in obesity and are low in malnutrition and malabsorption. The aim of the present study was to determine whether leptin integrates energy levels and growth in vivo, as shown previously in our ex vivo experiments, even in the presence of caloric restriction. In the first part of the study, mice were divided into three groups. Two groups were fed ad libitum and received leptin or vehicle only, and the third group was pair-fed with the group injected with leptin to dissociate leptin's effect on growth from its effect on food consumption. Mice given leptin had a significantly greater tibial length than untreated pair-fed animals and a similar tibial length as control mice fed ad libitum despite their lower weight. In addition, leptin significantly increased the overall size of the epiphyseal growth plate by 11%. On immunohistochemistry and in situ hybridization studies, leptin stimulated both the proliferation and differentiation of tibial growth plate chondrocytes without affecting the overall organization of the plate. There was also a marked increase in the expression and level of IGF-IR. In the second part of the study, two groups of mice were fed only 60% of their normal chow; one was injected with leptin, and the other was injected with vehicle alone. Caloric deprivation by itself reduced serum levels of IGF-I by 70% and the length of the tibia by 5%. Leptin treatment corrected the fasting-induced growth deficiency, but further reduced the level of serum IGF-I. These results indicate that leptin stimulates growth even in the presence of caloric restriction independently of peripheral IGF-I.

Leptin ( ob gene) of the South African clawed frog Xenopus laevis

“…Also, leptin injections enhanced limb bone mass and density in juvenile leptin-deficient ob͞ob mice (33), although others found that leptin had negative effects on bone growth that are mediated by the hypothalamus (34). Gat-Yablonski and colleagues (35) showed that leptin treatment restored starvation-induced decreases in limb bone mass in juvenile mice, which is consistent with our finding that leptin injections restored hind-limb growth and development in food-deprived tadpoles. Taken together, these findings highlight the potential for adipocyteindependent functions of leptin in early development.…”

In vivo leptin expression in cartilage and bone cells of growing rats and adult humans

“…Note that chondrocytes have also been found to express leptin receptor (Steppan et al 2000;Figenschau et al 2001;Cornish et al 2002;Kume et al 2002;Gat-Yablonski et al 2004). Because leptin has been observed to be present in synovial fluid and in chondrocytes of articular cartilage of patients affected by osteoarthritis as well as in osteophytes, it has been postulated that leptin might exert a modulatory effect on chondrocyte metabolism and consequently on the pathogenesis of osteoarthritis (Dumond et al 2003).…”

Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice

“…The direct action of leptin on bone and cartilage cells has been amply demonstrated in cell culture [20,36,39,48]. The systemic administration of leptin, via intraperitoneal or subcutaneous injection, has also been shown to increase total body bone mass and bone length in ob/ob mice and increase bone length in calorie-deprived mice, suggesting that bone growth is regulated by the circulating levels of leptin [30,32,44]. Increasing systemic leptin within the physiological range has consistently been shown to increase hypothalamic leptin levels, but the effects of central infusion on circulating leptin levels are less consistent [7,26,29,38,43,46,54].…”