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Adipose tissue, where fatty acids are stored as triglycerides in lipid droplets, is central to the regulation of energy balance [205]. White adipose tissue constitutes separate depots that contribute with the hypothalamus as the key centre for integration and control of energy balance [200]. Leptin, best known as a satiety hormone, a signal of energy sufficiency and long-term adiposity, is one of several cytokine-like hormones secreted by adipocytes [1, 2, 200]. In girls there are gradual age- and BMI-related increases in circulating leptin levels [206]. Molna-Carballo et al [12] from a longitudinal study reported that the leptin concentration increases in both sexes with the progression of puberty, this value being 40% greater in girls, which correlates with the increase in body volume and fat accumulation [206, 207]. Girls have higher serum leptin levels before, during, and after puberty than boys, even after accounting for the development of greater female adiposity [207]. The sexual dimorphism in leptin concentrations during puberty appears to be partly due to a stimulatory effect of estradiol on fat deposition and leptin concentration in females and a suppressive effect of testosterone on leptin concentration in males [207]. Leptin levels in men are lower than women at all decades of life [208].

Montague et al [229] reported two severely obese consanguinous children with congenital leptin deficiency, the findings of which strongly suggested that leptin critically influences energy balance in prepubertal humans. One child developed abnormalities of growth in long bones of her legs treated by corrective surgery, an abnormality attributed to growth plate fragility [180]. Subsequently, in three children who were congenitally deficient in leptin and morbidly obese, Farooqi et al [230] reported radiological skeletal maturation was increased by 2.1 years, and that leptin therapy produced beneficial effects on the skeleton.

b) Protein-tyrosine phosphatases (PTPs). PTP-1B also contributes to leptin resistance by inhibiting intracellular leptin receptor signaling by inhibiting JAK2 activation [232, 240, 252]. PTP-1B deficient mice by knockout and by an antisense (anti-DNA) oligonucleotide designed to blunt the expression of PTP-1B, showed improved leptin and insulin action [252]. PTP-1B is a major regulator of energy balance, insulin sensitivity, and body fat stores [246]. PTP-1B is also a human gene.

(5) Intracelluar stimulatory molecules (positive regulators) of leptin signaling. According to Morris and Rui [232], SH2B1 enhances leptin signaling. It appears to be required for the maintenance of leptin sensitivity, energy balance and body weight, ultimately through activation of the PI 3 kinase pathway. The ability of SH2B1 to enhance leptin sensitivity may be modulated by other members of the SH2B family. Cellular leptin sensitivity may be determined, at least in part, by a balance between positive (e.g. SH2B1) and negative (e.g. SOCS3 and PTP-1B) regulators.

Item (2) may exaggerate the putative sympathetic nervous system-induced vertebral asymmetry particularly in prepubertal and early pubertal growth and thereby contribute to curve progression (Figure 5). Hormonal involvement in AIS progression is supported by the finding that the initiation of the curve acceleration phase correlates with the timing of peak height velocity and simultaneously with digital changes in bone aging (400-425 of the Tanner-Whitehouse RUS III method, stage F covered phalangeal epiphysis to G capped phalangeal epiphysis [5]). 1e1e36bf2d