The signalling form of the leptin receptor is deleted in db/db mice (and disrupted in the fatty Zucker and Koletsky rat models) which are consequently unresponsive to endogenous or exogenous leptin (Tartaglia, 1997). In rodents, the phenotype is comparable to ob/ob, with earlier development of hyperglycemia on some backgrounds.
A mutation in the leptin receptor has been reported in several obese subjects from a consanguineous family of Kabilian origin (Clement et al., 1998). Affected individuals were homozygous for a mutation that truncates the receptor before the transmembrane domain and the mutated receptor circulates bound to leptin. Although this mutation does not result in a complete null phenotype, there are a number of phenotypic similarities with the leptin-deficient subjects. Leptin receptor deficient subjects were also born of normal birth weight, exhibited rapid weight gain in the first few months of life, with severe hyperphagia and aggressive behaviour when denied food. In contrast, some neuroendocrine features were unique to leptin receptor deficiency (Clement et al., 1998). The presence of mild growth retardation in early childhood with impaired basal and stimulated growth hormone secretion and decreased IGF-1 and IGF-BP3 levels and evidence of hypothalamic hypothyr-oidism in these subjects, suggest that loss of the leptin receptor might result in a more diverse phenotype than loss of its ligand, leptin.
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