Soluble leptin receptor in serum of subjects with complete resistance to leptin - Relation to fat mass

Leptin resistance and obesity have been related to mutations of the leptin receptor gene in rodents and, recently, in a consanguineous family. The lat ter mutation results in a receptor lacking transmembrane and intracellular domains. Homozygous and heterozygous individuals with this mutation had ser um leptin levels higher than expected, given their BMIs: 600, 670, and 526 ng/ml and 145, 362, 294, 240, and 212 ng/ml, respectively. Their serum lept in was fractionated by gel filtration: >80% was present as a high-molecular size complex vs. 7.5% in the nonmutated sister. Western blot analysis show ed a band at 146 kDa reacting specifically with an antibody directed agains t the leptin receptor ectodomain. In 10 obese control subjects, as in the m utated patients, free leptin levels correlated with BMI (r = 0.70, P = 0.00 11) and reflected fat mass, regardless of leptin receptor functioning. In t he patients, bound leptin levels correlated with BMI (r = 0.99, P = 0.0002) and were related to the number of mutated alleles. These data demonstrate that the truncated receptor is secreted into blood and binds the majority o f serum leptin, markedly increasing bound and total leptin. Free serum lept in was similarly correlated with BMI in the mutated and nonmutated obese in dividuals, providing evidence that the relationship between BMI and circula ting free leptin is preserved in this family. This finding suggests that th e leptin receptor itself may not be specifically involved in the control of leptin secretion, and it supports the concept of relative resistance to le ptin in common obesity.