Identification of Incidental Sequence Polymorphisms and Absence of the db/db Mouse and fa/fa Rat Mutations

Abstract

Leptin-receptor gene expression in hypothalamic tissue from lean and obese humans was examined. The full-length leptin receptor, that is believed to transmit the leptin signal, is expressed in human hypothalamus. There was no difference in the amount of leptin-receptor mRNA In seven lean (BMI 23.3 +/- 0.9 kg/m2) and eight obese (BMI 36.9 +/- 1.5) subjects as determined by reverse transcription-polymerase chain reaction. A sequence polymorphism (A-->G) was detected at position 668 of the leptin receptor cDNA. This second base substitution changed a glutamine to an arginine at position 223 of the leptin receptor protein. Of 15 subjects analyzed, 11 were heterozygous for this base change and 3 were homozygous. The occurrence [correction of occurance] of the polymorphic allele(s) did not correlate with BMI in the population studied. The mutation responsible for the defect in the leptin receptor in db/db mice was not detected in any obese human, nor was the fa/fa rat mutation. These results provide evidence that the leptin resistance observed in obese humans is not due to a defect in the leptin receptor.

The Leptin Receptor

“…It is possible that this resistance occurs as early in this pathway as the transport of leptin from the blood into the brain. Another more remote possibility beginning to be explored (59) is that significant numbers of humans will have a polymorphism in the OB-R gene, which results in the production of receptors with different signaling potency. More likely, perhaps, is the possibility that leptin resistance is a result of flaws within the signal-transducing pathway of the leptin receptor, more analogous to the mechanism of insulin resistance.…”

Diet-induced obese mice develop peripheral, but not central, resistance to leptin.

“…Whether administering leptin to obese humans will have similar effects is not yet known. To date, no mutations in the genes encoding leptin or the leptin receptor have been detected in humans, indicating that the majority of human obesity cannot be attributed to defects in leptin or its receptor (5,6). In fact, serum leptin levels are highly correlated with body mass index, and obese humans have been observed to have elevated levels of ob mRNA and serum leptin relative to nonobese humans (5,(7)(8)(9)(10)(11)(12)(13)(14).…”

Relationship between the Serum Level of Leptin and Life-Style Habits in Japanese Men

“…Leptin, the product of the OB gene [9], has a strong relation with food intake and regulation of body weight [10, 11, 12, 13]. Leptin also increases plasma norepinephrine, sympathetic nerve activity [14, 15], metabolic rate and energy expenditure [16, 17].…”