Leptin and the Neural Circuit Regulating Body Weight

Abstract

Leptin, the hormone encoded by the ob gene, plays an important role in regulating the size of the adipose tissue mass. Injections of recombinant leptin reduce body weight and food intake of normal and obese (ob) mice in a dose dependent manner but have no effect on diabetic (db) mice, another recessive obesity gene. These data identify leptin as an important signaling molecule that acts to maintain constant stores of body fat. The complete insensitivity of db mice to leptin and the identical phenotype of ob and db mice suggested that the db locus encodes the leptin receptor. The db gene was found to be identical to a leptin receptor (Ob-R) that was functionally cloned from choroid plexus. However, because this receptor was normal in C57BL/Ks db/db mice, the possibility was raised that this db mutation affected an alternatively spliced form. The Ob-R gene was found to encode at least five different splice variants. One of the splice variants is expressed at a high level in the hypothalamus and at a lower level in other tissues. This transcript is mutant in C57BLlKs db/db mice. The mutant protein is missing the cytoplasmic region and is defective in signal transduction. Further studies have revealed that the STAT3 transcription factor is activated specifically in hypothalamus within 15 minutes of a single injection of leptin in ob and wild type mice but not in db mice. In vitro studies indicate that SHP-2, a phosphoprotein phosphatase, is also a component of the leptin signal transduction pathway.