Defective STAT signaling by the leptin receptor in diabetic mice

Leptin and its receptor, obese receptor (OB-R), comprise an important signaling system for the regulation of body weight, Splice variants of OB-R mRNA encode proteins that differ in the length of their cytoplasmic domains, We cloned a long isoform of the wild-type leptin receptor that is preferentially expressed in the hypothalamus and show that it can activate signal transducers and activators of transcription (STAT)-3, STAT-5, and STAT-6. A point mutation within the OB-R gene of diabetic (db) mice generates a new splice donor site that dramatically reduces expression of this long isoform in homozygous db/db mice. In contrast, an OB-R protein with a shorter cytoplasmic domain is present in both db/db and wild-type mice, We show that this short isoform is unable to activate the STAT pathway, These data provide further evidence that the mutation in OB-R causes the db/db phenotype and identify three STAT proteins as potential mediators of the anti-obesity effects of leptin.