Defective STAT signaling by the leptin receptor in diabetic mice.

N Ghilardi, S Ziegler, A Wiestner… - Proceedings of the …, 1996 - National Acad Sciences
N Ghilardi, S Ziegler, A Wiestner, R Stoffel, MH Heim, RC Skoda
Proceedings of the National Academy of Sciences, 1996National Acad Sciences
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 …
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.
National Acad Sciences