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. 1996 Jun 25;93(13):6231–6235. doi: 10.1073/pnas.93.13.6231

Defective STAT signaling by the leptin receptor in diabetic mice.

N Ghilardi 1, S Ziegler 1, A Wiestner 1, R Stoffel 1, M H Heim 1, R C Skoda 1
PMCID: PMC39004  PMID: 8692797

Abstract

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.

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