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.
Ghilardi
N
N
Department of Pharmacology, Biozentrum, University of Basel, Switzerland.
Ziegler
S
S
Wiestner
A
A
Stoffel
R
R
Heim
M H
MH
Skoda
R C
RC
D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005091:Exons; D006801:Humans; D007438:Introns; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*
D002352:Carrier Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C515448:LEPR protein, human; D008894:Milk Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; C515447:leptin receptor, mouse