Identification of SOCS-3 as a potential mediator of central leptin resistance.
Leptin affects food intake and body weight by actions on the hypothalamus. Although leptin resistance is common in obesity, mechanisms have not been identified. We examined the effect of leptin on expression of the suppressors-of-cytokine-signaling (SOCS) family of proteins. Peripheral leptin administration to ob/ob, but not db/db mice, rapidly induced SOCS-3 mRNA in hypothalamus, but had no effect on CIS, SOCS-1, or SOCS-2. A leptin-dependent increase of SOCS-3 mRNA was seen in areas of hypothalamus expressing high levels of the leptin receptor long form. In mammalian cell lines, SOCS-3, but not CIS or SOCS-2, blocked leptin-induced signal transduction. Expression of SOCS-3 mRNA in the arcuate and dorsomedial hypothalamic nuclei is increased in Ay/a mice, a model of leptin-resistant murine obesity. In conclusion, SOCS-3 is a leptin-inducible inhibitor of leptin signaling, and a potential mediator of leptin resistance in obesity.
Bjørbaek
C
C
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Elmquist
J K
JK
Frantz
J D
JD
Shoelson
S E
SE
Flier
J S
JS
D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins; D017930:Genes, Reporter; D007031:Hypothalamus / Q000166:cytology; D017874:Immediate-Early Proteins / Q000235:genetics; D017403:In Situ Hybridization; D020738:Leptin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009474:Neurons / Q000737:chemistry / Q000502:physiology; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D020738:Leptin; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C491409:Socs2 protein, mouse; C491411:Socs3 protein, mouse