Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis.
OBJECTIVE
Hypothalamic leptin resistance is found in most common forms of obesity, such as diet-induced obesity, and is associated with increased expression of suppressor of cytokine signaling 3 (Socs3) in the hypothalamus of diet-induced obese animals. This study aims to determine the functional consequence of Socs3 upregulation on leptin signaling and obesity, and to investigate whether Socs3 upregulation affects energy balance in a cell type-specific way.


METHODS
We generated transgenic mice overexpressing Socs3 in either proopiomelanocortin (POMC) or leptin receptor-expressing neurons, at levels similar to what is observed in diet-induced obesity.


RESULTS
Upregulation of Socs3 in POMC neurons leads to impairment of STAT3 and mammalian target of rapamycin (mTOR)-S6K-S6 signaling, with subsequent leptin resistance, obesity, and glucose intolerance. Unexpectedly, Socs3 upregulation in leptin receptor neurons results in increased expression of STAT3 protein in mutant hypothalami, but does not lead to obesity.


CONCLUSIONS
Our study establishes that Socs3 upregulation alone in POMC neurons is sufficient to cause leptin resistance and obesity. Socs3 upregulation impairs both STAT3 and mTOR signaling before the onset of obesity. The lack of obesity in mice with upregulated Socs3 in leptin receptor neurons suggests that Socs3's effect on energy balance could be cell type specific. Our study indicates that POMC neurons are important mediators of Socs3's effect on leptin resistance and obesity, but that other cell types or alteration of other signaling regulators could contribute to the development of obesity.
Reed
Alison S
AS
Diabetes Center and the Department of Pediatrics, University of California San Francisco, San Francisco, California, USA.
Unger
Elizabeth K
EK
Olofsson
Louise E
LE
Piper
Merisa L
ML
Myers
Martin G
MG
Xu
Allison W
AW
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D005784:Gene Amplification; D005838:Genotype; D007031:Hypothalamus / Q000502:physiology; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D016133:Polymerase Chain Reaction; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000502:physiology*; D054411:Receptors, Leptin / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D015854:Up-Regulation
D001786:Blood Glucose; D017931:DNA Primers; D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011333:Pro-Opiomelanocortin