Selective inactivation of Socs3 in SF1 neurons improves glucose homeostasis without affecting body weight.
Suppressor of cytokine signaling 3 (Socs3) has been identified as a mediator of central leptin resistance, but the identity of specific neurons in which Socs3 acts to suppress leptin signaling remains elusive. The ventromedial hypothalamus (VMH) was recently shown to be an important site for leptin action because deleting leptin receptor within VMH neurons causes obesity. To examine the role of VMH Socs3 in leptin resistance and energy homeostasis, we generated mice lacking Socs3 specifically in neurons positive for steroidogenic factor 1 (SF1), which is expressed abundantly in the VMH. These mice had increased phosphorylation of signal transducer and activator of transcription-3 in VMH neurons, suggesting improved leptin signaling, and consistently, food intake and weight-reducing effects of exogenous leptin were enhanced. Furthermore, on either chow or high-fat diets, these mice had reduced food intake. Unexpectedly, energy expenditure was reduced as well. Mice lacking Socs3 in SF1 neurons, despite no change in body weight, had improved glucose homeostasis and were partially protected from hyperglycemia and hyperinsulinemia induced by high-fat diets. These results suggest that Socs3 in SF1 neurons negatively regulates leptin signaling and plays important roles in mediating leptin sensitivity, glucose homeostasis, and energy expenditure.
Zhang
Ren
R
Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Dhillon
Harveen
H
Yin
Huali
H
Yoshimura
Akihiko
A
Lowell
Bradford B
BB
Maratos-Flier
Eleftheria
E
Flier
Jeffrey S
JS
D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics*; D004435:Eating / Q000187:drug effects / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism
D007328:Insulin; D020738:Leptin; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D054339:Steroidogenic Factor 1; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C515058:steroidogenic factor 1, mouse; D005947:Glucose