Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells.
Suppressor of cytokine signaling-3 (Socs-3) negatively regulates the action of various cytokines, as well as the metabolic hormones leptin and insulin. Mice with haploinsufficiency of Socs-3, or those with neuronal deletion of Socs-3, are lean and more leptin and insulin sensitive. To examine the role of Socs-3 within specific neurons critical to energy balance, we created mice with selective deletion of Socs-3 within pro-opiomelanocortin (POMC)-expressing cells. These mice had enhanced leptin sensitivity, measured by weight loss and food intake after leptin infusion. On chow diet, glucose homeostasis was improved despite normal weight gain. On a high-fat diet, the rate of weight gain was reduced, due to increased energy expenditure rather than decreased food intake; glucose homeostasis and insulin sensitivity were substantially improved. These studies demonstrate that Socs-3 within POMC neurons regulates leptin sensitivity and glucose homeostasis, and plays a key role in linking high-fat diet to disordered metabolism.
Kievit
Paul
P
Division of Endocrinology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02215, USA.
Howard
Jane K
JK
Badman
Michael K
MK
Balthasar
Nina
N
Coppari
Roberto
R
Mori
Hiroyuki
H
Lee
Charlotte E
CE
Elmquist
Joel K
JK
Yoshimura
Akihiko
A
Flier
Jeffrey S
JS
D000818:Animals; D002478:Cells, Cultured; D004041:Dietary Fats / Q000494:pharmacology*; D005234:Fatty Liver / Q000517:prevention & control; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D015431:Weight Loss
D004041:Dietary Fats; D020738:Leptin; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011333:Pro-Opiomelanocortin; D005947:Glucose