Leptin suppresses stearoyl-CoA desaturase 1 by mechanisms independent of insulin and sterol regulatory element-binding protein-1c.
Stearoyl-CoA desaturase (SCD)1 catalyzes the rate-limiting reaction of monounsaturated fatty acid (MUFA) synthesis and plays an important role in the development of obesity. SCD1 is suppressed by leptin but induced by insulin. We have used animal models to dissect the effects of these hormones on SCD1. In the first model, leptin-deficient ob/ob mice were treated with either leptin alone or with both leptin and insulin to prevent the leptin-mediated fall in insulin. In the second model, mice with a liver-specific knockout of the insulin receptor (LIRKO) and their littermate controls (LOXs) were treated with leptin. As expected, leptin decreased SCD1 transcript, protein, and activity by >60% in ob/ob and LOX mice. However, the effects of leptin were not diminished by the continued presence of hyperinsulinemia in ob/ob mice treated with both leptin and insulin or the absence of insulin signaling in LIRKO mice. Furthermore, genetic knockout of sterol regulatory element-binding protein (SREBP)-1c, the lipogenic transcription factor that mediates the effects of insulin on SCD1, also had no effect on the ability of leptin to decrease either SCD1 transcript or activity. Thus, the effect of leptin on SCD1 in liver is independent of insulin and SREBP-1c, and leptin, rather than insulin, is the major regulator of hepatic MUFA synthesis in obesity-linked diabetes.
Biddinger
Sudha B
SB
Research Division, Joslin Diabetes Center, One Joslin Pl., Boston, MA 02215, USA.
Miyazaki
Makoto
M
Boucher
Jeremie
J
Ntambi
James M
JM
Kahn
C Ronald
CR
D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D017931:DNA Primers; D002149:Energy Intake; D007328:Insulin / Q000097:blood / Q000502:physiology*; D020738:Leptin / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D016133:Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D054411:Receptors, Leptin; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000502:physiology*
D001786:Blood Glucose; D017931:DNA Primers; D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; D051780:Sterol Regulatory Element Binding Protein 1; C515447:leptin receptor, mouse; D013230:Stearoyl-CoA Desaturase; D011972:Receptor, Insulin