Leptin Suppresses Stearoyl-CoA Desaturase 1 by Mechanisms Independent of Insulin and Sterol Regulatory Element–Binding Protein-1c
- 1Research Division, Joslin Diabetes Center, Boston, Massachusetts
- 2Department of Medicine, Harvard Medical School, Boston, Massachusetts
- 3Division of Endocrinology, Children’s Hospital, Boston, Massachusetts
- 4Department of Biochemistry, University of Wisconsin, Madison, Wisconsin
- 5Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin
- Address correspondence and reprint requests to C. Ronald Kahn, Research Division, Joslin Diabetes Center, One Joslin Pl., Boston, MA 02215. E-mail: c.ronald.kahn{at}joslin.harvard.edu
Abstract
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.
- ACC, acetyl-CoA carboxylase
- CNS, central nervous system
- IRS, insulin receptor substrate
- LXR, liver X receptor
- MCH, melanin-concentrating hormone
- MUFA, monounsaturated fatty acid
- SCD, stearoyl-CoA desaturase
- SFA, saturated fatty acid
- SREBP
- sterol regulatory element–binding protein
Footnotes
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S.B.B. and M.M. contributed equally to this work.
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
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- Accepted March 22, 2006.
- Received June 8, 2005.
- DIABETES
