Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

  1. Jessica B. Flowers12,
  2. Mary E. Rabaglia2,
  3. Kathryn L. Schueler2,
  4. Matthew T. Flowers12,
  5. Hong Lan2,
  6. Mark P. Keller2,
  7. James M. Ntambi12 and
  8. Alan D. Attie2
  1. 1Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin
  2. 2Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin
  1. Address correspondence and reprint requests to Alan D. Attie, Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Dr., Madison, WI 537606. E-mail: attie{at}biochem.wisc.edu

Abstract

The lipogenic gene stearoyl-CoA desaturase (SCD)1 appears to be a promising new target for obesity-related diabetes, as mice deficient in this enzyme are resistant to diet- and leptin deficiency–induced obesity. The BTBR mouse strain replicates many features of insulin resistance found in humans with excess visceral adiposity. Using the hyperinsulinemic-euglycemic clamp technique, we determined that insulin sensitivity was improved in heart, soleus muscle, adipose tissue, and liver of BTBR SCD1-deficient mice. We next determined whether SCD1 deficiency could prevent diabetes in leptin-deficient BTBR mice. Loss of SCD1 in leptinob/ob mice unexpectedly accelerated the progression to severe diabetes; 6-week fasting glucose increased ∼70%. In response to a glucose challenge, Scd1−/− leptinob/ob mice had insufficient insulin secretion, resulting in glucose intolerance. A morphologically distinct class of islets isolated from the Scd1−/− leptinob/ob mice had reduced insulin content and increased triglycerides, free fatty acids, esterified cholesterol, and free cholesterol and also a much higher content of saturated fatty acids. We believe the accumulation of lipid is due to an upregulation of lipoprotein lipase (20-fold) and Cd36 (167-fold) and downregulation of lipid oxidation genes in this class of islets. Therefore, although loss of Scd1 has beneficial effects on adiposity, this benefit may come at the expense of β-cells, resulting in an increased risk of diabetes.

Footnotes

  • Published online ahead of print at http://diabetes.diabetesjournals.org on 16 March 2007. DOI: 10.2337/db06-1142.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1142.

    M.P.K., J.M.N., and A.D.A. hold stock in Xenon Pharmaceuticals.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 9, 2007.
    • Received August 15, 2006.
| Table of Contents

This Article

  1. Diabetes vol. 56 no. 5 1228-1239
  1. Online-Only Appendix
  2. All Versions of this Article:
    1. db06-1142v1
    2. 56/5/1228 most recent