Regulation of Mitochondrial Biogenesis by Lipoprotein Lipase in Muscle of Insulin-Resistant Offspring of Parents With Type 2 Diabetes

  1. Gerald I. Shulman1,2,8
  1. 1Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
  2. 2Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
  3. 3Department of Internal Medicine, Shiga University of Medicine Science, Otsu, Japan
  4. 4Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
  5. 5Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
  6. 6Department of Medicine, Columbia University, New York, New York
  7. 7University of Colorado Health Sciences Center at Fitzsimons, Aurora, Colorado
  8. 8Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
  1. Corresponding author: Gerald I. Shulman, gerald.shulman{at}yale.edu.

Abstract

Recent studies reveal a strong relationship between reduced mitochondrial content and insulin resistance in human skeletal muscle, although the underling factors responsible for this association remain unknown. To address this question, we analyzed muscle biopsy samples from young, lean, insulin resistant (IR) offspring of parents with type 2 diabetes and control subjects by microarray analyses and found significant differences in expression of ∼512 probe pairs. We then screened these genes for their potential involvement in the regulation of mitochondrial biogenesis using RNA interference and found that mRNA and protein expression of lipoprotein lipase (LPL) in skeletal muscle was significantly decreased in the IR offspring and was associated with decreased mitochondrial density. Furthermore, we show that LPL knockdown in muscle cells decreased mitochondrial content by effectively decreasing fatty acid delivery and subsequent activation of peroxisome proliferator–activated receptor (PPAR)-δ. Taken together, these data suggest that decreased mitochondrial content in muscle of IR offspring may be due in part to reductions in LPL expression in skeletal muscle resulting in decreased PPAR-δ activation.

  • Received October 2, 2011.
  • Accepted December 7, 2011.

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