Lipin Deficiency Impairs Diurnal Metabolic Fuel Switching

  1. Jun Xu1,
  2. W.N. Paul Lee2,
  3. Jack Phan3,
  4. Mohammed F. Saad4,
  5. Karen Reue3567 and
  6. Irwin J. Kurland189
  1. 1Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York
  2. 2Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California
  3. 3Department of Human Genetics, University of California, Los Angeles, California
  4. 4Department of Preventative Medicine, State University of New York at Stony Brook, Stony Brook, New York
  5. 5Department of Medicine, University of California, Los Angeles, California
  6. 6Molecular Biology Institute, University of California, Los Angeles, California
  7. 7VA Greater Los Angeles Healthcare System, Los Angeles, California
  8. 8Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York
  9. 9Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York
  1. Address correspondence and reprint requests to Irwin J. Kurland, MD, PHD, State University of New York at Stony Brook, HSC T-15 Room 060, Stony Brook, NY 11794-8154. E-mail: irwin.kurland{at}stonybrook.edu

Abstract

Fatty liver is a common feature of both obesity and lipodystrophy, reflecting compromised adipose tissue function. The lipin-deficient fatty liver dystrophy (fld) mouse is an exception, as there is lipodystrophy without a fatty liver. Using a combination of indirect calorimetry and stable-isotope flux phenotyping, we determined that fld mice exhibit abnormal fuel utilization throughout the diurnal cycle, with increased glucose oxidation near the end of the fasting period and increased fatty acid oxidation during the feeding period. The mechanisms underlying these alterations include a twofold increase compared with wild-type mice in tissue glycogen storage during the fed state, a 40% reduction in hepatic glucose production in the fasted state, and a 27-fold increase in de novo fatty acid synthesis in liver during the fed state. Thus, the inability to store energy in adipose tissue in the fld mouse leads to a compensatory increase in glycogen storage for use during the fasting period and reliance upon hepatic fatty acid synthesis to provide fuel for peripheral tissues during the fed state. The increase in hepatic fatty acid synthesis and peripheral utilization provides a potential mechanism to ameliorate fatty liver in the fld that would otherwise occur as a consequence of adipose tissue dysfunction.

Footnotes

  • 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 August 4, 2006.
    • Received February 23, 2006.
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