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Originally published In Press as doi:10.1074/jbc.M201208200 on August 9, 2002
J. Biol. Chem., Vol. 277, Issue 52, 50237-50244, December 27, 2002
Peroxisome Proliferator-activated Receptor (PPAR )
Influences Substrate Utilization for Hepatic Glucose Production*
Jun
Xu §¶,
Gary
Xiao §,
Chuck
Trujillo §,
Vicky
Chang §,
Lilia
Blanco §,
Sean B.
Joseph ,
Sara
Bassilian**,
Mohammed F.
Saad§,
Peter
Tontonoz  §§,
W. N. Paul
Lee**, and
Irwin J.
Kurland § ¶¶
From the § Department of Medicine, the
Laboratory of Metabolomics, the ¶ Department of
Biological Chemistry, the Department of Pathology, David
Geffen School of Medicine at UCLA, Los Angeles, California
90095,  Molecular Biology Institute,
UCLA, Los Angeles, California 90095, and the ** Department of
Pediatrics, Harbor-UCLA Medical Center,
Torrance, California 90502
The hypoglycemia seen in the fasting
PPAR null mouse is thought to be due to impaired liver fatty acid
-oxidation. The etiology of hypoglycemia in the PPAR null mouse
was determined via stable isotope studies. Glucose, lactate, and
glycerol flux was assessed in the fasted and fed states in 4-month-old
PPAR null mice and in C57BL/6 WT maintained on standard chow using a
new protocol for flux assessment in the fasted and fed states. Hepatic
glucose production (HGP) and glucose carbon recycling were estimated
using [U-13C6]glucose, and HGP,
lactate, and glycerol turnover was estimated utilizing either
[U-13C3]lactate or
[2-13C]glycerol infused subcutaneously via Alza
miniosmotic pumps. At the end of a 17-h fast, HGP was higher in the
PPAR null mice than in WT by 37% (p < 0.01).
However, recycling of glucose carbon from lactate back to glucose was
lower in the PPAR null than in WT (39% versus 51%,
p < 0.02). The lack of conversion of lactate to
glucose was confirmed using an
[U-13C3]lactate infusion. In the fasted
state, HGP from lactate and lactate production were decreased by 65 and
55%, respectively (p < 0.05) in PPAR
null mice. In contrast, when [2-13C]glycerol
was infused, glycerol production and HGP from glycerol increased by 80 and 250%, respectively (p < 0.01), in the fasted state of PPAR null mice. The increased HGP from glycerol was not
suppressed in the fed state. While little change was evident for
phosphoenolpyruvate carboxykinase (PEPCK) expression, pyruvate kinase
expression was decreased 16-fold in fasted PPAR null mice as
compared with the wild-type control. The fasted and fed insulin levels
were comparable, but blood glucose levels were lower in the PPAR
null mice than in controls. In conclusion, PPAR receptor function
creates a setpoint for a metabolic network that regulates the rate and
route of HGP in the fasted and fed states, in part, by controlling the
flux of glycerol and lactate between the triose-phosphate and
pyruvate/lactate pools.
*
This work was supported by a grant from the American
Diabetes Association (to I. J. K.) and Grants DK56090-A1 (to
W. N. P. L.) and HL66088 (to P. T.). The GC/MS Facility is
supported by United States Public Health Service Grant
P01-CA42710 to the UCLA Clinical Nutrition Research Unit, Stable
Isotope Core and Grant M01-RR00425 to the General Clinical Research
Center.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
§§
Assistant investigator of the Howard Hughes Medical
Institute at the University of California, Los Angeles, CA 90095.
¶¶
To whom correspondence should be addressed. Tel.:
818-634-6953; Fax: 310-825-8534; E-mail address:
irwinjk@earthlink.net.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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