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Endocrinology Vol. 143, No. 7 2486-2490
Copyright © 2002 by The Endocrine Society

INSULIN-GLUCAGON-GI PEPTIDES-DIABETES MELLITUS

Increased Hepatic Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator-1 Gene Expression in a Rat Model of Intrauterine Growth Retardation and Subsequent Insulin Resistance

Robert H. Lane, Nicole K. MacLennan, Jennifer L. Hsu, Sara M. Janke and Tho D. Pham

UCLA School of Medicine, Department of Pediatrics, Mattel Children’s Hospital at UCLA, Los Angeles, California, 90095-1752

Address all correspondence and requests for reprints to: Robert H. Lane, M.D., Mattel Children’s Hospital at UCLA, B2-375 Marion Davis Children’s Center, Los Angeles, California 90095-1752. E-mail: . rlane{at}mednet.ucla.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Uteroplacental insufficiency and subsequent intrauterine growth retardation (IUGR) increase the risk of type 2 diabetes in humans and rats. Unsuppressed endogenous hepatic glucose production is a common component of the insulin resistance associated with type 2 diabetes. Peroxisome proliferator-activated receptor-{gamma} coactivator-1 (PGC-1) mediates hepatic glucose production by controlling mRNA levels of glucose-6-phosphatase (G-6-Pase), phosphoenolpyruvate carboxykinase (PEPCK), and fructose-1,6-bisphosphatase (FBPase). We therefore hypothesized that gene expression of PGC-1 would be increased in juvenile IUGR rat livers, and this increase would directly correlate with hepatic mRNA levels of PEPCK, G-6-Pase, and FBPase, but not glucokinase. We found that IUGR hepatic PGC-1 protein levels were increased to 230 ± 32% and 310 ± 47% of control values at d 0 and d 21 of life, respectively. Similarly, IUGR hepatic PGC-1 mRNA levels were significantly elevated at both ages. Concurrent with the increased PGC-1 gene expression, IUGR hepatic mRNA levels of G-6-Pase, PEPCK, and FBPase were also significantly increased, whereas glucokinase mRNA levels were significantly decreased. These data suggest that increased PGC-1 expression and subsequent hepatic glucose production contribute to the insulin resistance observed in the IUGR juvenile rat.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
BARKER’S FETAL ORIGINS of Adult Disease Hypothesis proposes that fetal adaptation to a deprived intrauterine milieu leads to permanent changes in cellular biology and systemic physiology. Intrauterine growth retardation (IUGR) predisposes affected newborns toward long-term morbidity from type 2 diabetes, as well as other components of syndrome X (1). Though both insulin deficiency and resistance contribute to the IUGR diabetic phenotype, low-ponderal-index [weight/length (see Ref. 3)] IUGR individuals are often characterized by a preponderance of insulin resistance (2). Uteroplacental insufficiency, a morbidity associated with many common complications of pregnancy (such as pregnancy induced hypertension) induces low ponderal index IUGR. In the rat, uteroplacental insufficiency results in juvenile IUGR animals whose glucose homeostasis is abnormal only when physiologically challenged on a pharmacological level (3). By adulthood, adult IUGR rats develop overt diabetes that is characterized by fasting hyperglycemia and hyperinsulinemia (3, 4).

An important component of the peripheral insulin resistance associated with type 2 diabetes is impaired suppression of endogenous hepatic glucose production, which is predominately the result of gluconeogenesis (5). The enzymes glucose-6-phosphatase (G-6-Pase), phosphoenolpyruvate carboxykinase (PEPCK), and fructose-1,6-bisphosphatase (FBPase) determine the rate of gluconeogenesis. It has been recently demonstrated that hepatic gene expression of these enzymes is controlled by peroxisome proliferator-activated receptor-{gamma} coactivator-1 (PGC-1) (6). IUGR persistently affects hepatic gene expression and function of several key metabolic enzymes throughout the life of the rat (7, 8). We therefore hypothesized that hepatic PGC-1 gene expression would also be altered in the juvenile postnatal IUGR rat and that the change in gene expression would directly correlate with G-6-Pase, PEPCK, and FBPase mRNA levels, but not with glucokinase (GK) mRNA levels.

To prove this hypothesis, bilateral uterine artery ligation (IUGR) and sham surgery (controls or CON) were performed on d 19 of gestation (term, 21.5 d). Similar to the human, pups in this model experience decreased serum levels of glucose, insulin, branched chain amino acids, and oxygen (4, 8, 9). Hepatic protein and mRNA levels of PGC-1 were measured in term CON and IUGR fetal rats (d 0) and 21-d-old rats (d 21); d 21 rats were investigated because peripheral insulin resistance without either fasting hyperglycemia or hyperinsulinemia characterizes these animals (3). Hepatic PGC-1 mRNA levels were measured using a standard RT-PCR technique control and real-time RT-PCR (10). Real-time RT-PCR was further used to measure hepatic mRNA levels of the gluconeogenic enzymes G-6-Pase, PEPCK, and FBPase, as well as GK, at d 21.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
All procedures were approved by the UCLA Chancellor’s Animal Research Committee. These surgical methods have been previous described (3, 4, 7, 8, 10, 11, 12, 13). On d 19 of gestation, the maternal rats were anesthetized with ip xylazine (8 mg/kg) and ketamine (40 mg/kg), and both uterine arteries were ligated (IUGR) (n = 8 litters). Sham surgery was performed on control animals, who underwent identical anesthetic and surgical procedures except for the uterine artery ligation (CON) (n = 8 litters). Day-zero pups were delivered by cesarean section (n = 4 litters, CON and IUGR, respectively). The remaining maternal rats were allowed to deliver spontaneously, and litters were randomly culled to 6; d 21 animals were separated from their dams for 4 h (to minimize individual hormonal variations associated with feeding), anesthetized, and killed (n = 4, CON and IUGR, respectively). Liver was harvested and frozen in liquid nitrogen.

Western blotting
Protein was isolated, by centrifugation, after tissue homogenization in Laemmeli lysis buffer. A total of 100 µg protein was separated on an SDS-PAGE gel along with molecular weight markers and subsequently transferred to nitrocellulose. The nitrocellulose was incubated in Blotto solution, and then with rabbit PGC-1 primary antibody (1:100) (Chemicon, Temecula, CA). The filters were then washed before incubation with secondary antirabbit antibody (1:1000 dilution). The filters were washed, and detection was performed using enhanced chemiluminescence (Amersham Pharmacia Biotech, Piscataway, NJ). The products were quantified by densitometry after standardization for loading. Each blot was replicated three times.

RNA isolation
Total RNA was extracted from liver and quantified in triplicate using UV absorbance (14). Gel electrophoresis confirmed the integrity of the samples. RNA was treated to deoxyribonuclease (Ambion, Inc., Austin, TX).

RT-PCR quantification using internal control and direct incorporation of radioactivity
To measure mRNA levels of PGC-1, a well-characterized method of RT-PCR was used that incorporates bovine retinal rhodopsin RNA as an internal control for both RT and amplification (4, 8, 10, 11, 12, 13). cDNA was synthesized using random hexamers and SuperScript II RT (Life Technologies, Inc., Gaithersburg, MD) from 1.0 µg hepatic RNA added to 0.01 µg bovine retinal RNA. Reactions were replicated three times. Primer sequences are found in Table 1Go. With each set of reverse transcription and amplification, serial dilutions were run to demonstrate that both PCR products were being produced in the exponential phase of amplification. Products were separated, and radioactivity was quantified by phosphorimaging. The relative abundance of target mRNA levels was quantified relative to that of the control rhodopsin band from the same reaction.


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  		Table 1. Sequences of PCR primers

 
Verification of PGC-1 expression in the IUGR rat
Previous investigators have found that PGC-1 controls expression of genes affecting mitochondrial biogenesis and respiration (15). Because the perinatal IUGR rat is characterized by increased hepatic mRNA levels of the mitochondrial gene reduced nicotinamide adenine dinucleotide ubiquinone-oxireductase 4 liter, we cross-referenced our findings by measuring mRNA levels of nuclear respiratory factor-1 (NRF-1), mitochondrial transcription factor A (mTFA), and cytochrome c oxidase subunit IV (CoxIV) in d 0 IUGR rats, using the technique described above (7).

Real-time RT-PCR
mRNA levels of PGC-1 were measured at d 0 and d 21, and mRNA levels of G-6-Pase, PEPCK, FBPase, and GK were measured at d 21. cDNA was synthesized from 0.5 µg deoxyribonuclease-treated mRNA, as described above. Target (PGC-1, G-6-Pase, PEPCK, FBPase) primers and probes were designed using Primer Express Software (PE Applied Biosystems, Foster City, CA) (Table 1Go); target probes were labeled with fluorescent reporter dye FAM. Before the performance of real-time PCR, all primer pairs are tested with serial Mg2+ and primer concentrations to determine the optimal reaction conditions and to demonstrate the specificity of each primer pair. Reporter dye emission is detected by an automated sequence detector combined with ABI Prism 7700 Sequence Detection System software (PE Applied Biosystems). An algorithm normalizes the reporter signal (Rn) to a passive reference and multiples the SD of the background Rn in the first cycles by a default factor of 10 to determine threshold CT. CT has a linear relation with the logarithm of the initial template copy number (16). Real-time PCR quantification is then performed using the Taqman glyceraldehyde-3-phosphate dehydrogenase (GAPDH) controls. Before the use of GAPDH as a control, serial dilutions of cDNA are quantified to prove the validity of using GAPDH as an internal control. Relative quantification of PCR products are then based upon value differences between the target and GAPDH control using the comparative CT method (17). Cycle parameters were 55 C x 5 min, 95 C x 10 min, and then 40 cycles of 95 C x 15 sec->60 C x 60 sec. Each sample was analyzed in triplicate in assays performed on three occasions. To exclude the possibility that real-time PCR findings were a result of a nonspecific increase in mRNA levels, we also measured Bcl-2 mRNA levels in the d 21 samples.

Statistics
All data presented are expressed as mean percent of control ± SEM. For RT-PCR using the internal control, statistical analyses were performed using the nonparametric Wilcoxon matched-pair test. For real-time RT-PCR and Western blotting, statistical analyses were performed using ANOVA (Fisher’s protected least-significance difference) and Student’s unpaired t test. The Z-test was used to correlate PGC-1 mRNA levels from individual samples with G-6-Pase, PEPCK, and FBPase mRNA levels at d 21 of life, respectively.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Hepatic protein levels of PGC-1 at d 0 and d 21
Hepatic protein levels of PGC-1 at d 0 and d 21 were significantly increased to 230 ± 32% and 310 ± 47% of sham-operated CON values, respectively (P < 0.05) (Fig. 1Go). In CON animals, d 21 hepatic protein levels were 189 ± 13% of d 0 values, respectively (P < 0.05). No difference at either age was noted secondary to gender.



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  		Figure 1. Quantification and representative PGC-1 hepatic Western blots at d 0 and d 21 of life. For each blot, the control specimen is on the left, and the specimen from the IUGR liver is on the right. Protein was quantified using NIH image software. Results are expressed as mean percentages ± SEM, relative to sham-operated controls. *, P < 0.05.

 
Hepatic mRNA levels of PGC-1 at d 0 and d 21
Using the traditional RT-PCR method, we found that d 0 and d 21 hepatic mRNA levels of PGC-1 were significantly increased in IUGR livers to 155 ± 17% and 210 ± 26% of control values, respectively (Fig. 2AGo) (P < 0.05 for both ages). Similarly, hepatic mRNA levels of NRF-1 (180 ± 16%), mTFA (229 ± 31%), and CoxIV (164 ± 19%) were significantly increased in IUGR animals, relative to sham-operated CON animals (Fig. 2BGo) (P < 0.05 for all three genes). No difference at either age was noted secondary to gender.



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  		Figure 2. A, Quantification and representative phosphorimage of PGC RT-PCR products at d 0 and d 21 of life. B, Quantification and representative phosphorimage of NRF-1, mTFA, Cox IV RT-PCR products at d 0 of life. In each inset, the control specimen is on the left, and the specimen from the IUGR liver is on the right. PCR products were quantified using phosphorimage analysis. Results are expressed as mean percentages ± SEM, relative to sham-operated controls. *, P < 0.05.

 
Hepatic mRNA levels of PGC-1, G-6-Pase, PEPCK, and FBPase
Using real-time RT-PCR, we found that hepatic d 0 and d 21 mRNA levels of PGC-1 were significantly increased to 186 ± 13% and 233 ± 17% of control values, respectively (Fig. 3Go) (P < 0.05). Concurrent with these d 21 findings, hepatic mRNA levels of G-6-Pase (301 ± 35%), PEPCK (385 ± 43%), and FBPase (240 ± 23%) were significantly increased in the IUGR animals (Fig. 3Go) (P < 0.05 for all three genes). Moreover, when the extent of these increases was analyzed in comparison with the rise in PGC-1 mRNA levels on a sample-to-sample basis, we found that the G-6-Pase (r = 0.86; P < 0.05), PEPCK (r = 0.79; P < 0.05), and FBPase (r = 0.87; P < 0.01) mRNA levels correlated directly to PGC-1 mRNA levels. In contrast, mRNA levels of GK were significantly decreased to 46 ± 7% of control values, and mRNA levels of Bcl-2 were not significantly altered in the IUGR animals (Fig. 3Go).



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  		Figure 3. Quantification of PGC-1, G-6-Pase, PEPCK, FBPase, GK, and Bcl-2 using real-time RT-PCR. Results are expressed as mean percentages ± SEM, relative to sham-operated controls. Relative quantification of PCR products are then based on value differences between the target and GAPDH control, using the comparative CT method. *, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
PGC-1 is a transcriptional coactivator of nuclear receptors that controls hepatic mRNA levels of the gluconeogenic enzymes G-6-Pase, PEPCK, and FBPase and subsequently affects hepatic gluconeogenesis (6). PGC-1 mRNA levels are increased in liver-specific insulin-receptor knockout mice, which have been previously characterized by the failure of insulin to suppress hepatic glucose production and increased mRNA levels of gluconeogenic enzymes (6, 18). Moreover, Wistar rats injected with adenovirus expressing PGC-1 demonstrate hyperglycemia and hyperinsulinemia, which are characteristic findings of increased hepatic glucose output in nondiabetic animals (6). As a result, the significant correlation between PGC-1 mRNA levels and the mRNA levels of G-6-Pase, PEPCK, and FBPase suggests that PGC-1 is similarly contributing directly to the increased mRNA levels of these enzymes in this rat model of IUGR. Moreover, the finding of persistently increased PGC-1 expression in juvenile IUGR livers further suggests a molecular mechanism through which hepatic endogenous glucose production contributes to the peripheral insulin resistance described by Simmons et al. (3).

Unsuppressed gluconeogenesis is often an early finding of NIDDM; and hormones such as insulin, glucagon, and glucocorticoids affect expression of the gluconeogenic hormones G-6-Pase, PEPCK, and FBPase at the transcriptional level, though the specific molecular mechanisms through which these hormones work, are not completely defined (19, 20). Animal models have provided some insight. For example, impaired regulation of FBPase in New Zealand obese mice leads to increased hepatic glucose production (21). Similarly, in transgenic rats that express a noninsulin responsive PEPCK gene, overt diabetes develops by 3 months of age, in association with other components of syndrome X (such as dyslipidemia) (22).

This study uses an in vivo rat model that similarly develops overt diabetes and dyslipidemia late in life as a result of a deprived intrauterine milieu (3, 8). The effect of this deprivation was the recent focus of the First World Congress on Fetal Origins of Adult Disease (23). The prototypical IUGR human endures a perinatal period characterized by hypoglycemia and hypoinsulinemia (24). During childhood and early adulthood, the IUGR individual is likely to demonstrate insulin resistance, and it is during the latter half of the adult years that clinically overt diabetes and the other components of syndrome X emerge (1).

Similar to the IUGR human, the juvenile IUGR rat initially develops peripheral insulin resistance; and the adult IUGR rat demonstrates fasting hyperglycemia, hyperinsulinemia, and hypertriglyceridemia (3, 4, 8). These pathophysiologies are associated with tissue-specific alterations in glucose and fatty acid metabolizing enzyme gene expression and function that persist after the initial insult, including increased hepatic expression of carnitine palmitoyl transferase I (4, 8, 11, 12). Though regulation of hepatic fatty acid metabolizing gene expression is complex, it is noteworthy that PGC-1 cotranscription factors peroxisome-proliferator-activated receptor-{alpha} and thyroid receptor contribute to the transcriptional regulation of liver carnitine palmitoyl transferase I (25, 26, 27).

Interestingly, protein malnutrition of the maternal dam and subsequent IUGR also results in impaired insulin suppression of hepatic glucose production, increased PEPCK activity, and dyslipidemia (5, 28, 29, 30). Moreover, similar to our findings, the progeny of protein-malnourished dams also demonstrate decreased GK activity, and it has been speculated that this plays a role in the glucose intolerance exhibited by these animals (29, 31).

At d 0 of life, increased hepatic PGC-1 mRNA and protein levels are associated with higher levels of NRF-1, mTFA, and CoxIV mRNA and corroborate with previous reports directly linking PGC-1 to the expression of these genes, as well as the earlier findings of increased mitochondrial gene expression in IUGR animals (7, 15).

In summary, IUGR leads to increased hepatic gene expression of PGC-1 during a time period when the affected animal is characterized by peripheral insulin resistance (3). PGC-1 controls hepatic gluconeogenesis and associates with multiple transcriptional coactivators. As a result, our data suggest that hepatic PGC-1 contributes to the early peripheral resistance and the long-term effects of uteroplacental insufficiency in the IUGR rat.


   Acknowledgments
 
We would like to thank Dr. Sherin U. Devaskar for her support and guidance.


   Footnotes
 
This work was supported by National Institute of Child Health and Human Development Grant K08-BD-01225-1 and an American Diabetes Association Grant (to R.H.L.).

Abbreviations: CON, Sham surgery controls; CoxIV, cytochrome c oxidase subunit IV; FBPase, fructose-1,6-bisphosphatase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GK, glucokinase; G-6-Pase, glucose-6-phosphatase; IUGR, intrauterine growth retardation; mTFA, mitochondrial transcription factor A; NRF-1, nuclear respiratory factor-1; PEPCK, phosphoenolpyruvate carboxykinase; PGC-1, peroxisome proliferator-activated receptor-{gamma} coactivator-1.

Received January 8, 2002.

Accepted for publication March 19, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM 1993 Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36:62–67[CrossRef][Medline]
  2. Phillips DI, Barker DJ, Hales CN, Hirst S, Osmond C 1994 Thinness at birth and insulin resistance in adult life. Diabetologia 37:150–154[CrossRef][Medline]
  3. Simmons RA, Templeton LJ, Gertz SJ 2001 Intrauterine growth retardation leads to the development of type 2 diabetes in the rat. Diabetes 50:2279–2286[Abstract/Free Full Text]
  4. Tsirka AE, Gruetzmacher EM, Kelley DE, Ritov VH, Devaskar SU, Lane RH 2001 Myocardial gene expression of glucose transporter 1 and glucose transporter 4 in response to uteroplacental insufficiency in the rat. J Endocrinol 169:373–380[Abstract]
  5. Song S, Andrikopoulos S, Filippis C, Thorburn AW, Khan D, Proietto J 2001 Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin. Am J Physiol Endocrinol Metab 281:E275–E282
  6. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM 2001 Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131–138[CrossRef][Medline]
  7. Lane RH, Flozak AS, Ogata ES, Bell GI, Simmons RA 1996 Altered hepatic gene expression of enzymes involved in energy metabolism in the growth-retarded fetal rat. Pediatr Res 39:390–394[Medline]
  8. Lane RH, Kelley DE, Gruetzmacher EM, Devaskar SU 2001 Uteroplacental insufficiency alters hepatic fatty acid-metabolizing enzymes in juvenile and adult rats. Am J Physiol Regul Integr Comp Physiol 280:R183–R190
  9. Ogata ES, Bussey ME, Finley S 1986 Altered gas exchange, limited glucose and branched chain amino acids, and hypoinsulinism retard fetal growth in the rat. Metabolism 35:970–977[CrossRef][Medline]
  10. Lane RH, Flozak AS, Simmons RA 1996 Measurement of GLUT mRNA in liver of fetal and neonatal rats using a novel method of quantitative polymerase chain reaction. Biochem Mol Med 59:192–199[CrossRef][Medline]
  11. Lane RH, Chandorkar AK, Flozak AS, Simmons RA 1998 Intrauterine growth retardation alters mitochondrial gene expression and function in fetal and juvenile rat skeletal muscle. Pediatr Res 43:563–570[Medline]
  12. Lane RH, Kelley DE, Ritov VH, Tsirka AE, Gruetzmacher EM 2001 Altered expression and function of mitochondrial ß-oxidation enzymes in juvenile intrauterine-growth-retarded rat skeletal muscle. Pediatr Res 50:83–90[Medline]
  13. Kloesz JL, Serdikoff CM, Maclennan NK, Adibi SA, Lane RH 2001 Uteroplacental insufficiency alters liver and skeletal muscle branched-chain amino acid metabolism in intrauterine growth-restricted fetal rats. Pediatr Res 50:604–610[Medline]
  14. Chomczynski P, Sacchi N 1987 Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159[Medline]
  15. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM 1999 Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124[CrossRef][Medline]
  16. Higuchi R, Fockler C, Dollinger G, Watson R 1993 Kinetic PCR analysis: real-time monitoring of DNA amplification reactions. Biotechnology 11:1026–1030[CrossRef][Medline]
  17. Menon RK, Shaufl A, Yu JH, Stephan DA, Friday RP 2001 Identification and characterization of a novel transcript of the murine growth hormone receptor gene exhibiting development- and tissue-specific expression. Mol Cell Endocrinol 172:135–146[CrossRef][Medline]
  18. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR 2000 Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 6:87–97[CrossRef][Medline]
  19. Perriello G, Pampanelli S, Del Sindaco P, Lalli C, Ciofetta M, Volpi E, Santeusanio F, Brunetti P, Bolli GB 1997 Evidence of increased systemic glucose production and gluconeogenesis in an early stage of NIDDM. Diabetes 46:1010–1016[Abstract]
  20. Vaag A, Alford F, Henriksen FL, Christopher M, Beck-Nielsen H 1995 Multiple defects of both hepatic and peripheral intracellular glucose processing contribute to the hyperglycaemia of NIDDM. Diabetologia 38:326–336[Medline]
  21. Andrikopoulos S, Rosella G, Gaskin E, Thorburn A, Kaczmarczyk S, Zajac JD, Proietto J 1993 Impaired regulation of hepatic fructose-1,6-bisphosphatase in the New Zealand obese mouse model of NIDDM. Diabetes 42:1731–1736[Abstract]
  22. Thorburn AW, Baldwin ME, Rosella G, Zajac JD, Fabris S, Song S, Proietto J 1999 Features of syndrome X develop in transgenic rats expressing a non-insulin-responsive phosphoenolpyruvate carboxykinase gene. Diabetologia 42:419–426[CrossRef][Medline]
  23. Aihie Sayer A 2001 First World Congress on the Fetal Origins of Adult Disease. J Pediatr Endocrinol Metab 14:921–924[Medline]
  24. Economides DL, Nicolaides KH, Gahl WA, Bernardini I, Bottoms S, Evans M 1989 Cordocentesis in the diagnosis of intrauterine starvation. Am J Obstet Gynecol 161:1004–1008[Medline]
  25. Barrero MJ, Marrero PF, Haro D 2000 Regulation of the rat liver carnitine palmitoyltransferase I gene transcription by thyroid hormone. Biochem Biophys Res Commun 279:81–88[CrossRef][Medline]
  26. Louet JF, Chatelain F, Decaux JF, Park EA, Kohl C, Pineau T, Girard J, Pegorier JP 2001 Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPAR{alpha})-independent pathway. Biochem J 354:189–197[CrossRef][Medline]
  27. Memon RA, Tecott LH, Nonogaki K, Beigneux A, Moser AH, Grunfeld C, Feingold KR 2000 Up-regulation of peroxisome proliferator-activated receptors (PPAR-{alpha}) and PPAR-{gamma} messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-{gamma}-responsive adipose tissue-specific genes in the liver of obese diabetic mice. Endocrinology 141:4021–4031[Abstract/Free Full Text]
  28. Ozanne SE, Smith GD, Tikerpae J, Hales CN 1996 Altered regulation of hepatic glucose output in the male offspring of protein-malnourished rat dams. Am J Physiol 270:E559–E564
  29. Desai M, Byrne CD, Meeran K, Martenz ND, Bloom SR, Hales CN 1997 Regulation of hepatic enzymes and insulin levels in offspring of rat dams fed a reduced-protein diet. Am J Physiol 273:G899–G904
  30. Kind KL, Clifton PM, Katsman AI, Tsiounis M, Robinson JS, Owens JA 1999 Restricted fetal growth and the response to dietary cholesterol in the guinea pig. Am J Physiol 277:R1675–R1682
  31. Burns SP, Desai M, Cohen RD, Hales CN, Iles RA, Germain JP, Going TC, Bailey RA 1997 Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation. J Clin Invest 100:1768–1774[Medline]



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Q. Fu, R. A. McKnight, X. Yu, L. Wang, C. W. Callaway, and R. H. Lane
Uteroplacental insufficiency induces site-specific changes in histone H3 covalent modifications and affects DNA-histone H3 positioning in day 0 IUGR rat liver
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[Abstract] [Full Text] [PDF]

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P. Vuguin, E. Raab, B. Liu, N. Barzilai, and R. Simmons
Hepatic Insulin Resistance Precedes the Development of Diabetes in a Model of Intrauterine Growth Retardation
Diabetes, October 1, 2004; 53(10): 2617 - 2622.
[Abstract] [Full Text] [PDF]

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L. Chen, T. Zhang, and B. L. G. Nyomba
Insulin resistance of gluconeogenic pathways in neonatal rats after prenatal ethanol exposure
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2004; 286(3): R554 - R559.
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T. D. Pham, N. K. MacLennan, C. T. Chiu, G. S. Laksana, J. L. Hsu, and R. H. Lane
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Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R962 - R970.
[Abstract] [Full Text] [PDF]

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K. Holemans, L. Aerts, and F. A. Van Assche
Fetal Growth Restriction and Consequences for the Offspring in Animal Models
Reproductive Sciences, October 1, 2003; 10(7): 392 - 399.
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