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* Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas, USA; Unité mixte Inserm U530-Université Paris 5; Centre Universitaire-U.F.R. Biomédicale; 75006 Paris; and
University of Texas Southwestern Medical Center at Dallas, Howard Hughes Medical Institute and Department of Biochemistry, Dallas, Texas, USA
1Correspondence: Department of Cell Biology and Biochemistry, Stop 6540, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. E-mail: elmus.beale{at}ttuhsc.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONREFERENCES |
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Key Words: phosphoenolpyruvate carboxykinase • lipid homeostasis • obesity • diabetes
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INTRODUCTION |
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. Subsequent studies revealed that its concentration in fat cells is similar to that in the liver, yet fat tissue is not gluconeogenic because adipocytes lack the terminal two enzymes of the pathway. This led two groups of researchers to independently undertake a series of studies to elucidate the role of PEPCK-C in fat tissue (2
3
4)
. They found that during fasting, gluconeogenic precursors such as pyruvate are converted into the glycerol backbone of triacylglycerol, the major storage form of fat. Reshef, Hanson, and Ballard coined the term glyceroneogenesis to describe this pathway (3)
and developed the model in Fig. 1
to explain its metabolic role (4)
. They proposed that glyceroneogenesis modulates fatty acid release from adipose tissue during fasting when diet cannot provide glycerol-3-phosphate for triacylglycerol synthesis. Indeed, they demonstrated that fasting induces PEPCK-C and glyceroneogenesis and that fatty acid release from fat tissue is reduced.
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Although this model fits the data, it seemed that the control of lipolysis (triacylglycerol breakdown) should be the most important means by which fatty acid release is controlled. Thus, the need to invoke an opposing futile cycle was difficult to reconcile. The tools of molecular biology were not available to prove the model 30 years ago, so little effort was expended on further studies until four recent lines of investigation demonstrated the quantitative importance of glyceroneogenesis in both liver and fat.
First, glyceroneogenesis has been measured by tracer studies in rats and humans (5
, 6)
. Kalhan et al. showed that whole body glyceroneogenesis, primarily from the liver, provides up to 60% of plasma glyceride-glycerol (the glycerol portion of triglyceride) in fasted pregnant women (6)
. Similarly, adipocyte glyceroneogenesis provides > 80% of the glyceride-glycerol in epididymal fat of rats fed a high protein diet (5)
.
Second, Olswang et al. genetically engineered mice that lack a DNA element required for the PEPCK-C gene to function in fat cells (7
, 8)
. This produced a mutant line of mice that have normal levels of PEPCK-C in their livers and kidneys but none in their white adipose tissue depots (most adipose tissue is "white" and functions to store fuel compared to brown adipose tissue, which functions to generate heat). The phenotype of these mice is consistent with the glyceroneogenic role of fat cell PEPCK-C since the rate of fatty acid release from fat tissue was increased and could not be suppressed by pyruvate. Furthermore, the mice had reduced amounts of body fat, and 
25% of the mice were notably lipodystrophic (abnormally low body fat content). The most lipodystrophic mice appeared to have slightly elevated levels of insulin and glucose, suggesting a mild insulin resistance. The differing genetic backgrounds of these null mice probably explains why only a fourth were lipodystrophic and tended to be insulin resistant. This parallels human diabetes and obesity, which are strongly affected by inheritance. Finally, hepatic triacylglycerol content correlated with fat tissue size in these mice, suggesting that fatty acids from fat tissue are used for hepatic triacylglycerol synthesis.
Third, Franckhauser et al. created transgenic mice that overproduce PEPCK-C in white adipose tissue (9)
. The phenotype of these mice supports a glyceroneogenic role of adipocyte PEPCK-C in that they are obese due to increased re-esterification rates and glyceroneogenesis, which depress circulating fatty acids. Moreover, they are nondiabetic and appear to have a slightly increased sensitivity to insulin.
Fourth, Tordjman et al. have shown that glyceroneogenesis (via PEPCK-C) is a target for thiazolidinediones, the latest generation of antidiabetic drugs, to lower fatty acid output from adipose tissue (J. Tordjman et al., unpublished results). Since elevated serum fatty acid levels cause insulin resistance and diabetes (10)
, this raises the exciting possibility that adipocyte PEPCK-C is a critical target for the antidiabetic actions of this class of drugs and could point the way to the design of more effective drugs.
These recent studies provide strong support for the important metabolic role of PEPCK-C in glyceroneogenesis originally proposed by R. Hanson and L. Reshef (3)
. More than 30 years later, these same investigators have been major players in confirming their original predictions (6
, 8)
. Moreover, these recent studies have confirmed the prediction that PEPCK-C in fat tissue is involved in lipid metabolism (5
, 6
, 8
, 9
; Tordjman et al., unpublished results). Like other areas of physiology and metabolism, molecular biology is providing tools to revisit and answer old questions.
These recent studies raise the possibility that aberrant regulation of PEPCK-C in fat tissue may well be an etiologic factor in type 2 diabetes mellitus. The logic is as follows. An elevation of plasma fatty acids causes insulin resistance leading to diabetes (10)
. Any disorder that leads to a PEPCK-C deficiency in adipose tissue will enhance the rate of fatty acid release into the blood. Moreover, the same DNA element that was ablated to generate the adipose-specific PEPCK-C null mutant mice also mediates the response of PEPCK-C to thiazolidinediones (11)
. The new transgenic mice will provide invaluable model systems to further examine the metabolic consequences of PEPCK-C deficiency and overproduction under a variety of conditions such as varying genetic background, aging, treatment with antidiabetic drugs, and dietary composition to name a few.
Finally, there is strong evidence that glyceroneogenesis occurs to a significant degree in the liver (5
, 6)
. Indeed, tissue-specific ablation of the PEPCK-C gene in the liver resulted in a fatty liver (12)
. Perhaps this perplexing observation is caused by the loss of hepatic glyceroneogenesis. In any event, glyceroneogenesis should now merit inclusion in the biochemistry textbooks.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONREFERENCES |
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and 9-cis-retinoic acid receptor binding to an adipocyte-specific enhancer in vivo. J. Biol. Chem. 274,13604-13612This article has been cited by other articles:
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  A. G. Gomez-Valades, A. Mendez-Lucas, A. Vidal-Alabro, F. X. Blasco, M. Chillon, R. Bartrons, J. Bermudez, and J. C. Perales Pck1 Gene Silencing in the Liver Improves Glycemia Control, Insulin Sensitivity, and Dyslipidemia in db/db Mice Diabetes, August 1, 2008; 57(8): 2199 - 2210. [Abstract] [Full Text] [PDF]
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 M.-S. Gauthier, H. Miyoshi, S. C. Souza, J. M. Cacicedo, A. K. Saha, A. S. Greenberg, and N. B. Ruderman AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte: POTENTIAL MECHANISM AND PHYSIOLOGICAL RELEVANCE J. Biol. Chem., June 13, 2008; 283(24): 16514 - 16524. [Abstract] [Full Text] [PDF]
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J. Tordjman, S. Leroyer, G. Chauvet, J. Quette, C. Chauvet, C. Tomkiewicz, C. Chapron, R. Barouki, C. Forest, M. Aggerbeck, et al. Cytosolic Aspartate Aminotransferase, a New Partner in Adipocyte Glyceroneogenesis and an Atypical Target of Thiazolidinedione J. Biol. Chem., August 10, 2007; 282(32): 23591 - 23602. [Abstract] [Full Text] [PDF]
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 W. Khazen, E. Distel, M. Collinet, V. E. Chaves, J.-P. M'Bika, C. Chany, A. Achour, C. Benelli, and C. Forest Acute and Selective Inhibition of Adipocyte Glyceroneogenesis and Cytosolic Phosphoenolpyruvate Carboxykinase by Interferon {gamma} Endocrinology, August 1, 2007; 148(8): 4007 - 4014. [Abstract] [Full Text] [PDF]
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S. N. Leroyer, J. Tordjman, G. Chauvet, J. Quette, C. Chapron, C. Forest, and B. Antoine Rosiglitazone Controls Fatty Acid Cycling in Human Adipose Tissue by Means of Glyceroneogenesis and Glycerol Phosphorylation J. Biol. Chem., May 12, 2006; 281(19): 13141 - 13149. [Abstract] [Full Text] [PDF]
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S. C. Burgess, N. Hausler, M. Merritt, F. M. H. Jeffrey, C. Storey, A. Milde, S. Koshy, J. Lindner, M. A. Magnuson, C. R. Malloy, et al. Impaired Tricarboxylic Acid Cycle Activity in Mouse Livers Lacking Cytosolic Phosphoenolpyruvate Carboxykinase J. Biol. Chem., November 19, 2004; 279(47): 48941 - 48949. [Abstract] [Full Text] [PDF]
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 I. Bogacka, H. Xie, G. A. Bray, and S. R. Smith The Effect of Pioglitazone on Peroxisome Proliferator-Activated Receptor-{gamma} Target Genes Related to Lipid Storage In Vivo Diabetes Care, July 1, 2004; 27(7): 1660 - 1667. [Abstract] [Full Text] [PDF]
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M. A. Magnuson, P. She, and M. Shiota Gene-altered Mice and Metabolic Flux Control J. Biol. Chem., August 29, 2003; 278(35): 32485 - 32488. [Full Text] [PDF]
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L. Reshef, Y. Olswang, H. Cassuto, B. Blum, C. M. Croniger, S. C. Kalhan, S. M. Tilghman, and R. W. Hanson Glyceroneogenesis and the Triglyceride/Fatty Acid Cycle J. Biol. Chem., August 15, 2003; 278(33): 30413 - 30416. [Full Text] [PDF]
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J. Tordjman, G. Chauvet, J. Quette, E. G. Beale, C. Forest, and B. Antoine Thiazolidinediones Block Fatty Acid Release by Inducing Glyceroneogenesis in Fat Cells J. Biol. Chem., May 23, 2003; 278(21): 18785 - 18790. [Abstract] [Full Text] [PDF]
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