Glyceroneogenesis & The Triglyceride/Fatty Acid Cycle Revisited

Glyceroneogenesis and the Triglyceride/Fatty Acid Cycle   (TAG/FA)
JBC Papers in Press, June 4, 2003, DOI 10.1074/jbc.R300017200
Lea Reshef, Yael Olswang, Hanoch Cassuto, Barak Blum, Colleen M. Croniger, Satish C. Kalhan, Shirley M. Tilghman , and Richard W. Hanson

The above paper is referenced in Good Calories, Bad Calories, and is a paper I believe one cannot read thoroughly and still believe that dietary carbohydrate is required in order to "fix" fat and become obese.  It has been quite a while since I read it in its entirety.  Doing so in recent days I've noticed even more information in this paper that counters the whole notion that more dietary carb leads to more glycerol-3-phosphate leads to more esterification of fatty acids to the storage triglyceride form.   More specifically, these four paragraphs/excerpts were somewhat drowned out for me in my first reading:

The mutation [PEPCK-PPARE -/-  that abolished the PEPCK-C gene expression in WAT] virtually abolished glyceroneogenesis in WAT of [these] mice, as determined by their inability to synthesize glyceride-glycerol from pyruvate; this establishes PEPCK-C as a key enzyme in glyceroneogenesis. The PEPCK-PPARE - /- mice also lost considerable triglyceride from their adipose tissue, and about 30% of the animals became lipodystrophic as adults.   The lipodystrophy noted in the PEPCK-PPARE - /- mice differs considerably from that found in other models of this disorder because the animals do not have altered glucose metabolism, except for a very moderate hyperglycemia noted in older mice.
Further support for the importance of glyceroneogenesis in adipose tissue was provided by the experiments of Franckhauser et al. who overexpressed a chimeric transgene containing the PEPCK-C structural gene linked to the aP2 promoter in transgenic mice. The gene was expressed at high levels, specifically in WAT because of the specificity of the aP2 gene promoter.   Adult transgenic mice had greatly enhanced rates of glyceroneogenesis and higher levels of triglyceride synthesis in their WAT; the animals were also markedly obese and did not exhibit signs of altered glucose metabolism. These findings, together with those of Olswang et al.,  provide strong support for the pathway of glyceroneogenesis in WAT and the key role that is played by PEPCK-C in controlling the turnover of triglyceride during fasting.
Summary:  PEPCK-C is a key enzyme in the glyceroneogenesis pathway.  Indeed it is one of the enzymes found in adipose tissue that led to the discovery of this metabolic path.  So what happens when it is under or over-expressed in animal models?

Insufficient PEPCK-C → reduced fat mass        Excess PEPCK-C → obesity

So, putting this together with other information, we can create mice that are obesity resistant by knocking out insulin receptors (FIRKO), ASP (C3KO), ASP-receptor (C5L2KO), and now PEPCK-C (I'm going to call these Diet Pepsi K Cola mice!).  There's to this fat tissue regulation than insulin.  This is obvious to the real scientists Gary Taubes thinks are all idiots, but not to a science journalist who claims to have read this paper.  
The importance of glyceroneogenesis in controlling triglyceride turnover in WAT is supported by other lines of evidence.   Glucose is the major precursor of 3-glycerol phosphate for triglyceride synthesis in this tissue in the fed state.   During diabetes, there is both an elevated level of lipolysis and a greatly diminished rate of transport of glucose into the adipocyte, resulting in mobilization of triglyceride from adipose tissue.   Adipocyte-specific deletion of the gene for the transporter that is required for glucose entry into the adipocyte (GLUT4) generated mice that were insulin-resistant.  Despite this, these mice did not have a loss of triglycerides from WAT.  Thus, there must be an alternative source of 3-glycerol phosphate for triglyceride synthesis in WAT in the GLUT4-deficient mice.   It is likely that these mice will have an enhanced activity of glyceroneogenesis in their WAT in order to maintain triglyceride homeostasis.  
Summary:  Impaired glucose transport does not alter the balance of the TAG/FA cycle by reducing esterification.  If it did, the balance would be shifted towards FA and we would see TAG loss, e.g. loss of fat mass.
Finally, it is of interest that the gene for the mitochondrial dicarboxylate transporter is highly expressed in WAT and the level of its mRNA is induced by fatty acids and inhibited by insulin.   The dicarboxylate transporter is required for the movement of malate in exchange for other anions, such as α -ketoglutarate, from the mitochondria to the cytosol. This pathway would provide the major route for the generation of cytosolic oxalacetate, a substrate of PEPCK-C in glyceroneogenesis.
Summary:  Genes for a metabolic pathway that provides a major substrate for the formation of G3P through glyceroneogenesis are highly expressed in WAT.

We shall be revisiting this paper at least once more in the coming days ...