To the Editor:

We have read with interest the recent article by Orellana-Gavaldà et al.,1 who report that a long-term increase in hepatic fatty acid oxidation (FAO) leads to a beneficial effect in a mouse model of obesity and diabetes. This effect of increased FAO is induced by the overexpression of carnitine palmitoyltransferase 1A (CPT1A) or its malonyl–coenzyme A insensitive mutant isoform (CPT1AM). With the reduction in hepatic steatosis, there should be an accompanying increase in insulin sensitivity. CPT1AM overexpression is the more effective treatment in this obese/diabetes phenotype animal model. An important finding is that an increase in FAO during the postprandial phase contributes to the overall effect; during this time, endogenous CPT1A activity is reduced by a concomitant increase of malonyl–coenzyme A, its physiological inhibitor. Greater FAO activity during the phase in which the liver is primarily engaged in the synthesis of fatty acids and triglycerides (TAGs) may lead to important long-term changes in metabolic intermediates (i.e., acyl coenzyme A). These intermediates may mediate the observed improvements in glucose and lipid metabolism by affecting the complex network of transcriptional factors (i.e., peroxisome proliferator-activated receptors, hepatocyte nuclear factor, and sirtuins).2 Furthermore, the lowering of liver TAG levels may be associated with a reduction of TAG metabolic intermediates, which are known to counteract insulin signaling.3 This article describes a remarkable decrease in plasma glucose levels in CPT1AM+/+ db/db mice (genetically obese and diabetic mice). This counterintuitive effect occurs in a murine model in which the severe hyperglycemic condition is primarily dictated by an increased rate of gluconeogenesis (GNG). Indeed, this metabolic pathway is strongly dependent on increased FAO activity according to the following observations: it provides adenosine triphosphate and reducing equivalents, and it increases the intramitochondrial levels of acetyl coenzyme A, which is an obligate allosteric activator of the key enzyme pyruvate carboxylase in the GNG pathway.4

Metformin, a first-line therapy for type 2 diabetes, depresses GNG via the reduction of intracellular adenosine triphosphate contents.5 Also, an efficient way of reducing hepatic GNG is the inhibition of CPT1A. We have recently shown that selectively inhibiting CPT1A depresses GNG both in vitro and in vivo and results in improvement in the diabetic phenotype for db/db mice; this is also accompanied by improved insulin sensitivity in diet-induced obese mice.6 These effects have been observed despite concomitant increases in liver TAG levels. According to these metabolic considerations, promoting FAO seems to conflict with the antidiabetic outcomes reported in db/db mice expressing CPT1AM in the liver. An analysis of the molecular mechanism or mechanisms underlying the antidiabetic effects resulting from the greater activity of liver FAO perhaps may open new approaches to modulating GNG in type 2 diabetes. One scientific inaccuracy in this work is the erroneous report by the authors that β-hydroxybutyryl coenzyme A in the liver is an intermediate of ketone body metabolism (see Table 1 and p 825 of their article). D-β-Hydroxybutyrate is a ketone body enantiomer oxidized through the formation of acetoacetate and not through its esterification to coenzyme A, whereas the enantiomer L-β-hydroxybutyl coenzyme A is an intermediate of FAO.7, 8


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  • 1
    Orellana-Gavaldà JM, Herrero L, Malandrino MI, Pañeda A, Sol Rodríguez-Peña M, Petry H, et al. Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation. Hepatology 2011; 53: 821-832.
  • 2
    Sugden MC, Caton PW, Holness MJ. PPAR control: it's SIRTainly as easy as PGC. J Endocrinol 2010; 204: 93-104.
  • 3
    Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 2007; 87: 507-520.
  • 4
    Nuttall FQ, Ngo A, Gannon MC. Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant? Diabetes Metab Res Rev 2008; 24: 438-458.
  • 5
    Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010; 120: 2355-2369.
  • 6
    Conti R, Mannucci E, Pessotto P, Tassoni E, Carminati P, Giannessi F, et al. Selective reversible inhibition of liver carnitine palmitoyl-transferase 1 by teglicar reduces gluconeogenesis and improves glucose homeostasis. Diabetes 2011; 60: 644-651.
  • 7
    Scofield RF, Brady PS, Schumann WC, Kumaran K, Ohgaku S, Margolis JM, et al. On the lack of formation of L-(+)-3-hydroxybutyrate by liver. Arch Biochem Biophys 1982; 214: 268-272.
  • 8
    Lincoln BC, Des Rosiers C, Brunengraber H. Metabolism of S-3-hydroxybutyrate in the perfused rat liver. Arch Biochem Biophys 1987; 259: 149-156.

Arduino Arduini M.D.*, Mario Bonomini M.D.†, * R&D Department, CoreQuest Sagl, Bioggio, Switzerland, † Institute of Nephrology, Department of Medicine, G. d'Annunzio University, Chieti, Italy.