The impact of altered carnitine availability on acylcarnitine metabolism, energy expenditure and glucose tolerance in diet-induced obese mice

Abstract

Aim: Acylcarnitines are fatty acid oxidation (FAO) intermediates, which have been implicated in diet-induced insulin resistance. Elevated acylcarnitine levels are found in obese, insulin resistant humans and rodents, and coincide with lower free carnitine. We hypothesized that increasing free carnitine levels by administration of the carnitine precursor γ-butyrobetaine (γBB) could facilitate FAO, thereby improving insulin sensitivity.

Methods: C57BL/6N mice were fed with a high fat or chow diet with or without γBB supplementation (n=10 per group). After 8weeks of diet, indirect calorimetry, glucose tolerance and insulin sensitivity tests were performed. AC profiles and carnitine biosynthesis intermediates were analyzed in plasma and tissues by tandem mass spectrometry (MS) and liquid chromatography tandem MS.

Results: γBB supplementation did not facilitate FAO, was unable to curb bodyweight and did not prevent impaired glucose homeostasis in the HFD fed mice in spite of marked alterations in the acylcarnitine profiles in plasma and liver. Remarkably, γBB did not affect the acylcarnitine profile in other tissues, most notably muscle. Administration of a bolus acetylcarnitine also caused significant changes in plasma and liver, but not in muscle acylcarnitine profiles, again without effect on glucose tolerance.

Conclusion: Altogether, increasing carnitine availability affects acylcarnitine profiles in plasma and liver but does not modulate glucose tolerance or insulin sensitivity. This may be due to the lack of an effect on muscle acylcarnitine profiles, as muscle tissue is an important contributor to whole body insulin sensitivity. These results warrant caution on making associations between plasma acylcarnitine levels and insulin resistance.

Keywords: Fatty acid oxidation; Insulin resistance; Lipotoxicity.