Abstract
BackgroundEvidence from several recent metabolomic studies suggests that increased concentrations of triacylglycerols with shorter (14–16 carbon atoms), saturated fatty acids are associated with insulin resistance and the risk of type 2 diabetes. Although causality cannot be inferred from association studies, patients in whom the primary cause of insulin resistance can be genetically defined offer unique opportunities to address this challenge.MethodsWe compared metabolite profiles in patients with congenital lipodystrophy or loss-of-function insulin resistance (INSR gene) mutations with healthy controls.ResultsThe absence of significant differences in triacylglycerol species in the INSR group suggest that changes previously observed in epidemiological studies are not purely a consequence of insulin resistance. The presence of triacylglycerols with lower carbon numbers and high saturation in patients with lipodystrophy suggests that these metabolite changes may be associated with primary adipose tissue dysfunction. The observed pattern of triacylglycerol species is indicative of increased de novo lipogenesis in the liver. To test this we investigated the distribution of these triacylglycerols in lipoprotein fractions using size exclusion chromatography prior to mass spectrometry. This associated these triacylglycerols with very low-density lipoprotein particles, and hence release of triacylglycerols into the blood from the liver. To test further the hepatic origin of these triacylglycerols we induced de novo lipogenesis in the mouse, comparing ob/ob and wild-type mice on a chow or high fat diet, confirming that de novo lipogenesis induced an increase in relatively shorter, more saturated fatty acids.ConclusionsOverall, these studies highlight hepatic de novo lipogenesis in the pathogenesis of metabolic dyslipidaemia in states where energy intake exceeds the capacity of adipose tissue.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0179-6) contains supplementary material, which is available to authorized users.
Highlights
Evidence from several recent metabolomic studies suggests that increased concentrations of triacylglycerols with shorter (14–16 carbon atoms), saturated fatty acids are associated with insulin resistance and the risk of type 2 diabetes
The lipidomic profile of the insulin receptoropathies’ (INSR) group was largely normal, whereas that of the LD group was associated with a relative increase in TAGs containing shorter (14–18 carbon atom fatty acids) and more saturated fatty acids. We show that these TAGs are exported by the liver in very-lowdensity lipoprotein (VLDL), and that similar changes are observed when de novo lipogenesis (DNL) is stimulated in the mouse by increasing consumption of a diet rich in carbohydrates
This pattern was observed in samples from five healthy men fed a hypercaloric carbohydrate-enriched diet designed to stimulate hepatic DNL [21]. These data are consistent with stable isotope-based measurements of the rate of DNL in patients with LD and INSR mutations [7]. In this previous study DNL was found to increase over threefold in lipodystrophic individuals compared with the control group, with those with insulin receptoropathies and mutations in AKT2 being intermediate in terms of their DNL capacity
Summary
Evidence from several recent metabolomic studies suggests that increased concentrations of triacylglycerols with shorter (14–16 carbon atoms), saturated fatty acids are associated with insulin resistance and the risk of type 2 diabetes. Insulin resistance (IR) is a major factor in the development of type 2 diabetes mellitus (T2DM) and underpins the tight relationships among obesity and many of its metabolic complications, including hyperglycaemia, high triacylglycerol (TAG) levels, low high-density lipoprotein (HDL)-cholesterol, non-alcoholic fatty liver disease (NAFLD), and hypoadiponectinaemia as well as hyperandrogenism in women. Obesity is the major association with the recent increase in IR incidence, so understanding the mechanistic basis of this association is a priority.
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