Dataset Information

Mechanistic insights revealed by lipid profiling in monogenic insulin resistance syndromes (Human data)

ABSTRACT: Evidence from several recent metabolomic studies suggests that increased concentrations of triacylglycerols (TAGs) 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. Therefore, we compared metabolite profiles in patients with congenital lipodystrophy or loss-of-function insulin resistance (INSR) mutations with healthy controls. The absence of significant differences in TAG species in the INSR group suggest that changes previously observed in epidemiological studies are not purely a consequence of insulin resistance. The presence of TAGs 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 TAG species is indicative of increased de novo lipogenesis (DNL). To test this we investigated the distribution of these TAGs in lipoprotein fractions using size exclusion chromatography prior to mass spectrometry. This associated these TAGs with VLDL particles, and hence release of TAGs into the blood from the liver. To test further the hepatic origin of these TAGs we induced DNL in the mouse, comparing ob/ob and wild type mice on a chow or high fat diet, confirming that DNL induced an increase in relatively shorter, more saturated fatty acids. Overall, these studies highlight DNL in the pathogenesis of metabolic dyslipidaemia in states where energy intake exceeds the capacity of adipose tissue.

The protocols and data for human samples are reported in the current study MTBLS162.
The protocols and data for mice samples are reported in the study MTBSL327.

INSTRUMENT(S): Exactive (Thermo Scientific)

SUBMITTER: Xinzhu Wang

PROVIDER: MTBLS162 | MetaboLights | 2015-10-05

REPOSITORIES: MetaboLights

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Dataset's files

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			Action	DRS
	MTBLS162	Other
	FILES	Other
	a_MTBLS162_lypodystrophy_metabolite_profiling_mass_spectrometry.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS162_lypodystrophy_metabolite_profiling_mass_spectrometry_v2_maf.tsv	Tabular

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Publications

Mechanistic insights revealed by lipid profiling in monogenic insulin resistance syndromes.

Eiden Michael M Koulman Albert A Hatunic Mensud M West James A JA Murfitt Steven S Osei Michael M Adams Claire C Wang Xinzhu X Chu Yajing Y Marney Luke L Roberts Lee D LD O'Rahilly Stephen S Semple Robert K RK Savage David B DB Griffin Julian L JL

Genome medicine 20150628

<h4>Background</h4>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. 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.<h4>Methods</h4>We compared metabolite prof ...[more]

PMID: 26273324

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Project description:Background: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Our aims were to investigate whether a sub-set of TAGs were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. Results: We conducted direct infusion mass spectrometry of lipids in plasma to study the association between specific triacylglycerols (TAGs) and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study (n=1507), and evaluated clustering of TAGs in the National Survey of Health and Development UK cohort (n=1701). TAGs formed 3 clusters, with those TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons being specifically associated with hepatic steatosis. These TAGs were associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL was measured in hyperphagic ob/ob mice, mice on a Western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs were increased in plasma from patients with biopsy-confirmed steatosis. Conclusion: A sub-set of TAGs are associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in Western populations is in part driven by increased DNL following carbohydrate rich meals. The protocols and data of the human carbohydrate feeding study in healthy volunteers are reported in the study MTBLS616. Linked Studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS616' target='_blank'>MTBLS616</a>

Project description:Background: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Our aims were to investigate whether a sub-set of TAGs were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. Results: We conducted direct infusion mass spectrometry of lipids in plasma to study the association between specific triacylglycerols (TAGs) and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study (n=1507), and evaluated clustering of TAGs in the National Survey of Health and Development UK cohort (n=1701). TAGs formed 3 clusters, with those TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons being specifically associated with hepatic steatosis. These TAGs were associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL was measured in hyperphagic ob/ob mice, mice on a Western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs were increased in plasma from patients with biopsy-confirmed steatosis. Conclusion: A sub-set of TAGs are associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in Western populations is in part driven by increased DNL following carbohydrate rich meals. The protocols and data of the murine study of de novo lipogenesis are included in the study MTBLS614. Linked Studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS614' target='_blank'>MTBLS614</a>