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The proposed systemic thermogenic metabolites succinate and 12,13-diHOME are inversely associated with adiposity and related metabolic traits: evidence from a large human cross-sectional study

The proposed systemic thermogenic metabolites succinate and 12,13-diHOME are inversely associated with adiposity and related metabolic traits: evidence from a large human cross-sectional study
The proposed systemic thermogenic metabolites succinate and 12,13-diHOME are inversely associated with adiposity and related metabolic traits: evidence from a large human cross-sectional study
Aims/hypothesis
Circulating succinate and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were recently shown to promote brown adipocyte thermogenesis and protect against metabolic disorders in rodents. This study aimed to evaluate the associations between plasma levels of these metabolites and adiposity and metabolic profile in humans.

Methods
Fasting plasma succinate and 12,13-diHOME levels were quantified using ultra HPLC-tandem MS in 2248 individuals (50% female, mean age 41.3 ± 5.9 years, mean BMI 26.1 ± 4.6 kg/m2) in addition to fasting plasma biochemistry. Total and regional adiposity were assessed with dual-energy x-ray absorptiometry. An age- and sex-adjusted linear regression model was used to determine the associations between succinate and 12,13-diHOME levels and body composition and metabolic profile. Two-sample Mendelian randomisation was used to assess the associations between genetically determined BMI and metabolic traits with circulating plasma succinate and 12,13-diHOME.

Results
A one-SD higher plasma succinate and 12,13-diHOME concentration was associated with a 0.15 SD (95% CI 0.28, 0.03) and 0.08 SD (0.15, 0.01) lower total fat mass respectively. Additionally, a one-SD higher plasma 12,13-diHOME level was associated with a 0.09 SD (0.16, 0.02) lower fasting plasma insulin and 0.10 SD (0.17, 0.04) lower plasma triacylglycerol. In Mendelian randomisation analyses, genetically determined higher BMI, fasting hyperinsulinaemia and elevated lipid levels were not associated with changes in either plasma succinate or plasma 12,13-diHOME concentrations. No indications of bias due to directional pleiotropy were detected in the Mendelian randomisation analyses.

Conclusions/interpretation
Our findings tentatively suggest that plasma succinate and 12,13-diHOME may play a role in the regulation of energy metabolism and brown adipose tissue activation in humans. Further studies encompassing direct assessment of brown adipose tissue activity and dietary supplementation are necessary to investigate the potential beneficial effects of these metabolites on systemic metabolism.
0012-186X
1-9
Vasan, Senthil K.
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Noordam, Raymond
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Gowri, Mahasampath S.
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Neville, Matthew J.
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Karpe, Fredrik
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Christodoulides, Constantinos
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Vasan, Senthil K.
eab07837-caeb-4651-802f-fdc07ed15d1c
Noordam, Raymond
d72f2b3c-673b-4994-a35b-4283beec142a
Gowri, Mahasampath S.
d1fb9132-b696-4498-b8f8-a50d1818fb96
Neville, Matthew J.
b7c9383b-0713-4c97-9d84-cb79ebde7949
Karpe, Fredrik
05abcb32-83b7-44eb-ab12-7c360f4f9c12
Christodoulides, Constantinos
f5ad503b-bd23-4f57-8e5f-4a7d9ab6c7e5

Vasan, Senthil K., Noordam, Raymond, Gowri, Mahasampath S., Neville, Matthew J., Karpe, Fredrik and Christodoulides, Constantinos (2019) The proposed systemic thermogenic metabolites succinate and 12,13-diHOME are inversely associated with adiposity and related metabolic traits: evidence from a large human cross-sectional study. Diabetologia, 1-9. (doi:10.1007/s00125-019-4947-5).

Record type: Article

Abstract

Aims/hypothesis
Circulating succinate and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were recently shown to promote brown adipocyte thermogenesis and protect against metabolic disorders in rodents. This study aimed to evaluate the associations between plasma levels of these metabolites and adiposity and metabolic profile in humans.

Methods
Fasting plasma succinate and 12,13-diHOME levels were quantified using ultra HPLC-tandem MS in 2248 individuals (50% female, mean age 41.3 ± 5.9 years, mean BMI 26.1 ± 4.6 kg/m2) in addition to fasting plasma biochemistry. Total and regional adiposity were assessed with dual-energy x-ray absorptiometry. An age- and sex-adjusted linear regression model was used to determine the associations between succinate and 12,13-diHOME levels and body composition and metabolic profile. Two-sample Mendelian randomisation was used to assess the associations between genetically determined BMI and metabolic traits with circulating plasma succinate and 12,13-diHOME.

Results
A one-SD higher plasma succinate and 12,13-diHOME concentration was associated with a 0.15 SD (95% CI 0.28, 0.03) and 0.08 SD (0.15, 0.01) lower total fat mass respectively. Additionally, a one-SD higher plasma 12,13-diHOME level was associated with a 0.09 SD (0.16, 0.02) lower fasting plasma insulin and 0.10 SD (0.17, 0.04) lower plasma triacylglycerol. In Mendelian randomisation analyses, genetically determined higher BMI, fasting hyperinsulinaemia and elevated lipid levels were not associated with changes in either plasma succinate or plasma 12,13-diHOME concentrations. No indications of bias due to directional pleiotropy were detected in the Mendelian randomisation analyses.

Conclusions/interpretation
Our findings tentatively suggest that plasma succinate and 12,13-diHOME may play a role in the regulation of energy metabolism and brown adipose tissue activation in humans. Further studies encompassing direct assessment of brown adipose tissue activity and dietary supplementation are necessary to investigate the potential beneficial effects of these metabolites on systemic metabolism.

Text
19-0398_R2-Vasan-edited-SKV CC Final - Accepted Manuscript
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More information

Accepted/In Press date: 3 June 2019
e-pub ahead of print date: 15 July 2019

Identifiers

Local EPrints ID: 432759
URI: http://eprints.soton.ac.uk/id/eprint/432759
ISSN: 0012-186X
PURE UUID: d65959dd-96d4-4793-943b-27e392e1f39e

Catalogue record

Date deposited: 26 Jul 2019 16:30
Last modified: 26 Nov 2021 05:34

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Contributors

Author: Senthil K. Vasan
Author: Raymond Noordam
Author: Mahasampath S. Gowri
Author: Matthew J. Neville
Author: Fredrik Karpe
Author: Constantinos Christodoulides

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