Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

Kenneth D'Souza; Carine Nzirorera; Andrew M. Cowie; Geena P. Varghese; Purvi Trivedi; Thomas O. Eichmann; Dipsikha Biswas; Mohamed Touaibia; Andrew J. Morris; Vassilis Aidinis; Daniel A. Kane; Thomas Pulinilkunnil; Petra C. Kienesberger

doi:10.1194/jlr.M082008

Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

Kenneth D'Souza, Carine Nzirorera, Andrew M. Cowie, Geena P. Varghese, Purvi Trivedi, Thomas O. Eichmann, Dipsikha Biswas, Mohamed Touaibia, Andrew J. Morris, Vassilis Aidinis, Daniel A. Kane, Thomas Pulinilkunnil, Petra C. Kienesberger

Internal Medicine

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX^+/) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX^+/ mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS-fed ATX^+/ mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.

Original language	English
Pages (from-to)	1805-1817
Number of pages	13
Journal	Journal of Lipid Research
Volume	59
Issue number	10
DOIs	https://doi.org/10.1194/jlr.M082008
State	Published - 2018

Bibliographical note

Funding Information:
This work was supported by Natural Sciences and Engineering Research Council of Canada Discovery Grant RGPIN-2014-04454, Canadian Institutes of Health Research Project Grant 156308, and grants from the Banting Research Foundation, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Heart and Stroke Foundation of Canada to P.C.K. Additional support was provided by the Natural Sciences and Engineering Research Council of Canada, the Canadian Diabetes Association, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Canada Foundation for Innovation to T.P. The authors declare that no conflict of interest exists.

Funding Information:
This work was supported by Natural Sciences and Engineering Research Council of Canada Discovery Grant RGPIN-2014-04454, Canadian Institutes of Health Research Project Grant 156308, and grants from the Banting Research Foundation, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Heart and Stroke Foundation of Canada to P.C.K. Additional support was provided by the Natural Sciences and Engineering Research Council of Canada, the Canadian Diabetes Association, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Canada Foundation for Innovation to T.P. The authors declare that no conflict of interest exists. Manuscript received 27 November 2017 and in revised form 26 June 2018. Published, JLR Papers in Press, August 2, 2018 DOI https://doi.org/10.1194/jlr.M082008

Publisher Copyright:
© 2018 American Society for Biochemistry and Molecular Biology Inc. All rights reserved.

Keywords

Diet effects/lipid metabolism
Glucose
Pyruvate
Respiration
Skeletal muscle

ASJC Scopus subject areas

Biochemistry
Endocrinology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1194/jlr.M082008

Cite this

D'Souza, K., Nzirorera, C., Cowie, A. M., Varghese, G. P., Trivedi, P., Eichmann, T. O., Biswas, D., Touaibia, M., Morris, A. J., Aidinis, V., Kane, D. A., Pulinilkunnil, T., & Kienesberger, P. C. (2018). Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism. Journal of Lipid Research, 59(10), 1805-1817. https://doi.org/10.1194/jlr.M082008

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title = "Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism",

abstract = "Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX+/) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX+/ mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS-fed ATX+/ mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.",

keywords = "Diet effects/lipid metabolism, Glucose, Pyruvate, Respiration, Skeletal muscle",

author = "Kenneth D'Souza and Carine Nzirorera and Cowie, {Andrew M.} and Varghese, {Geena P.} and Purvi Trivedi and Eichmann, {Thomas O.} and Dipsikha Biswas and Mohamed Touaibia and Morris, {Andrew J.} and Vassilis Aidinis and Kane, {Daniel A.} and Thomas Pulinilkunnil and Kienesberger, {Petra C.}",

note = "Funding Information: This work was supported by Natural Sciences and Engineering Research Council of Canada Discovery Grant RGPIN-2014-04454, Canadian Institutes of Health Research Project Grant 156308, and grants from the Banting Research Foundation, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Heart and Stroke Foundation of Canada to P.C.K. Additional support was provided by the Natural Sciences and Engineering Research Council of Canada, the Canadian Diabetes Association, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Canada Foundation for Innovation to T.P. The authors declare that no conflict of interest exists. Funding Information: This work was supported by Natural Sciences and Engineering Research Council of Canada Discovery Grant RGPIN-2014-04454, Canadian Institutes of Health Research Project Grant 156308, and grants from the Banting Research Foundation, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Heart and Stroke Foundation of Canada to P.C.K. Additional support was provided by the Natural Sciences and Engineering Research Council of Canada, the Canadian Diabetes Association, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Canada Foundation for Innovation to T.P. The authors declare that no conflict of interest exists. Manuscript received 27 November 2017 and in revised form 26 June 2018. Published, JLR Papers in Press, August 2, 2018 DOI https://doi.org/10.1194/jlr.M082008 Publisher Copyright: {\textcopyright} 2018 American Society for Biochemistry and Molecular Biology Inc. All rights reserved.",

year = "2018",

doi = "10.1194/jlr.M082008",

language = "English",

volume = "59",

pages = "1805--1817",

number = "10",

}

D'Souza, K, Nzirorera, C, Cowie, AM, Varghese, GP, Trivedi, P, Eichmann, TO, Biswas, D, Touaibia, M, Morris, AJ, Aidinis, V, Kane, DA, Pulinilkunnil, T & Kienesberger, PC 2018, 'Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism', Journal of Lipid Research, vol. 59, no. 10, pp. 1805-1817. https://doi.org/10.1194/jlr.M082008

TY - JOUR

T1 - Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

AU - D'Souza, Kenneth

AU - Nzirorera, Carine

AU - Cowie, Andrew M.

AU - Varghese, Geena P.

AU - Trivedi, Purvi

AU - Eichmann, Thomas O.

AU - Biswas, Dipsikha

AU - Touaibia, Mohamed

AU - Morris, Andrew J.

AU - Aidinis, Vassilis

AU - Kane, Daniel A.

AU - Pulinilkunnil, Thomas

AU - Kienesberger, Petra C.

N1 - Funding Information: This work was supported by Natural Sciences and Engineering Research Council of Canada Discovery Grant RGPIN-2014-04454, Canadian Institutes of Health Research Project Grant 156308, and grants from the Banting Research Foundation, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Heart and Stroke Foundation of Canada to P.C.K. Additional support was provided by the Natural Sciences and Engineering Research Council of Canada, the Canadian Diabetes Association, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Canada Foundation for Innovation to T.P. The authors declare that no conflict of interest exists. Funding Information: This work was supported by Natural Sciences and Engineering Research Council of Canada Discovery Grant RGPIN-2014-04454, Canadian Institutes of Health Research Project Grant 156308, and grants from the Banting Research Foundation, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Heart and Stroke Foundation of Canada to P.C.K. Additional support was provided by the Natural Sciences and Engineering Research Council of Canada, the Canadian Diabetes Association, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Canada Foundation for Innovation to T.P. The authors declare that no conflict of interest exists. Manuscript received 27 November 2017 and in revised form 26 June 2018. Published, JLR Papers in Press, August 2, 2018 DOI https://doi.org/10.1194/jlr.M082008 Publisher Copyright: © 2018 American Society for Biochemistry and Molecular Biology Inc. All rights reserved.

PY - 2018

Y1 - 2018

N2 - Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX+/) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX+/ mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS-fed ATX+/ mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.

AB - Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX+/) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX+/ mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS-fed ATX+/ mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.

KW - Diet effects/lipid metabolism

KW - Glucose

KW - Pyruvate

KW - Respiration

KW - Skeletal muscle

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DO - 10.1194/jlr.M082008

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AN - SCOPUS:85054086353

VL - 59

SP - 1805

EP - 1817

IS - 10

ER -

Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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