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Article ; Online: Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes.

Bassot, Arthur / Prip-Buus, Carina / Alves, Anaïs / Berdeaux, Olivier / Perrier, Johan / Lenoir, Véronique / Ji-Cao, Jingwei / Berger, Marie-Agnès / Loizon, Emmanuelle / Cabaret, Stephanie / Panthu, Baptiste / Rieusset, Jennifer / Morio, Béatrice

Biochimica et biophysica acta. Molecular and cell biology of lipids

2021 Volume 1866, Issue 12, Page(s) 159030

Abstract: In the liver, contact sites between the endoplasmic reticulum (ER) and mitochondria (named MAMs) may be crucial hubs for the regulation of lipid metabolism, thus contributing to the exacerbation or prevention of fatty liver. We hypothesized that tether ... ...

Abstract	In the liver, contact sites between the endoplasmic reticulum (ER) and mitochondria (named MAMs) may be crucial hubs for the regulation of lipid metabolism, thus contributing to the exacerbation or prevention of fatty liver. We hypothesized that tether proteins located at MAMs could play a key role in preventing triglyceride accumulation in hepatocytes and nonalcoholic fatty liver disease (NAFLD) occurrence. To test this, we explored the role of two key partners in building MAM integrity and functionality, the glucose-regulated protein 75 (Grp75) and mitofusin 2 (Mfn2), which liver contents are altered in obesity and NAFLD. Grp75 or Mfn2 expression was either silenced using siRNA or overexpressed with adenoviruses in Huh7 cells. Silencing of Grp75 and Mfn2 resulted in decreased ER-mitochondria interactions, mitochondrial network fusion state and mitochondrial oxidative capacity, while overexpression of the two proteins induced mirror impacts on these parameters. Furthermore, Grp75 or Mfn2 silencing decreased cellular cholesterol content and enhanced triglyceride secretion in ApoB100 lipoproteins, while their overexpression led to reverse effects. Cellular phosphatidylcholine/phosphatidylethanolamine ratio was decreased only upon overexpression of the proteins, potentially contributing to altered ApoB100 assembly and secretion. Despite the opposite differences, both silencing and overexpression of Grp75 or Mfn2 induced triglyceride storage, although a fatty acid challenge was required to express the alteration upon protein silencing. Among the mechanisms potentially involved in this phenotype, ER stress was closely associated with altered triglyceride metabolism after Grp75 or Mfn2 overexpression, while blunted mitochondrial FA oxidation capacity may be the main defect causing triglyceride accumulation upon Grp75 or Mfn2 silencing. Further studies are required to decipher the link between modulation of Grp75 or Mfn2 expression, change in MAM integrity and alteration of cholesterol content of the cell. In conclusion, Grp75 or Mfn2 silencing and overexpression in Huh7 cells contribute to altering MAM integrity and cholesterol storage in opposite directions, but all promote triglyceride accumulation through distinct cellular pathways. This study also highlights that besides Mfn2, Grp75 could play a central role in hepatic lipid and cholesterol metabolism in obesity and NAFLD.
MeSH term(s)	Apolipoprotein B-100/genetics ; Cell Line ; Cholesterol/metabolism ; Endoplasmic Reticulum/genetics ; Endoplasmic Reticulum/metabolism ; GTP Phosphohydrolases/antagonists & inhibitors ; GTP Phosphohydrolases/genetics ; Gain of Function Mutation/genetics ; Gene Expression Regulation/genetics ; Gene Silencing ; HSP70 Heat-Shock Proteins/antagonists & inhibitors ; HSP70 Heat-Shock Proteins/genetics ; Hepatocytes/metabolism ; Humans ; Liver/metabolism ; Loss of Function Mutation/genetics ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Proteins/antagonists & inhibitors ; Mitochondrial Proteins/genetics ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/metabolism ; Non-alcoholic Fatty Liver Disease/pathology ; Triglycerides/metabolism
Chemical Substances	Apolipoprotein B-100 ; HSP70 Heat-Shock Proteins ; HSPA9 protein, human ; Mitochondrial Proteins ; Triglycerides ; Cholesterol (97C5T2UQ7J) ; GTP Phosphohydrolases (EC 3.6.1.-) ; MFN2 protein, human (EC 3.6.1.-)
Language	English
Publishing date	2021-08-20
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbalip.2021.159030
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Article: Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes

Biochimica et biophysica acta. 2021 Dec., v. 1866, no. 12

2021

Abstract	In the liver, contact sites between the endoplasmic reticulum (ER) and mitochondria (named MAMs) may be crucial hubs for the regulation of lipid metabolism, thus contributing to the exacerbation or prevention of fatty liver. We hypothesized that tether proteins located at MAMs could play a key role in preventing triglyceride accumulation in hepatocytes and nonalcoholic fatty liver disease (NAFLD) occurrence. To test this, we explored the role of two key partners in building MAM integrity and functionality, the glucose-regulated protein 75 (Grp75) and mitofusin 2 (Mfn2), which liver contents are altered in obesity and NAFLD. Grp75 or Mfn2 expression was either silenced using siRNA or overexpressed with adenoviruses in Huh7 cells.Silencing of Grp75 and Mfn2 resulted in decreased ER-mitochondria interactions, mitochondrial network fusion state and mitochondrial oxidative capacity, while overexpression of the two proteins induced mirror impacts on these parameters. Furthermore, Grp75 or Mfn2 silencing decreased cellular cholesterol content and enhanced triglyceride secretion in ApoB100 lipoproteins, while their overexpression led to reverse effects. Cellular phosphatidylcholine/phosphatidylethanolamine ratio was decreased only upon overexpression of the proteins, potentially contributing to altered ApoB100 assembly and secretion. Despite the opposite differences, both silencing and overexpression of Grp75 or Mfn2 induced triglyceride storage, although a fatty acid challenge was required to express the alteration upon protein silencing. Among the mechanisms potentially involved in this phenotype, ER stress was closely associated with altered triglyceride metabolism after Grp75 or Mfn2 overexpression, while blunted mitochondrial FA oxidation capacity may be the main defect causing triglyceride accumulation upon Grp75 or Mfn2 silencing. Further studies are required to decipher the link between modulation of Grp75 or Mfn2 expression, change in MAM integrity and alteration of cholesterol content of the cell.In conclusion, Grp75 or Mfn2 silencing and overexpression in Huh7 cells contribute to altering MAM integrity and cholesterol storage in opposite directions, but all promote triglyceride accumulation through distinct cellular pathways. This study also highlights that besides Mfn2, Grp75 could play a central role in hepatic lipid and cholesterol metabolism in obesity and NAFLD.
Keywords	Adenoviridae ; cholesterol ; cholesterol metabolism ; endoplasmic reticulum ; fatty acids ; fatty liver ; gain-of-function mutation ; hepatocytes ; lipoproteins ; liver ; mitochondria ; obesity ; oxidation ; phenotype ; phosphatidylcholines ; phosphatidylethanolamines ; secretion ; triacylglycerols
Language	English
Dates of publication	2021-12
Publishing place	Elsevier B.V.
Document type	Article
ISSN	1388-1981
DOI	10.1016/j.bbalip.2021.159030
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis.

Beaulant, Agathe / Dia, Maya / Pillot, Bruno / Chauvin, Marie-Agnes / Ji-Cao, Jingwei / Durand, Christine / Bendridi, Nadia / Chanon, Stephanie / Vieille-Marchiset, Aurelie / Da Silva, Claire Crola / Patouraux, Stéphanie / Anty, Rodolphe / Iannelli, Antonio / Tran, Albert / Gual, Philippe / Vidal, Hubert / Gomez, Ludovic / Paillard, Melanie / Rieusset, Jennifer

Journal of hepatology

2022 Volume 77, Issue 3, Page(s) 710–722

Abstract: Background & aims: Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated membranes: MAMs) are highly dynamic and ... ...

Abstract	Background & aims: Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated membranes: MAMs) are highly dynamic and involved in many functions; however, whether MAM dysfunction plays a causal role in hepatic insulin resistance and steatosis is not clear. Thus, we aimed to determine whether and how organelle miscommunication plays a role in the onset and progression of hepatic metabolic impairment. Methods: We analyzed hepatic ER-mitochondria interactions and calcium exchange in a time-dependent and reversible manner in mice with diet-induced obesity. Additionally, we used recombinant adenovirus to express a specific organelle spacer or linker in mouse livers, to determine the causal impact of MAM dysfunction on hepatic metabolic alterations. Results: Disruption of ER-mitochondria interactions and calcium exchange is an early event preceding hepatic insulin resistance and steatosis in mice with diet-induced obesity. Interestingly, an 8-week reversal diet concomitantly reversed hepatic organelle miscommunication and insulin resistance in obese mice. Mechanistically, disrupting structural and functional ER-mitochondria interactions through the hepatic overexpression of the organelle spacer FATE1 was sufficient to impair hepatic insulin action and glucose homeostasis. In addition, FATE1-mediated organelle miscommunication disrupted lipid-related mitochondrial oxidative metabolism and induced hepatic steatosis. Conversely, reinforcement of ER-mitochondria interactions through hepatic expression of a synthetic linker prevented diet-induced glucose intolerance after 4 weeks' overnutrition. Importantly, ER-mitochondria miscommunication was confirmed in the liver of obese patients with type 2 diabetes, and correlated with glycemia, HbA1c and HOMA-IR index. Conclusions: ER-mitochondria miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be reversed by switching to a healthy diet. Thus, targeting MAMs could help to restore metabolic homeostasis. Lay summary: The literature suggests that interactions between the endoplasmic reticulum and mitochondria could play a role in hepatic insulin resistance and steatosis during chronic obesity. In the present study, we reappraised the time-dependent regulation of hepatic endoplasmic reticulum-mitochondria interactions and calcium exchange, investigating reversibility and causality, in mice with diet-induced obesity. We also assessed the relevance of our findings to humans. We show that organelle miscommunication is an early causal trigger of hepatic insulin resistance and steatosis that can be improved by nutritional strategies.
MeSH term(s)	Animals ; Calcium/metabolism ; Communication ; DNA-Binding Proteins/metabolism ; Diabetes Mellitus, Type 2/etiology ; Diabetes Mellitus, Type 2/metabolism ; Endoplasmic Reticulum/metabolism ; Fatty Liver/etiology ; Fatty Liver/metabolism ; Glucose/metabolism ; Humans ; Insulin Resistance ; Liver/metabolism ; Liver Diseases/metabolism ; Mice ; Mitochondria/metabolism ; Obesity/complications ; Obesity/metabolism ; Transcription Factors/metabolism
Chemical Substances	DNA-Binding Proteins ; FATE1 protein, human ; Transcription Factors ; Glucose (IY9XDZ35W2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-03-28
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2022.03.017
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Article ; Online: Regulation of Mitochondria-Associated Membranes (MAMs) by NO/sGC/PKG Participates in the Control of Hepatic Insulin Response.

Bassot, Arthur / Chauvin, Marie-Agnès / Bendridi, Nadia / Ji-Cao, Jingwei / Vial, Guillaume / Monnier, Léa / Bartosch, Birke / Alves, Anaïs / Cottet-Rousselle, Cécile / Gouriou, Yves / Rieusset, Jennifer / Morio, Béatrice

Cells

2019 Volume 8, Issue 11

Abstract: Under physiological conditions, nitric oxide (NO) produced by the endothelial NO synthase (eNOS) upregulates hepatic insulin sensitivity. Recently, contact sites between the endoplasmic reticulum and mitochondria named mitochondria-associated membranes ( ... ...

Abstract	Under physiological conditions, nitric oxide (NO) produced by the endothelial NO synthase (eNOS) upregulates hepatic insulin sensitivity. Recently, contact sites between the endoplasmic reticulum and mitochondria named mitochondria-associated membranes (MAMs) emerged as a crucial hub for insulin signaling in the liver. As mitochondria are targets of NO, we explored whether NO regulates hepatic insulin sensitivity by targeting MAMs. In Huh7 cells, primary rat hepatocytes and mouse livers, enhancing NO concentration increased MAMs, whereas inhibiting eNOS decreased them. In vitro, those effects were prevented by inhibiting protein kinase G (PKG) and mimicked by activating soluble guanylate cyclase (sGC) and PKG. In agreement with the regulation of MAMs, increasing NO concentration improved insulin signaling, both in vitro and in vivo, while eNOS inhibition disrupted this response. Finally, inhibition of insulin signaling by wortmannin did not affect the impact of NO on MAMs, while experimental MAM disruption, using either targeted silencing of cyclophilin D or the overexpression of the organelle spacer fetal and adult testis-expressed 1 (FATE-1), significantly blunted the effects of NO on both MAMs and insulin response. Therefore, under physiological conditions, NO participates to the regulation of MAM integrity through the sGC/PKG pathway and concomitantly improves hepatic insulin sensitivity. Altogether, our data suggest that the induction of MAMs participate in the impact of NO on hepatocyte insulin response.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cyclic GMP-Dependent Protein Kinases/metabolism ; Endoplasmic Reticulum/metabolism ; Glucose/metabolism ; Hepatocytes/metabolism ; Humans ; Insulin/metabolism ; Insulin Resistance/physiology ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III ; Primary Cell Culture ; Rats ; Signal Transduction/drug effects ; Soluble Guanylyl Cyclase/metabolism ; Wortmannin/metabolism
Chemical Substances	Insulin ; Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; Cyclic GMP-Dependent Protein Kinases (EC 2.7.11.12) ; Soluble Guanylyl Cyclase (EC 4.6.1.2) ; Glucose (IY9XDZ35W2) ; Wortmannin (XVA4O219QW)
Language	English
Publishing date	2019-10-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8111319
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Article ; Online: Disruption of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Contributes to Muscle Insulin Resistance in Mice and Humans.

Tubbs, Emily / Chanon, Stéphanie / Robert, Maud / Bendridi, Nadia / Bidaux, Gabriel / Chauvin, Marie-Agnès / Ji-Cao, Jingwei / Durand, Christine / Gauvrit-Ramette, Daphné / Vidal, Hubert / Lefai, Etienne / Rieusset, Jennifer

Diabetes

2018 Volume 67, Issue 4, Page(s) 636–650

Abstract: Modifications of the interactions between endoplasmic reticulum (ER) and mitochondria, defined as mitochondria-associated membranes (MAMs), were recently shown to be involved in the control of hepatic insulin action and glucose homeostasis, but with ... ...

Abstract	Modifications of the interactions between endoplasmic reticulum (ER) and mitochondria, defined as mitochondria-associated membranes (MAMs), were recently shown to be involved in the control of hepatic insulin action and glucose homeostasis, but with conflicting results. Whereas skeletal muscle is the primary site of insulin-mediated glucose uptake and the main target for alterations in insulin-resistant states, the relevance of MAM integrity in muscle insulin resistance is unknown. Deciphering the importance of MAMs on muscle insulin signaling could help to clarify this controversy. Here, we show in skeletal muscle of different mice models of obesity and type 2 diabetes (T2D) a marked disruption of ER-mitochondria interactions as an early event preceding mitochondrial dysfunction and insulin resistance. Furthermore, in human myotubes, palmitate-induced insulin resistance is associated with a reduction of structural and functional ER-mitochondria interactions. Importantly, experimental increase of ER-mitochondria contacts in human myotubes prevents palmitate-induced alterations of insulin signaling and action, whereas disruption of MAM integrity alters the action of the hormone. Lastly, we found an association between altered insulin signaling and ER-mitochondria interactions in human myotubes from obese subjects with or without T2D compared with healthy lean subjects. Collectively, our data reveal a new role of MAM integrity in insulin action of skeletal muscle and highlight MAM disruption as an essential subcellular alteration associated with muscle insulin resistance in mice and humans. Therefore, reduced ER-mitochondria coupling could be a common alteration of several insulin-sensitive tissues playing a key role in altered glucose homeostasis in the context of obesity and T2D.
MeSH term(s)	Aged ; Animals ; Diabetes Mellitus, Type 2 ; Disease Models, Animal ; Endoplasmic Reticulum/metabolism ; Female ; Glucose/metabolism ; Homeostasis ; Humans ; Insulin/metabolism ; Insulin Resistance ; Intracellular Membranes/metabolism ; Male ; Mice ; Middle Aged ; Mitochondria, Muscle/metabolism ; Muscle Fibers, Skeletal/metabolism ; Muscle, Skeletal/metabolism ; Obesity/metabolism ; Palmitates/adverse effects ; Signal Transduction
Chemical Substances	Insulin ; Palmitates ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2018
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db17-0316
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Article ; Online: Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance.

Tubbs, Emily / Theurey, Pierre / Vial, Guillaume / Bendridi, Nadia / Bravard, Amélie / Chauvin, Marie-Agnès / Ji-Cao, Jingwei / Zoulim, Fabien / Bartosch, Birke / Ovize, Michel / Vidal, Hubert / Rieusset, Jennifer

Diabetes

2014 Volume 63, Issue 10, Page(s) 3279–3294

Abstract: Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are functional domains between both organelles involved in Ca(2+) exchange, through the voltage-dependent anion channel (VDAC)-1/glucose-regulated protein 75 (Grp75)/inositol 1,4,5- ... ...

Abstract	Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are functional domains between both organelles involved in Ca(2+) exchange, through the voltage-dependent anion channel (VDAC)-1/glucose-regulated protein 75 (Grp75)/inositol 1,4,5-triphosphate receptor (IP3R)-1 complex, and regulating energy metabolism. Whereas mitochondrial dysfunction, ER stress, and altered Ca(2+) homeostasis are associated with altered insulin signaling, the implication of MAM dysfunctions in insulin resistance is unknown. Here we validated an approach based on in situ proximity ligation assay to detect and quantify VDAC1/IP3R1 and Grp75/IP3R1 interactions at the MAM interface. We demonstrated that MAM integrity is required for insulin signaling and that induction of MAM prevented palmitate-induced alterations of insulin signaling in HuH7 cells. Disruption of MAM integrity by genetic or pharmacological inhibition of the mitochondrial MAM protein, cyclophilin D (CypD), altered insulin signaling in mouse and human primary hepatocytes and treatment of CypD knockout mice with metformin improved both insulin sensitivity and MAM integrity. Furthermore, ER-mitochondria interactions are altered in liver of both ob/ob and diet-induced insulin-resistant mice and improved by rosiglitazone treatment in the latter. Finally, increasing organelle contacts by overexpressing CypD enhanced insulin action in primary hepatocytes of diabetic mice. Collectively, our data reveal a new role of MAM integrity in hepatic insulin action and resistance, providing a novel target for the modulation of insulin action.
MeSH term(s)	Animals ; Cell Line ; Cells, Cultured ; Endoplasmic Reticulum/metabolism ; Hepatocytes/cytology ; Hepatocytes/metabolism ; Humans ; Insulin/metabolism ; Insulin Resistance/physiology ; Intracellular Membranes/metabolism ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Signal Transduction/physiology
Chemical Substances	Insulin
Language	English
Publishing date	2014-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db13-1751
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Article: Insulin resistance is associated with MCP1-mediated macrophage accumulation in skeletal muscle in mice and humans

Ji-Cao, Jingwei / Vial, Guillaume / Bravard, Amelie / Lefai, Etienne / Durand, Annie / Durand, Christine / Chauvin, Marie-Agnés / Laugerette, Fabienne / Debard, Cyrille / Michalski, Marie-Caroline / Laville, Martine / Vidal, Hubert / Rieusset, Jennifer

Plos One 10 (9), 1-14. (2014)

Abstract: Inflammation is now recognized as a major factor contributing to type 2 diabetes (T2D). However, while the mechanisms and consequences associated with white adipose tissue inflammation are well described, very little is known concerning the situation in ... ...

Abstract	Inflammation is now recognized as a major factor contributing to type 2 diabetes (T2D). However, while the mechanisms and consequences associated with white adipose tissue inflammation are well described, very little is known concerning the situation in skeletal muscle. The aim of this study was to investigate, in vitro and in vivo, how skeletal muscle inflammation develops and how in turn it modulates local and systemic insulin sensitivity in different mice models of T2D and in humans, focusing on the role of the chemokine MCP1. Here, we found that skeletal muscle inflammation and macrophage markers are increased and associated with insulin resistance in mice models and humans. In addition, we demonstrated that intra-muscular TNFα expression is exclusively restricted to the population of intramuscular leukocytes and that the chemokine MCP1 was associated with skeletal muscle inflammatory markers in these models. Furthermore, we demonstrated that exposure of C2C12 myotubes to palmitate elevated the production of the chemokine MCP1 and that the muscle-specific overexpression of MCP1 in transgenic mice induced the local recruitment of macrophages and altered local insulin sensitivity. Overall our study demonstrates that skeletal muscle inflammation is clearly increased in the context of T2D in each one of the models we investigated, which is likely consecutive to the lipotoxic environment generated by peripheral insulin resistance, further increasing MCP1 expression in muscle. Consequently, our results suggest that MCP1-mediated skeletal muscle macrophages recruitment plays a role in the etiology of T2D.
Language	English
Document type	Article
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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Article: Insulin resistance is associated with MCP1-mediated macrophage accumulation in skeletal muscle in mice and humans

Plos One 10 (9), 1-14. (2014)

Abstract	Inflammation is now recognized as a major factor contributing to type 2 diabetes (T2D). However, while the mechanisms and consequences associated with white adipose tissue inflammation are well described, very little is known concerning the situation in skeletal muscle. The aim of this study was to investigate, in vitro and in vivo, how skeletal muscle inflammation develops and how in turn it modulates local and systemic insulin sensitivity in different mice models of T2D and in humans, focusing on the role of the chemokine MCP1. Here, we found that skeletal muscle inflammation and macrophage markers are increased and associated with insulin resistance in mice models and humans. In addition, we demonstrated that intra-muscular TNFα expression is exclusively restricted to the population of intramuscular leukocytes and that the chemokine MCP1 was associated with skeletal muscle inflammatory markers in these models. Furthermore, we demonstrated that exposure of C2C12 myotubes to palmitate elevated the production of the chemokine MCP1 and that the muscle-specific overexpression of MCP1 in transgenic mice induced the local recruitment of macrophages and altered local insulin sensitivity. Overall our study demonstrates that skeletal muscle inflammation is clearly increased in the context of T2D in each one of the models we investigated, which is likely consecutive to the lipotoxic environment generated by peripheral insulin resistance, further increasing MCP1 expression in muscle. Consequently, our results suggest that MCP1-mediated skeletal muscle macrophages recruitment plays a role in the etiology of T2D.
Language	English
Document type	Article
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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Article ; Online: Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes.

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Article ; Online: Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis.

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Article ; Online: Regulation of Mitochondria-Associated Membranes (MAMs) by NO/sGC/PKG Participates in the Control of Hepatic Insulin Response.

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Article ; Online: Disruption of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Contributes to Muscle Insulin Resistance in Mice and Humans.

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Article ; Online: Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance.

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