Adiponectin improves insulin sensitivity via activation of autophagic flux

Skeletal muscle insulin resistance is known to play an important role in the pathogenesis of diabetes, and one potential causative cellular mechanism is endoplasmic reticulum (ER) stress. Adiponectin mediates anti-diabetic effects via direct metabolic actions and by improving insulin sensitivity, an...

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Veröffentlicht in:Journal of molecular endocrinology 2017-11, Vol.59 (4), p.339-350
Hauptverfasser: Ahlstrom, Penny, Rai, Esther, Chakma, Suharto, Cho, Hee Ho, Rengasamy, Palanivel, Sweeney, Gary
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container_end_page 350
container_issue 4
container_start_page 339
container_title Journal of molecular endocrinology
container_volume 59
creator Ahlstrom, Penny
Rai, Esther
Chakma, Suharto
Cho, Hee Ho
Rengasamy, Palanivel
Sweeney, Gary
description Skeletal muscle insulin resistance is known to play an important role in the pathogenesis of diabetes, and one potential causative cellular mechanism is endoplasmic reticulum (ER) stress. Adiponectin mediates anti-diabetic effects via direct metabolic actions and by improving insulin sensitivity, and we recently demonstrated an important role in stimulation of autophagy by adiponectin. However, there is limited knowledge on crosstalk between autophagy and ER stress in skeletal muscle and in particular how they are regulated by adiponectin. Here, we utilized the model of high insulin/glucose (HIHG)-induced insulin resistance, determined by measuring Akt phosphorylation (T308 and S473) and glucose uptake in L6 skeletal muscle cells. HIHG reduced autophagic flux measured by LC3 and p62 Western blotting and tandem fluorescent RFP/GFP-LC3 immunofluorescence (IF). HIHG also induced ER stress assessed by thioflavin T/KDEL IF, pIRE1, pPERK, peIF2α and ATF6 Western blotting and induction of a GRP78-mCherry reporter. Induction of autophagy by adiponectin or rapamycin attenuated HIHG-induced ER stress and improved insulin sensitivity. The functional significance of enhanced autophagy was validated by demonstrating a lack of improved insulin sensitivity in response to adiponectin in autophagy-deficient cells generated by overexpression of dominant negative mutant of Atg5. In , adiponectin-induced autophagy in skeletal muscle cells alleviated HIHG-induced ER stress and insulin resistance.
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Adiponectin mediates anti-diabetic effects via direct metabolic actions and by improving insulin sensitivity, and we recently demonstrated an important role in stimulation of autophagy by adiponectin. However, there is limited knowledge on crosstalk between autophagy and ER stress in skeletal muscle and in particular how they are regulated by adiponectin. Here, we utilized the model of high insulin/glucose (HIHG)-induced insulin resistance, determined by measuring Akt phosphorylation (T308 and S473) and glucose uptake in L6 skeletal muscle cells. HIHG reduced autophagic flux measured by LC3 and p62 Western blotting and tandem fluorescent RFP/GFP-LC3 immunofluorescence (IF). HIHG also induced ER stress assessed by thioflavin T/KDEL IF, pIRE1, pPERK, peIF2α and ATF6 Western blotting and induction of a GRP78-mCherry reporter. Induction of autophagy by adiponectin or rapamycin attenuated HIHG-induced ER stress and improved insulin sensitivity. The functional significance of enhanced autophagy was validated by demonstrating a lack of improved insulin sensitivity in response to adiponectin in autophagy-deficient cells generated by overexpression of dominant negative mutant of Atg5. 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subjects Adiponectin
Adiponectin - metabolism
AKT protein
Animals
Autophagy
Autophagy - drug effects
Diabetes mellitus
Endoplasmic reticulum
Endoplasmic Reticulum Stress - drug effects
Glucose
Glucose - metabolism
Humans
Immunofluorescence
Insulin
Insulin - metabolism
Insulin Resistance
Muscle, Skeletal - metabolism
Musculoskeletal system
Myoblasts - metabolism
Phagocytosis
Phosphorylation
Proto-Oncogene Proteins c-akt - metabolism
Rapamycin
Sirolimus - pharmacology
Skeletal muscle
Unfolded Protein Response - drug effects
Western blotting
title Adiponectin improves insulin sensitivity via activation of autophagic flux
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