Essential Role of Mitochondrial Function in Adiponectin Synthesis in Adipocytes

Koh, Eun Hee; Park, Joong‐Yeol; Park, Hye-Sun; Jeon, Min Jae; Ryu, Je Won; Kim, Mina; Kim, Sun Young; Kim, Min‐Seon; Kim, Seung Whan; Park, In Sun; Youn, Jang H.; Lee, Ki‐Up

doi:10.2337/db07-0510

Cited by 248 publications

(236 citation statements)

References 50 publications

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“…This strongly indicates that other factors contribute to the lower insulin-stimulated glucose metabolism in type 2 diabetes compared with obesity alone. There is evidence that a lower protein content of ATPsyn-β may affect beta cell and adipocyte function [44][45][46][47], and it is also a hallmark of most human carcinomas [48,49]. Thus, aberrant phosphorylation of ATPsyn-β may have putative consequences in other tissues in insulin-resistant individuals as well as in other disorders.…”

Section: Discussionmentioning

confidence: 99%

Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal phosphorylation at specific sites in insulin-resistant muscle

Højlund

Lefort

et al. 2009

Diabetologia

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Aims/hypothesis Insulin resistance in skeletal muscle is linked to mitochondrial dysfunction in obesity and type 2 diabetes. Emerging evidence indicates that reversible phosphorylation regulates oxidative phosphorylation (OxPhos) proteins. The aim of this study was to identify and quantify site-specific phosphorylation of the catalytic beta subunit of ATP synthase (ATPsyn-β) and determine protein abundance of ATPsyn-β and other OxPhos components in skeletal muscle from healthy and insulin-resistant individuals. Methods Skeletal muscle biopsies were obtained from lean, healthy, obese, non-diabetic and type 2 diabetic volunteers (each group n=10) for immunoblotting of proteins, and hypothesis-driven identification and quantification of phosphorylation sites on ATPsyn-β using targeted nanospray tandem mass spectrometry. Volunteers were metabolically characterised by euglycaemic-hyperinsulinaemic clamps. Results Seven phosphorylation sites were identified on ATPsyn-β purified from human skeletal muscle. Obese individuals with and without type 2 diabetes were characterised by impaired insulin-stimulated glucose disposal rates, and showed a ∼30% higher phosphorylation of ATPsyn-β at Tyr361 and Thr213 (within the nucleotidebinding region of ATP synthase) as well as a coordinated downregulation of ATPsyn-β protein and other OxPhos components. Insulin increased Tyr361 phosphorylation of ATPsyn-β by ∼50% in lean and healthy, but not insulinresistant, individuals. Conclusions/interpretation These data demonstrate that ATPsyn-β is phosphorylated at multiple sites in human skeletal muscle, and suggest that abnormal site-specific phosphorylation of ATPsyn-β together with reduced content of OxPhos proteins contributes to mitochondrial dysfunction in insulin resistance. Further characterisation of phosphorylation of ATPsyn-β may offer novel targets of treatment in human diseases with mitochondrial dysfunction, such as diabetes.

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Section: Discussionmentioning

confidence: 99%

Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal phosphorylation at specific sites in insulin-resistant muscle

Højlund

Lefort

et al. 2009

Diabetologia

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“…Mitochondrial function is linked with adiponectin synthesis in adipocytes (Koh et al 2007. Adiponectin expressed in skeletal muscle can be posttranslationally modified within the myotubes, allowing the formation of biologically active forms that exert local metabolic effects that are independent of circulating levels of adiponectin (Liu et al 2009a).…”

Section: Discussionmentioning

confidence: 99%

“…Adiponectin expression in WAT is also greater in females than in males (Amengual-Cladera et al 2012a,b,c), a fact that in humans has been associated with sex hormone milieu (Riestra et al 2013, Wildman et al 2013. Proper mitochondrial function is essential for the production of adiponectin in adipocytes (Koh et al 2007), so impaired mitochondrial function in WAT also has negative effects on the insulin response in other tissues through a decrease in the expression and secretion of adiponectin . Furthermore, adiponectin plays an important role in the regulation of mitochondrial content and function in other tissues such as skeletal muscle (Civitarese et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle

Capllonch-Amer¹,

Sbert-Roig²,

Galmés-Pascual³

et al. 2014

Journal of Endocrinology

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Sexual dimorphism has been found in mitochondrial features of skeletal muscle, with female rats showing greater mitochondrial mass and function compared with males. Adiponectin is an insulin-sensitizing adipokine whose expression has been related to mitochondrial function and that is also expressed in skeletal muscle, where it exerts local metabolic effects. The aim of this research was to elucidate the role of sex hormones in modulation of mitochondrial function, as well as its relationship with adiponectin production in rat skeletal muscle. An in vivo study with ovariectomized Wistar rats receiving or not receiving 17b-estradiol (E 2 ) (10 mg/kg per 48 h for 4 weeks) was carried out, in parallel with an assay of cultured myotubes (L6E9) treated with E 2 (10 nM), progesterone (Pg; 1 mM), or testosterone (1 mM). E 2 upregulated the markers of mitochondrial biogenesis and dynamics, and also of mitochondrial function in skeletal muscle and L6E9. Although in vivo E 2 supplementation only partially restored the decreased adiponectin expression levels induced by ovariectomy, these were enhanced by E 2 and Pg treatment in cultured myotubes, whereas testosterone showed no effects. Adiponectin receptor 1 expression was increased by E 2 treatment, both in vivo and in vitro, but testosterone decreased it. In conclusion, our results are in agreement with the sexual dimorphism previously reported in skeletal muscle mitochondrial function and indicate E 2 to be its main effector, as it enhances mitochondrial function and diminishes oxidative stress. Moreover, our data support the idea of the existence of a link between mitochondrial function and adiponectin expression in skeletal muscle, which could be modulated by sex hormones.

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“…Even though we could not definitively propose how BNIP3 mediates PGC1α upregulation by rosiglitazone, we propose that adiponectin-AMPK is one of the axes responsible. Considering that mitochondrial function is essential for adiponectin synthesis in adipocytes [46], BNIP3 might be a checkpoint for mitochondrial quality control [47] and the AMPK-PGC1α mitochondrial bioenergetics pathway through which rosiglitazone acts. Further investigation of the precise mechanism of BNIP3-mediated mitochondrial biogenesis is warranted.…”

Section: Discussionmentioning

confidence: 99%

BNIP3 is essential for mitochondrial bioenergetics during adipocyte remodelling in mice

Choi

Kim

et al. 2015

Diabetologia

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Aims/hypothesis Adipose tissue is a highly versatile system in which mitochondria in adipocytes undergo significant changes during active tissue remodelling. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) is a mitochondrial protein and a known mitochondrial quality regulator. In this study, we investigated the role of BNIP3 in adipocytes, specifically under conditions of peroxisome proliferator-activated receptor-γ (PPARγ)-induced adipose tissue remodelling. Methods The expression of BNIP3 was evaluated in 3T3-L1 adipocytes in vitro, C57BL/6 mice fed a high-fat diet and db/db mice in vivo. Mitochondrial bioenergetics was investigated in BNIP3-knockdown adipocytes after rosiglitazone treatment. A putative peroxisome proliferator hormone responsive element (PPRE) was characterised by promoter assay and electrophoretic mobility shift assay (EMSA). ResultsThe protein BNIP3 was more abundant in brown adipose tissue than white adipose tissue. Furthermore, BNIP3 expression was upregulated by 3T3-L1 pre-adipocyte differentiation, starvation and rosiglitazone treatment. Conversely, BNIP3 expression in adipocytes decreased under various conditions associated with insulin resistance. This downregulation of BNIP3 was restored by rosiglitazone treatment. Knockdown of BNIP3 in adipocytes inhibited rosiglitazoneinduced mitochondrial biogenesis and function, partially mediated by the 5′ AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor γ, co-activator 1 α (PGC1α) signalling pathway. Rosiglitazone treatment increased the transcription level of Bnip3 in the reporter assay and the presence of the PPRE site in the Bnip3 promoter was demonstrated by EMSA. Conclusions/interpretation The protein BNIP3 contributes to the improvement of mitochondrial bioenergetics that occurs

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Essential Role of Mitochondrial Function in Adiponectin Synthesis in Adipocytes

Cited by 248 publications

References 50 publications

Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal phosphorylation at specific sites in insulin-resistant muscle

Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal phosphorylation at specific sites in insulin-resistant muscle

Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle

BNIP3 is essential for mitochondrial bioenergetics during adipocyte remodelling in mice

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