Protein kinase N2 regulates AMP kinase signaling and insulin responsiveness of glucose metabolism in skeletal muscle

Ruby, Maxwell A.; Riedl, Isabelle; Massart, Julie; Åhlin, Marcus; Zierath, Juleen R.

doi:10.1152/ajpendo.00147.2017

Cited by 20 publications

(14 citation statements)

References 39 publications

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“…The molecular machinery that integrates these processes downstream of the Crb module is not well defined. We identify here a VMZassociated interactome of proteins with reported or proposed functions in HIPPO signaling (ARHGAP29, STXBP4, PTPN13) [44,45,80,81], TJ formation (PKN2 and ARHGAP29) [55,82,83], cell polarity (HOMER3) [84], and mTOR/AMPK signaling (PKN2) [85,86]. We speculate that this protein network receives mechanical and nutrient sensing ques at the VMZ and transmits these to the HIPPO and mTOR/AMPK signaling pathways.…”

Section: Discussionmentioning

confidence: 77%

The Mammalian Crumbs Complex Defines a Distinct Polarity Domain Apical of Epithelial Tight Junctions

et al. 2020

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Epithelial apico-basal polarity is established through the asymmetric cortical distribution of the Par, Crumbs and Scribble polarity modules. Apical (Par and Crumbs) and basolateral (Scribble) polarity modules overlap at the apicallateral border, which, in mammals, is defined by the apical junctional complex (AJC). The AJC is composed of tight junctions (TJ) and adherens junctions (AJ) and plays fundamental roles in epithelial morphogenesis and plasticity.However, the molecular composition and precise sub-junctional organization of the AJC and its associated polarity regulators are still not well defined. Here we used the peroxidase APEX2 for quantitative proximity proteomics (QPP) and electron microscopy (EM) imaging to generate a nanometer-scale spatiomolecular map of the apical-lateral border in fully polarized MDCK-II cells.Using Par3 and Pals1 as surrogates for QPP we present a spatially resolved . CC-BY-NC-ND 4.

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Section: Discussionmentioning

confidence: 77%

The Mammalian Crumbs Complex Defines a Distinct Polarity Domain Apical of Epithelial Tight Junctions

et al. 2020

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“…Since Pkn2 modulates Akt activity during skeletal muscle differentiation, it may also modulate Akt signaling in obese mice. In cultured human skeletal muscle myotubes, siRNA against Pkn2 impaires insulin‐mediated glucose metabolism and augments AMPK signaling, with concominant effects on protein and lipid metabolism . MAPK/ERK signaling regulates insulin sensitivity and is a potential target for treatment of insulin resistance .…”

Section: Discussionmentioning

confidence: 99%

Proteomics Analysis of Skeletal Muscle from Leptin‐Deficient ob/ob Mice Reveals Adaptive Remodeling of Metabolic Characteristics and Fiber Type Composition

et al. 2018

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Skeletal muscle insulin resistance, an early metabolic defect in the pathogenesis of type 2 diabetes (T2D), may be a cause or consequence of altered protein expression profiles. Proteomics technology offers enormous promise to investigate molecular mechanisms underlying pathologies, however, the analysis of skeletal muscle is challenging. Using state-of-the-art multienzyme digestion and filter-aided sample preparation (MED-FASP) and a mass spectrometry (MS)-based workflow, we performed a global proteomics analysis of skeletal muscle from leptin-deficient, obese, insulin resistant (ob/ob) and lean mice in mere two fractions in a short time (8 h per sample). We identified more than 6000 proteins with 118 proteins differentially regulated in obesity. This included protein kinases, phosphatases, and secreted and fiber type associated proteins. Enzymes involved in lipid metabolism in skeletal muscle from ob/ob mice were increased, providing evidence against reduced fatty acid oxidation in lipid-induced insulin resistance. Mitochondrial and peroxisomal proteins, as well as components of pyruvate and lactate metabolism, were increased. Finally, the skeletal muscle proteome from ob/ob mice displayed a shift toward the "slow fiber type." This detailed characterization of an obese rodent model of T2D demonstrates an efficient workflow for skeletal muscle proteomics, which may easily be adapted to other complex tissues.

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“…Under normal circumstances, pancreatic β cells can secrete insulin in response to meal-induced increase in blood glucose (Kang et al, 2017). First, insulin promotes muscle tissue to assimilate blood glucose and convert it into muscle glycogen and protein (Kleinert et al, 2013; Ruby et al, 2017). Second, insulin not only promotes hepatocytes to absorb blood glucose and convert it into liver glycogen, but also inhibits glycogenolysis and gluconeogenesis to reduce postprandial blood glucose (Unger, 2011).…”

Section: Insulin Resistancementioning

confidence: 99%

Mitophagy in Hepatic Insulin Resistance: Therapeutic Potential and Concerns

Nie

Huang

et al. 2019

Front. Pharmacol.

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Metabolic syndrome, characterized by central obesity, hypertension, and hyperlipidemia, increases the morbidity and mortality of cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease, and other metabolic diseases. It is well known that insulin resistance, especially hepatic insulin resistance, is a risk factor for metabolic syndrome. Current research has shown that hepatic fatty acid accumulation can cause hepatic insulin resistance through increased gluconeogenesis, lipogenesis, chronic inflammation, oxidative stress and endoplasmic reticulum stress, and impaired insulin signal pathway. Mitochondria are the major sites of fatty acid β-oxidation, which is the major degradation mechanism of fatty acids. Mitochondrial dysfunction has been shown to be involved in the development of hepatic fatty acid–induced hepatic insulin resistance. Mitochondrial autophagy (mitophagy), a catabolic process, selectively degrades damaged mitochondria to reverse mitochondrial dysfunction and preserve mitochondrial dynamics and function. Therefore, mitophagy can promote mitochondrial fatty acid oxidation to inhibit hepatic fatty acid accumulation and improve hepatic insulin resistance. Here, we review advances in our understanding of the relationship between mitophagy and hepatic insulin resistance. Additionally, we also highlight the potential value of mitophagy in the treatment of hepatic insulin resistance and metabolic syndrome.

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Protein kinase N2 regulates AMP kinase signaling and insulin responsiveness of glucose metabolism in skeletal muscle

Abstract: 26Insulin resistance is central to the development of type 2 diabetes and related metabolic 27 disorders. As skeletal muscle is responsible for the majority of whole body insulin-stimulated 28 glucose uptake, regulation of glucose metabolism in this tissue is of particular importance.

Cited by 20 publications

References 39 publications

The Mammalian Crumbs Complex Defines a Distinct Polarity Domain Apical of Epithelial Tight Junctions

The Mammalian Crumbs Complex Defines a Distinct Polarity Domain Apical of Epithelial Tight Junctions

Proteomics Analysis of Skeletal Muscle from Leptin‐Deficient ob/ob Mice Reveals Adaptive Remodeling of Metabolic Characteristics and Fiber Type Composition

Mitophagy in Hepatic Insulin Resistance: Therapeutic Potential and Concerns

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