title: Nitrite augments glucose uptake in adipocytes through the protein kinase A-dependent stimulation of mitochondrial fusion.
abstract: Though it is well accepted that adipose tissue is central in the regulation of glycemic homeostasis, the molecular mechanisms governing adipocyte glucose uptake remain unclear. Recent studies demonstrate that mitochondrial dynamics (fission and fusion) regulate lipid accumulation and differentiation in adipocytes. However, the role of mitochondrial dynamics in glucose homeostasis has not been explored. The nitric oxide oxidation products nitrite and nitrate are endogenous signaling molecules and dietary constituents that have recently been shown to modulate glucose metabolism, prevent weight gain, and reverse the development of metabolic syndrome in mice. Although the mechanism of this protection is unclear, the mitochondrion is a known subcellular target for nitrite signaling. Thus, we hypothesize that nitrite modulates mitochondrial dynamics and function to regulate glucose uptake in adipocytes. Herein, we demonstrate that nitrite significantly increases glucose uptake in differentiated murine adipocytes through a mechanism dependent on mitochondrial fusion. Specifically, nitrite promotes mitochondrial fusion by increasing the profusion protein mitofusin 1 while concomitantly activating protein kinase A (PKA), which phosphorylates and inhibits the profission protein dynamin-related protein 1 (Drp1). Functionally, this signaling augments cellular respiration, fatty acid oxidation, mitochondrial oxidant production, and glucose uptake. Importantly, inhibition of PKA or Drp1 significantly attenuates nitrite-induced mitochondrial respiration and glucose uptake. These findings demonstrate that mitochondria play an essential metabolic role in adipocytes, show a novel role for both nitrite and mitochondrial fusion in regulating adipocyte glucose homeostasis, and have implications for the potential therapeutic use of nitrite and mitochondrial modulators in glycemic regulation.
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Nicholas K H
authors.initials: NK
authors.lastname: Khoo
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Mo
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Zharikov
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Kamga-Pride
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Quesnelle
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Franca
authors.initials: F
authors.lastname: Golin-Bisello
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Li
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Yinna
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: sss43@pitt.edu.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019069:Cell Respiration / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000235:genetics; D009573:Nitrites / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D005609:Free Radicals; D009573:Nitrites; D017868:Cyclic AMP-Dependent Protein Kinases; C486391:Dnm1l protein, mouse; D034281:Dynamins; D005947:Glucose
keywords: Adipocyte; Free radicals; Fusion; Glucose uptake; Mitochondria; Nitrite