title: Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells.
abstract: Adipocyte function is crucial for the control of whole body energy homeostasis. Pathway analysis of differentiating 3T3-L1 adipocytes reveals that major metabolic pathways induced during differentiation involve mitochondrial function. However, it is not clear why differentiated white adipocytes require enhanced respiratory chain activity relative to pre-adipocytes. To address this question, we used small interference RNA to interfere with the induction of the transcription factor Tfam, which is highly induced between days 2 and 4 of differentiation and is crucial for replication of mitochondrial DNA. Interference with Tfam resulted in cells with decreased respiratory chain capacity, reflected by decreased basal oxygen consumption, and decreased mitochondrial ATP synthesis, but no difference in many other adipocyte functions or expression levels of adipose-specific genes. However, insulin-stimulated GLUT4 translocation to the cell surface and subsequent glucose transport are impaired in Tfam knockdown cells. Paradoxically, insulin-stimulated Akt phosphorylation is significantly enhanced in these cells. These studies reveal independent links between mitochondrial function, insulin signaling, and glucose transport, in which impaired respiratory chain activity enhances insulin signaling to Akt phosphorylation, but impairs GLUT4 translocation. These results indicate that mitochondrial respiratory chain dysfunction in adipocytes can cause impaired insulin responsiveness of GLUT4 translocation by a mechanism downstream of the Akt protein kinase.
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Xiarong
authors.initials: X
authors.lastname: Shi
authors.forename: Alison
authors.initials: A
authors.lastname: Burkart
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nicoloro
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
authors.forename: Juerg
authors.initials: J
authors.lastname: Straubhaar
authors.forename: Silvia
authors.initials: S
authors.lastname: Corvera
mesh_terms: D041721:3T3-L1 Cells; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; D006609:High Mobility Group Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D034741:RNA, Small Interfering; C495693:Slc2a4 protein, mouse; C081930:Tfam protein, mouse; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
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