Title

Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells

UMMS Affiliation

Graduate School of Biomedical Sciences; Program in Molecular Medicine

Publication Date

2008-09-10

Document Type

Article

Disciplines

Life Sciences | Medicine and Health Sciences

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.

DOI of Published Version

10.1074/jbc.M800510200

Source

J Biol Chem. 2008 Nov 7;283(45):30658-67. Epub 2008 Sep 8. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of biological chemistry

Related Resources

Link to Article in PubMed

PubMed ID

18779333

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