Brochard, Léa; (2019) Fatty acid-induced stress signalling in adipocytes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Insulin resistance has been shown to be caused by saturated fatty acids (SFA), especially palmitate found in abundance in the Western diet. The enzyme phosphatidylinositol 3 kinase (PI3K) has been identified as a key modulator of SFAinduced insulin resistance. To further the current understanding of the molecular mechanisms at play, we performed a transcriptome analysis comparing the gene expression profiles of 3T3-L1 adipocytes treated with palmitate, in the presence or absence of an inhibitor selective for p110α, one of the catalytic subunits of class IA PI3K. It revealed that the expression of a number of genes induced by type I interferon (IFN) is stimulated in response to palmitate, an effect abrogated by p110α inhibition. Such finding was of particular interest as IFN is known, like palmitate, to trigger insulin resistance. We studied the molecular links between IFN- and palmitate-mediated insulin resistance in both murine and human pre- and mature adipocytes. This allowed the confirmation of the positive metabolic effect of inhibiting p110α. The effect of palmitate on components of the IFN pathway was further explored and led to the establishment of a pivotal role of IFN-stimulated genes (ISGs) in the development of SFA-induced metabolic dysfunctions in adipocytes.

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