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Saturated fatty acids promote GDF15 expression in human macrophages through the PERK/eIF2/CHOP signaling pathway

Abstract : Growth differentiation factor-15 (GDF-15) and its receptor GFRAL are both involved in the development of obesity and insulin resistance. Circulating GDF-15 level increases with obesity and is positively associated with disease progression. Despite macrophages have been recently suggested as a key source of GDF-15 in obesity, little is known about the regulation of GDF-15 in these cells. In the present work, we sought for potential pathophysiological activators of GDF15 expression in human macrophages and identified saturated fatty acids (SFAs) as strong inducers of GDF15 expression and secretion. SFAs increase GDF15 expression through the induction of an ER stress and the activation of the PERK/eIF2/CHOP signaling pathway in both PMA-differentiated THP-1 cells and in primary monocyte-derived macrophages. The transcription factor CHOP directly binds to the GDF15 promoter region and regulates GDF15 expression. Unlike SFAs, unsaturated fatty acids do not promote GDF15 expression and rather inhibit both SFA-induced GDF15 expression and ER stress. These results suggest that free fatty acids may be involved in the control of GDF-15 and provide new molecular insights about how diet and lipid metabolism may regulate the development of obesity and T2D.
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https://www.hal.inserm.fr/inserm-03054593
Contributor : Marie-Hélène Derudas Connect in order to contact the contributor
Submitted on : Friday, December 11, 2020 - 2:40:57 PM
Last modification on : Friday, July 30, 2021 - 4:25:17 PM
Long-term archiving on: : Friday, March 12, 2021 - 7:46:36 PM

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Laurent L’homme, Benan Sermikli, Bart Staels, Jacques Piette, Sylvie Legrand-Poels, et al.. Saturated fatty acids promote GDF15 expression in human macrophages through the PERK/eIF2/CHOP signaling pathway. Nutrients, MDPI, 2020, 12 (12), pp.3771. ⟨10.3390/nu12123771⟩. ⟨inserm-03054593⟩

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