GDF15; macrophage; obesity; saturated fatty acids; stearate; ER stress; CHOP
Abstract :
[en] Growth di erentiation factor-15 (GDF-15) and its receptor GFRAL are both involved in the
development of obesity and insulin resistance. Plasmatic 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-di erentiated 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.
Disciplines :
Immunology & infectious disease
Author, co-author :
L'homme, Laurent; Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, Lille, FRANCE
Sermikli, Benan Pelin; Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, Lille, FRANCE
Staels, Bart; Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, F-59000 Lille, France
Piette, Jacques ; Université de Liège - ULiège > GIGA I3 - Virology and Immunology
Legrand, Sylvie ✱; Université de Liège - ULiège > GIGA I3 - Immunometabolism and Nutrition
Dombrowicz, David ✱; Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, F-59000 Lille, France
✱ These authors have contributed equally to this work.
Language :
English
Title :
Saturated Fatty Acids Promote GDF15 Expression in Human Macrophages through the PERK/eIF2/CHOP Signaling Pathway
Publication date :
December 2020
Journal title :
Nutrients
ISSN :
2072-6643
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
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