Expression of lipogenic markers is decreased in subcutaneous adipose tissue and adipocytes of older women and is negatively linked to GDF15 expression
In aging, the capacity of subcutaneous adipose tissue (SAT) to store lipids decreases and this results in metabolically unfavorable fat redistribution. Triggers of this age-related SAT dysfunction may include cellular senescence or endoplasmic reticulum (ER) stress. Therefore, we compared lipogenic capacity of SAT between young and older women and investigated its relation to senescence and ER stress markers. Samples of SAT and corresponding SAT-derived primary preadipocytes were obtained from two groups of women differing in age (36 vs. 72 years, n = 15 each) but matched for fat mass. mRNA levels of selected genes (lipogenesis: ACACA, FASN, SCD1, DGAT2, ELOVL6; senescence: p16, p21, NOX4, GDF15; ER stress-ATF4, XBP1s, PERK, HSPA5, GADD34, HYOU1, CHOP, EDEM1, DNAJC3) were assessed by qPCR, protein levels of GDF15 by ELISA, and mitochondrial function by the Seahorse Analyzer. Compared to the young, SAT and in vitro differentiated adipocytes from older women exhibited reduced mRNA expression of lipogenic enzymes. Out of analyzed senescence and ER stress markers, the only gene, whose expression correlated negatively with the expression of lipogenic enzymes in both SAT and adipocytes, was GDF15, a marker of not only senescence but also mitochondrial dysfunction. In line with this, inhibition of mitochondrial ATP synthase in adipocytes strongly upregulated GDF15 while reduced expression of lipogenic enzymes. Moreover, adipocytes from older women had a tendency for diminished mitochondrial capacity. Thus, a reduced lipogenic capacity of adipocytes in aged SAT appears to be linked to mitochondrial dysfunction rather than to ER stress or accumulation of senescent cells.
KeywordsSubcutaneous adipose tissue Lipogenesis Aging Senescence Stress of endoplasmic reticulum Mitochondrial dysfunction
D.L. is a member of Institut Universitaire de France. We thank Zdenek Hodny, MD, PhD, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, for his help with the selection of senescent markers.
Ve.Š. performed experiments and data analysis and wrote the manuscript; E. K. performed adipose tissue biopsies; M.K, M.E., and J.K. performed experiments; M. Š and D.L. contributed to the discussion and writing of the manuscript; V.Š. performed adipose tissue biopsies and contributed to the discussion and writing of the manuscript; and L.R. designed the study, performed experiments and data analysis, and wrote the manuscript. L.R. is a guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
The study was supported by grant GAP16-00477S of the Grant Agency of the Czech Republic, AZV 16-29182A of the Czech Health Research Council, and PROGRES Q36 of Charles University.
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