Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function.


Type
Article
Change log
Authors
Barbarroja, Nuria 
Rodriguez-Cuenca, Sergio  ORCID logo  https://orcid.org/0000-0001-9635-0504
Nygren, Heli 
Camargo, Antonio 
Pirraco, Ana 
Abstract

Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.

Description
Keywords
3T3-L1 Cells, Adipocytes, Adipogenesis, Adipose Tissue, White, Adult, Animals, Cell Cycle, Cell Death, Ceramides, Fatty Acid Desaturases, Female, Humans, Insulin, Lipolysis, Male, Mice, Middle Aged, Obesity, Oxidative Stress, Signal Transduction
Journal Title
Diabetes
Conference Name
Journal ISSN
0012-1797
1939-327X
Volume Title
64
Publisher
American Diabetes Association
Sponsorship
Medical Research Council (G0802051)
Medical Research Council (MC_UU_12012/2)
Medical Research Council (G0600717)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_UU_12012/5/B)
European Commission (222639)
This work was funded by Medical Research Council, MDU MRC, FP7- ETHERPATHS and the British Heart Foundation (BHF). We declare no conflict of interest.