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

Nuria Barbarroja (Corresponding Author), Sergio Rodriguez-Cuenca, Heli Nygren, Antonio Camargo, Ana Pirraco, Joana Relat, Irene Cuadrado, Vanessa Pellegrinelli, Gema Medina-Gomez, Chary Lopez-Pedrera, Francisco J. Tinahones, J. David Symons, Scott A. Summers, Matej Oresic, Antonio Vidal-Puig

Research output: Contribution to journalArticleScientificpeer-review

23 Citations (Scopus)

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 catalysing 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 validate 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.
Original languageEnglish
Pages (from-to)1180-1192
JournalDiabetes
Volume64
Issue number4
DOIs
Publication statusPublished - 2015
MoE publication typeA1 Journal article-refereed

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Ceramides
Adipocytes
Adipose Tissue
Obesity
Lipids
Oxidative Stress
Nutrigenomics
Pharmacology
Adipogenesis
Genetic Models
Biosynthetic Pathways
Insulin Resistance
Cell Survival
Cell Cycle
Cell Proliferation
Muscles
dihydroceramide

Cite this

Barbarroja, N., Rodriguez-Cuenca, S., Nygren, H., Camargo, A., Pirraco, A., Relat, J., ... Vidal-Puig, A. (2015). Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function. Diabetes, 64(4), 1180-1192. https://doi.org/10.2337/db14-0359
Barbarroja, Nuria ; Rodriguez-Cuenca, Sergio ; Nygren, Heli ; Camargo, Antonio ; Pirraco, Ana ; Relat, Joana ; Cuadrado, Irene ; Pellegrinelli, Vanessa ; Medina-Gomez, Gema ; Lopez-Pedrera, Chary ; Tinahones, Francisco J. ; Symons, J. David ; Summers, Scott A. ; Oresic, Matej ; Vidal-Puig, Antonio. / Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function. In: Diabetes. 2015 ; Vol. 64, No. 4. pp. 1180-1192.
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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 catalysing 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 validate 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.",
author = "Nuria Barbarroja and Sergio Rodriguez-Cuenca and Heli Nygren and Antonio Camargo and Ana Pirraco and Joana Relat and Irene Cuadrado and Vanessa Pellegrinelli and Gema Medina-Gomez and Chary Lopez-Pedrera and Tinahones, {Francisco J.} and Symons, {J. David} and Summers, {Scott A.} and Matej Oresic and Antonio Vidal-Puig",
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Barbarroja, N, Rodriguez-Cuenca, S, Nygren, H, Camargo, A, Pirraco, A, Relat, J, Cuadrado, I, Pellegrinelli, V, Medina-Gomez, G, Lopez-Pedrera, C, Tinahones, FJ, Symons, JD, Summers, SA, Oresic, M & Vidal-Puig, A 2015, 'Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function', Diabetes, vol. 64, no. 4, pp. 1180-1192. https://doi.org/10.2337/db14-0359

Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function. / Barbarroja, Nuria (Corresponding Author); Rodriguez-Cuenca, Sergio; Nygren, Heli; Camargo, Antonio; Pirraco, Ana; Relat, Joana; Cuadrado, Irene; Pellegrinelli, Vanessa; Medina-Gomez, Gema; Lopez-Pedrera, Chary; Tinahones, Francisco J.; Symons, J. David; Summers, Scott A.; Oresic, Matej; Vidal-Puig, Antonio.

In: Diabetes, Vol. 64, No. 4, 2015, p. 1180-1192.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function

AU - Barbarroja, Nuria

AU - Rodriguez-Cuenca, Sergio

AU - Nygren, Heli

AU - Camargo, Antonio

AU - Pirraco, Ana

AU - Relat, Joana

AU - Cuadrado, Irene

AU - Pellegrinelli, Vanessa

AU - Medina-Gomez, Gema

AU - Lopez-Pedrera, Chary

AU - Tinahones, Francisco J.

AU - Symons, J. David

AU - Summers, Scott A.

AU - Oresic, Matej

AU - Vidal-Puig, Antonio

PY - 2015

Y1 - 2015

N2 - 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 catalysing 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 validate 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.

AB - 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 catalysing 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 validate 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.

U2 - 10.2337/db14-0359

DO - 10.2337/db14-0359

M3 - Article

VL - 64

SP - 1180

EP - 1192

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 4

ER -