Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility

Sergio Rodriguez-Cuenca, Stefania Carobbio, Vidya Velagapudi, Nuria Barbarroja, Jose Maria Moreno-Navarrete, Francisco Jose Tinahones, Jose Manuel Fernandez-Real, Matej Orešič, Antonio Vidal-Puig

Research output: Contribution to journalArticleScientificpeer-review

34 Citations (Scopus)

Abstract

Optimal lipid storage and mobilization are essential for efficient adipose tissue. Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) regulates adipocyte differentiation and lipid deposition, but its role in lipolysis and dysregulation in obesity is not well defined. This investigation aimed to understand the molecular impact of dysfunctional PPARγ on the lipolytic axis and to explore whether these defects are also confirmed in common forms of human obesity. For this purpose, we used the P465L PPARγ mouse as a model of dysfunctional PPARγ that recapitulates the human pparγ mutation (P467L). We demonstrated that defective PPARγ impairs catecholamine-induced lipolysis. This abnormal lipolytic response is exacerbated by a state of positive energy balance in leptin-deficient ob/ob mice. We identified the protein kinase A (PKA) network as a PPARγ-dependent regulatory node of the lipolytic response. Specifically, defective PPARγ is associated with decreased basal expression of prkaca (PKAcatα) and d-akap1, the lipase genes Pnplaz (ATGL) and Lipe (HSL), and lipid droplet protein genes fsp27 and adrp in vivo and in vitro. Our data indicate that PPARγ is required for activation of the lipolytic regulatory network, dysregulation of which is an important feature of obesity-induced insulin resistance in humans.
Original languageEnglish
Pages (from-to)1555-1565
JournalMolecular and Cellular Biology
Volume32
Issue number8
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

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Peroxisome Proliferator-Activated Receptors
Obesity
Lipolysis
Lipid Mobilization
Cytoplasmic and Nuclear Receptors
Leptin
Cyclic AMP-Dependent Protein Kinases
Lipase
Adipocytes
Genes
Catecholamines
Insulin Resistance
Adipose Tissue
Lipids
Mutation

Cite this

Rodriguez-Cuenca, S., Carobbio, S., Velagapudi, V., Barbarroja, N., Moreno-Navarrete, J. M., Tinahones, F. J., ... Vidal-Puig, A. (2012). Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility. Molecular and Cellular Biology, 32(8), 1555-1565. https://doi.org/10.1128/MCB.06154-11
Rodriguez-Cuenca, Sergio ; Carobbio, Stefania ; Velagapudi, Vidya ; Barbarroja, Nuria ; Moreno-Navarrete, Jose Maria ; Tinahones, Francisco Jose ; Fernandez-Real, Jose Manuel ; Orešič, Matej ; Vidal-Puig, Antonio. / Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility. In: Molecular and Cellular Biology. 2012 ; Vol. 32, No. 8. pp. 1555-1565.
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abstract = "Optimal lipid storage and mobilization are essential for efficient adipose tissue. Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) regulates adipocyte differentiation and lipid deposition, but its role in lipolysis and dysregulation in obesity is not well defined. This investigation aimed to understand the molecular impact of dysfunctional PPARγ on the lipolytic axis and to explore whether these defects are also confirmed in common forms of human obesity. For this purpose, we used the P465L PPARγ mouse as a model of dysfunctional PPARγ that recapitulates the human pparγ mutation (P467L). We demonstrated that defective PPARγ impairs catecholamine-induced lipolysis. This abnormal lipolytic response is exacerbated by a state of positive energy balance in leptin-deficient ob/ob mice. We identified the protein kinase A (PKA) network as a PPARγ-dependent regulatory node of the lipolytic response. Specifically, defective PPARγ is associated with decreased basal expression of prkaca (PKAcatα) and d-akap1, the lipase genes Pnplaz (ATGL) and Lipe (HSL), and lipid droplet protein genes fsp27 and adrp in vivo and in vitro. Our data indicate that PPARγ is required for activation of the lipolytic regulatory network, dysregulation of which is an important feature of obesity-induced insulin resistance in humans.",
author = "Sergio Rodriguez-Cuenca and Stefania Carobbio and Vidya Velagapudi and Nuria Barbarroja and Moreno-Navarrete, {Jose Maria} and Tinahones, {Francisco Jose} and Fernandez-Real, {Jose Manuel} and Matej Orešič and Antonio Vidal-Puig",
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Rodriguez-Cuenca, S, Carobbio, S, Velagapudi, V, Barbarroja, N, Moreno-Navarrete, JM, Tinahones, FJ, Fernandez-Real, JM, Orešič, M & Vidal-Puig, A 2012, 'Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility', Molecular and Cellular Biology, vol. 32, no. 8, pp. 1555-1565. https://doi.org/10.1128/MCB.06154-11

Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility. / Rodriguez-Cuenca, Sergio; Carobbio, Stefania; Velagapudi, Vidya; Barbarroja, Nuria; Moreno-Navarrete, Jose Maria; Tinahones, Francisco Jose; Fernandez-Real, Jose Manuel; Orešič, Matej; Vidal-Puig, Antonio.

In: Molecular and Cellular Biology, Vol. 32, No. 8, 2012, p. 1555-1565.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility

AU - Rodriguez-Cuenca, Sergio

AU - Carobbio, Stefania

AU - Velagapudi, Vidya

AU - Barbarroja, Nuria

AU - Moreno-Navarrete, Jose Maria

AU - Tinahones, Francisco Jose

AU - Fernandez-Real, Jose Manuel

AU - Orešič, Matej

AU - Vidal-Puig, Antonio

PY - 2012

Y1 - 2012

N2 - Optimal lipid storage and mobilization are essential for efficient adipose tissue. Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) regulates adipocyte differentiation and lipid deposition, but its role in lipolysis and dysregulation in obesity is not well defined. This investigation aimed to understand the molecular impact of dysfunctional PPARγ on the lipolytic axis and to explore whether these defects are also confirmed in common forms of human obesity. For this purpose, we used the P465L PPARγ mouse as a model of dysfunctional PPARγ that recapitulates the human pparγ mutation (P467L). We demonstrated that defective PPARγ impairs catecholamine-induced lipolysis. This abnormal lipolytic response is exacerbated by a state of positive energy balance in leptin-deficient ob/ob mice. We identified the protein kinase A (PKA) network as a PPARγ-dependent regulatory node of the lipolytic response. Specifically, defective PPARγ is associated with decreased basal expression of prkaca (PKAcatα) and d-akap1, the lipase genes Pnplaz (ATGL) and Lipe (HSL), and lipid droplet protein genes fsp27 and adrp in vivo and in vitro. Our data indicate that PPARγ is required for activation of the lipolytic regulatory network, dysregulation of which is an important feature of obesity-induced insulin resistance in humans.

AB - Optimal lipid storage and mobilization are essential for efficient adipose tissue. Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) regulates adipocyte differentiation and lipid deposition, but its role in lipolysis and dysregulation in obesity is not well defined. This investigation aimed to understand the molecular impact of dysfunctional PPARγ on the lipolytic axis and to explore whether these defects are also confirmed in common forms of human obesity. For this purpose, we used the P465L PPARγ mouse as a model of dysfunctional PPARγ that recapitulates the human pparγ mutation (P467L). We demonstrated that defective PPARγ impairs catecholamine-induced lipolysis. This abnormal lipolytic response is exacerbated by a state of positive energy balance in leptin-deficient ob/ob mice. We identified the protein kinase A (PKA) network as a PPARγ-dependent regulatory node of the lipolytic response. Specifically, defective PPARγ is associated with decreased basal expression of prkaca (PKAcatα) and d-akap1, the lipase genes Pnplaz (ATGL) and Lipe (HSL), and lipid droplet protein genes fsp27 and adrp in vivo and in vitro. Our data indicate that PPARγ is required for activation of the lipolytic regulatory network, dysregulation of which is an important feature of obesity-induced insulin resistance in humans.

U2 - 10.1128/MCB.06154-11

DO - 10.1128/MCB.06154-11

M3 - Article

VL - 32

SP - 1555

EP - 1565

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 8

ER -

Rodriguez-Cuenca S, Carobbio S, Velagapudi V, Barbarroja N, Moreno-Navarrete JM, Tinahones FJ et al. Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility. Molecular and Cellular Biology. 2012;32(8):1555-1565. https://doi.org/10.1128/MCB.06154-11