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Peroxisome proliferator-activated receptor γ-dependent regulation of lipolytic nodes and metabolic flexibility
Department of Clinical Biochemistry, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Department of Clinical Biochemistry, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
VTT Technical Research Centre of Finland, Espoo, Finland.
VTT Technical Research Centre of Finland, Espoo, Finland; Hospital Virgen de la Victoria, CIBERobn Fisiopatología de la Obesidad y Nutrición, Malaga, Spain.
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2012 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 32, no 8, 1555-1565 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society for Microbiology , 2012. Vol. 32, no 8, 1555-1565 p.
National Category
Cell Biology Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:oru:diva-63664DOI: 10.1128/MCB.06154-11ISI: 000302152500020PubMedID: 22310664Scopus ID: 2-s2.0-84861312625OAI: oai:DiVA.org:oru-63664DiVA: diva2:1169227
Note

Funding agencies:

Diabetes UK

MRC

MITIN

Cambridge NIHR Biomedical Research Centre

FP6 HEPADIP

Human Frontier Science Programme

Junta de Andalucia P08-CTS-04369

Fondo de Investigacion Sanitaria PS09/00997

Ministerio de Educacion y Ciencia SAF2008-02073

Instituto de Salud Carlos III-CIBERobn

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-01-22Bibliographically approved

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Oresic, Matej

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