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Norepinephrine and rosiglitazone synergistically induce Elovl3 expression in brown adipocytes
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
2007 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 293, no 5, E1159-68 p.Article in journal (Refereed) Published
Abstract [en]

The Elovl3 gene, which putatively encodes for a protein involved in the elongation of saturated and monounsaturated fatty acids in the C20–C24 range, is expressed in murine liver, skin, and brown adipose tissue (BAT). In BAT, Elovl3 is dramatically upregulated during tissue activation in response to cold exposure, and functional data imply that ELOVL3 is a critical enzyme for lipid accumulation in brown adipocytes during the early phase of tissue recruitment. The activation of BAT is controlled by sympathetic nerve activity and norepinephrine release. By using primary cultures of brown adipocytes, we show here that the induced Elovl3 gene expression is synergistically regulated by norepinephrine and the peroxisome proliferator-activated receptor (PPAR) γ ligand rosiglitazone. In addition, the potency of rosiglitazone to induce Elovl3 expression was several orders of magnitude higher than for the PPARα and PPARδ ligands WY-14643 and L-165041, respectively. The maximal increase in mRNA level by norepinephrine and rosiglitazone is achieved by induced transcription as well as increased mRNA stability, and the whole process requires novel protein synthesis. We conclude that norepinehrine and PPARγ, despite having different roles in brown adipocyte activation and differentiation, cooperate in expanding the intracellular lipid pool by synergistically stimulating Elovl3 expression.

Place, publisher, year, edition, pages
American Physiological Society , 2007. Vol. 293, no 5, E1159-68 p.
Keyword [en]
fatty acid synthesis; fatty acid elongation; very long-chain fatty acids; lipid metabolism; peroxisome proliferator-activated receptor-γ
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:su:diva-21011DOI: 10.1152/ajpendo.00213.2007ISI: 000250800500005PubMedID: 17726147OAI: oai:DiVA.org:su-21011DiVA: diva2:187537
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2011-03-18Bibliographically approved
In thesis
1. Metabolic Significance of Fatty Acid Elongation
Open this publication in new window or tab >>Metabolic Significance of Fatty Acid Elongation
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Very long-chain fatty acids (VLCFAs), including polyunsaturated fatty acids (PUFAs), are essential lipids whose functional diversity is made possible by variation in their chain length and degree of unsaturation. Fatty acids can either be derived directly from the diet or they can be synthesized de novo through lipogenesis, up to 16 carbons in length by fatty acid synthase. Further elongation into VLCFAs is catalysed by the enzymes referred to as elongation of very long-chain fatty acids (ELOVLs). Seven ELOVL proteins have been identified, all of which display distinct fatty acid substrate specificity. The enclosed papers discuss issues regarding the regulation, function and contribution to lipid composition of the Elovl genes with special emphasis on Elovl2 and Elovl3.

In primary brown adipocytes the Elovl3 gene was shown to be regulated by all three PPAR isoforms, involving both transcriptional activation and mRNA stability. In an attempt to clarify the role of ELOVL3 in whole-body lipid homeostasis, the metabolic effects associated with Elovl3 ablation in mice were investigated. Elovl3-ablated mice were lean and showed markedly reduced triglyceride and leptin levels in serum. In addition, the mice were completely resistant to diet-induced obesity, associated with a reduced hepatic lipogenic gene expression and triglyceride content.

Over-expression of Elovl2 in cells promoted accumulation of lipid droplets, associated with enhanced fatty acid uptake and induction of PPARγ target genes. To further assess the in vivo function of ELOVL2, the Elovl2 gene was disrupted in mice by homologous recombination. Elovl2-ablated mice exhibited a severe reduction of the elongation products of C24:5n-6 in the testis, indicating a novel role of ELOVL2 in the formation of very-long-chain PUFAs ≥C26. In addition, Elovl2+/- male mice displayed both pre- and post-meiotic deficiency of spermatogenesis. These results specify an indispensable function of ELOVL2-derived fatty acids, which can give new insights into nutritional intervention as an aid in assisting male fertility problems.

Place, publisher, year, edition, pages
Stockholm: Department of Physiology, Stockholm University, 2010. 54 p.
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-34815 (URN)978-91-7155-993-7 (ISBN)
Public defence
2010-02-11, Hörsalen, Frescati backe 107, Svante Arrhenius väg 21 A, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defence, the following papers were unpublished and had status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript.Available from: 2010-01-21 Created: 2010-01-12 Last updated: 2011-03-17Bibliographically approved

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