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Concealed metabolic effects in adipose depots and liver of Elovl3-/- mice
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 .
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The Elovl3 gene belongs to a highly conserved family of microsomal enzymes involved in the formation of very long-chain fatty acids (VLCFAs). The recognized role for the enzyme is to control the elongation of saturated and monounsaturated fatty acids up to 24 carbons in length. Elovl3 was originally identified as a highly expressed gene in brown adipose tissue (BAT) upon cold exposure, however significant amounts of transcript can also be found in liver, kidney, white adipose tissue (WAT), heart and in the sebaceous glands of the skin. We have recently seen that Elovl3 ablation gives rise to diminished body weight. These mice are resistant to diet-induced obesity and both female and male knockout mice have reduced hepatic lipogenic gene expression and TG secretion as well as a decreased ratio between energy intake and energy expenditure.

In an attempt to identify early markers of metabolic disturbance, we used mice at an age before the onset of impaired weight gain is recognized to analyze the expression of genes involved in lipid metabolism in liver, brown and inguinal white adipose tissue, where Elovl3 is significantly expressed under normal conditions. Furthermore, we analyzed the expression under conditions when energy intake exceeds energy expenditure and during increased energy demand.

Here we show that besides BAT, Elovl3 expression is also regulated in depot specific adipose tissue at different ambient temperatures. We also show that, in addition to impaired expression of both liver (MUP1) and adipose derived (leptin and adiponectin) factors, the Elovl3-/- mice have decreased adipose mass and TG levels already at 30°C, suggesting that factors other than skin barrier dysfunction are involved in the metabolic disturbance associated with Elovl3 ablation.

National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:su:diva-34401OAI: oai:DiVA.org:su-34401DiVA: diva2:284662
Available from: 2010-01-12 Created: 2010-01-08 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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