Research Article: Fatty acids from fish or vegetable oils promote the adipogenic fate of mesenchymal stem cells derived from gilthead sea bream bone potentially through different pathways

Date Published: April 24, 2019

Publisher: Public Library of Science

Author(s): Natàlia Riera-Heredia, Esmail Lutfi, Joaquim Gutiérrez, Isabel Navarro, Encarnación Capilla, José L. Soengas.


Fish are rich in n-3 long-chain polyunsaturated fatty acids (LC-PUFA), such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, thus they have a great nutritional value for human health. In this study, the adipogenic potential of fatty acids commonly found in fish oil (EPA and DHA) and vegetable oils (linoleic (LA) and alpha-linolenic (ALA) acids), was evaluated in bone-derived mesenchymal stem cells (MSCs) from gilthead sea bream. At a morphological level, cells adopted a round shape upon all treatments, losing their fibroblastic form and increasing lipid accumulation, especially in the presence of the n-6 PUFA, LA. The mRNA levels of the key transcription factor of osteogenesis, runx2 significantly diminished and those of relevant osteogenic genes remained stable after incubation with all fatty acids, suggesting that the osteogenic process might be compromised. On the other hand, transcript levels of the main adipogenesis-inducer factor, pparg increased in response to EPA. Nevertheless, the specific PPARγ antagonist T0070907 appeared to suppress the effects being caused by EPA over adipogenesis. Moreover, LA, ALA and their combinations, significantly up-regulated the fatty acid transporter and binding protein, fatp1 and fabp11, supporting the elevated lipid content found in the cells treated with those fatty acids. Overall, this study has demonstrated that fatty acids favor lipid storage in gilthead sea bream bone-derived MSCs inducing their fate into the adipogenic versus the osteogenic lineage. This process seems to be promoted via different pathways depending on the fatty acid source, being vegetable oils-derived fatty acids more prone to induce unhealthier metabolic phenotypes.

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In the last decades, both the world population and the consumption of fish and seafood per capita have increased and will continue to rise. Fish products are rich in n-3 long chain polyunsaturated fatty acids (LC-PUFA) such as eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic (DHA, 22:6n-3) acids [1], which are crucial nutrients for overall health [2]. For these reasons, scientific research is indispensable to improve aquaculture production under sustainable conditions, which implies among others, a reduction in the use of fish oil in aquafeeds formulation [3]. The alternatives are vegetable oils, which in contrast to fish oil, are richer in n-6 or n-9 PUFA such as linoleic (LA, 18:2n-6), oleic (18:1n-9) or alpha-linolenic (ALA, 18:3n-3) acids [4]. Moreover, fish (especially marine) may have limited ability to convert C18 PUFA to C20/22 [4], [5] so, it should be considered that feeding fish with highly substituted diets can result in tissues with lower n-3 LC-PUFA content [6], [7]. Apart from changes in the fatty acid composition of the fish filet [8], [9], [10], dietary vegetable oils in excess can cause adipose tissue and hepatic metabolic alterations [11], [12] or affect the immune system [13], [14]. Besides, low concentrations of dietary EPA and DHA during development, have been related to increased incidence of skeletal malformations [15], [16]. Overall, these can lead to unhealthier or low-quality fish having consequences in aquaculture production.

This study has focused on the characterization of the likely differential effects of fatty acids typical from fish oil (EPA and DHA) and those most commonly found in vegetable oils (LA and ALA) on cellular plasticity and metabolism. To this end, we used as a model an in vitro culture of MSCs derived from vertebra bone of gilthead sea bream (S. aurata), one of the most cultivated species in Mediterranean aquaculture. The main objective was to evaluate the lineage-induction potential over the MSCs of these fatty acids, not only for its possible relevance in fish nutrition and welfare, but also to validate the cell system to further study the multipotentiality of piscine MSCs and their regulation.

Gilthead sea bream bone-derived MSCs treated with one or two combined fatty acids undergo morphological and transcriptional changes, increasing lipid accumulation as well as the expression of adipogenic genes while decreasing or maintaining stable those related to the osteogenic process. This confirms the plasticity of these cells and supports their use as a model to study MSCs fate modulation. Besides, these findings should be also considered when studying fish bone structure and function, since at least in humans, there is a correlation between the appearance of bone marrow fat and the reduced bone forming capacity observed during diabetes and aging [75], [76]. Our data also suggest that fatty acids might be inducing adipogenesis potentially through different pathways, with fish oil-derived fatty acids such as EPA causing mainly formation of new adipocytes through activation of PPARγ, whereas vegetable fatty acids like LA appear to rather induce a process of fat accumulation in committed pre-adipocytes (Fig 7). These results advise that fatty acids from plant origin should be wisely used in aquafeeds, as they could induce the formation of less sensitive and functional hypertrophic adipocytes as previously suggested [12]. While we should be cautious because most of our data is based on a transcriptional level, and further studies are required to validate these observations; overall, this needs to be considered in feeds formulation to carefully find a balance according to the nature of the oil sources to ensure a healthy and high-quality fish.