Bioactive compounds, including some fatty acids (FAs), can induce beneficial effects on body fat-content and metabolism. In this work, we have used C. elegans as a model to examine the effects of several FAs on body fat accumulation. Both omega-3 and omega-6 fatty acids induced a reduction of fat content in C. elegans, with linoleic, gamma-linolenic and dihomo-gamma-linolenic acids being the most effective ones. These three FAs are sequential metabolites especially in omega-6 PUFA synthesis pathway and the effects seem to be primarily due to dihomo-gamma-linolenic acid, and independent of its transformation into omega-3 or arachidonic acid. Gene expression analyses suggest that peroxisomal beta oxidation is the main mechanism involved in the observed effect. These results point out the importance of further analysis of the activity of these omega-6 FAs, due to their potential application in obesity and related diseases.

Obesity is a medical condition with increasing prevalence, characterized by an accumulation of excess fat that could be improved using some bioactive compounds. However, many of these compounds with in vitro activity fail to respond in vivo, probably due to the sophistication of the physiological energy regulatory networks. In this context, C. elegans has emerged as a plausible model for the identification and characterization of the effect of such compounds on fat storage in a complete organism. However, the results obtained in such a simple model are not easily extrapolated to more complex organisms such as mammals, which hinders its application in the short term. Therefore, it is necessary to obtain new experimental data about the evolutionary conservation of the mechanisms of fat loss between worms and mammals. Previously, we found that some omega-6 fatty acids promote fat loss in C. elegans by up-regulation of peroxisomal fatty acid β-oxidation in an omega-3 independent manner. In this work, we prove that the omega-6 fatty acids' effects on worms are also seen when they are supplemented with a natural omega-6 source (borage seed oil, BSO). Additionally, we explore the anti-obesity effects of two doses of BSO in a diet-induced obesity rat model, validating the up-regulation of peroxisomal fatty acid β-oxidation. The supplementation with BSO significantly reduces body weight gain and energy efficiency and prevents white adipose tissue accumulation without affecting food intake. Moreover, BSO also increases serum HDL-cholesterol levels, improves insulin resistance and promotes the down-regulation of Cebpa, an adipogenesis-related gene. Therefore, we conclude that the effects of omega-6 fatty acids are highly conserved between worms and obesity-induced mammals, so these compounds could be considered to treat or prevent obesity-related disorders.

The online version of this article has a Supplementary Appendix. BackgroundDespite the discovery of the p.V617F in JAK2, the molecular pathogenesis of some chronic myeloproliferative neoplasms remains unclear. Although very rare, different studies have identified CBL (Cas-Br-Murine ecotropic retroviral transforming sequence) mutations in V617FJAK2-negative patients, mainly located in the RING finger domain. In order to determine the frequency of CBL mutations in these diseases, we studied different regions of all CBL family genes (CBL, CBLB and CBLC) in a selected group of patients with myeloproliferative neoplasms. We also included V617FJAK2-positive patients to check whether mutations in CBL and JAK2 are mutually exclusive events. Design and MethodsUsing denaturing high performance liquid chromatography, we screened for mutations in CBL, CBLB and CBLC in a group of 172 V617FJAK2-negative and 232 V617FJAK2-positive patients with myeloproliferative neoplasms not selected for loss of heterozygosity. The effect on cell proliferation of the mutations detected was analyzed on a 32D(FLT3) cell model. ResultsAn initial screening of all coding exons of CBL, CBLB and CBLC in 44 V617FJAK2-negative samples revealed two new CBL mutations (p.C416W in the RING finger domain and p.A678V in the proline-rich domain). Analyses performed on 128 additional V617FJAK2-negative and 232 V617FJAK2-positive samples detected three CBL changes (p.T402HfsX29, p.P417R and p.S675C in two cases) in four V617FJAK2-positive patients. None of these mutations was found in 200 control samples. Cell proliferation assays showed that all of the mutations promoted hypersensitivity to interleukin-3 in 32D(FLT3) cells. ConclusionsAlthough mutations described to date have been found in the RING finger domain and in the linker region of CBL, we found a similar frequency of mutations in the proline-rich domain. In addition, we found CBL mutations in both V617FJAK2-positive (4/232; 1.7%) and negative (2/172; 1.2%) patients and all of them promoted hypersensitivity to interleukin-3.Key words: CBL, MPN, mutation analysis.Citation: Aranaz P, Hurtado C, Erquiaga I, Miguéliz I, Ormazábal C, Cristobal I, García-Delgado M, Novo FJ, and Vizmanos JL. CBL mutations in myeloproliferative neoplasms are also found in the gene 's proline-rich domain and in patients with the V617FJAK2. Haematologica 2012;97(8):1234-1241. doi:10.3324/haematol.2011 This is an open-access paper.CBL mutations in myeloproliferative neoplasms are also found in the gene's proline-rich domain and in patients with the V617FJAK2 ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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Core-binding factor acute myeloid leukemia ( CBF -AML) is an acute myeloid neoplasm characterized by the presence of t(8;21)(q22;q22) [abbreviated as t(8;21)] or inv(16)(p13q22)/ t(16;16)(p13;q22) [inv(16)] that lead to fusion genes RUNX1/ RUNX1T1 and CBFB -MYH11 , respectively. Both chimeric transcripts are considered diagnostic markers of disease [1]. RUNX1 and CBFB code for subunits of the heterodimeric transcription factor core-binding factor (CBF).AML development is a multistep process that requires the cooperation of several genetic aberrations [2]. Class I mutations activate signal transduction pathways conferring a proliferative advantage, and they are mainly found in the receptor tyrosine kinase (RTK) genes FLT3 and KIT , but also in the GTPase-coding genes KRAS or NRAS . On the other hand, class II mutations aff ect transcription factors impairing differentiation, and are mainly found in CBF, C/EBP α and MLL. Both types of mutations would explain the accumulation of a large number of immature myeloid cells and loss of the capacity of diff erentiation into mature functional blood cells that characterize AML. In the last few years, the discovery of other aberrations in genes involved in epigenetic regulation has revealed an increasing complexity of cooperation of different abnormalities (for a review see [3]). Th e identifi cation of these mutations might have a signifi cant impact on the development of new therapeutic strategies and could explain the low rate of clinical responses with some single targeted therapies, such as FLT3 inhibitors [1].In CBF -leukemias, class I activating mutations are mainly found in KIT (up to 40%), although some patients show the FLT3 D835Y change (up to 24% of CBFB -MYH11 and 7% of RUNX1/RUNX1T1 positive patients) and HRAS , NRAS and KRAS mutations. FLT3 internal tandem duplication (ITD) seems to be rare [1]. Several studies have identifi ed CBL mutations in myeloid neoplasms with frequencies ranging from 1 to 33%, mainly in patients without mutations in other molecules involved in signaling pathways such as FLT3 , JAK2 , NF1 , PTPN11 or RAS [4 -7]. CBL ( Cas-Br-Murine ecotropic retroviral transforming sequence ) encodes an E3-ubiquitin ligase that acts as negative regulator of several RTKs [8], so mutations of this gene could be considered also as class I aberrations.Here, we have analyzed 26 samples of patients with primary AML for the presence of CBL mutations. All of them were classifi ed as CBF -leukemias, characterized by the presence of CBFB -MYH11 (in 12 cases) or RUNX1/RUNX1T1