Unmasking Differential Effects of Rosiglitazone and Pioglitazone in the Combination Treatment with n-3 Fatty Acids in Mice Fed a High-Fat Diet

Combining pharmacological treatments and life style interventions is necessary for effective therapy of major diseases associated with obesity, which are clustered in the metabolic syndrome. Acting via multiple mechanisms, combination treatments may reduce dose requirements and, therefore, lower the risk of adverse side effects, which are usually associated with long-term pharmacological interventions. Our previous study in mice fed high-fat diet indicated additivity in preservation of insulin sensitivity and in amelioration of major metabolic syndrome phenotypes by the combination treatment using n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and rosiglitazone, i.e. an anti-diabetic drug of the thiazolidinedione (TZD) family. We investigated here whether pioglitazone, a TZD-drug in clinical use, could elicit the additive beneficial effects when combined with n-3 LC-PUFA. Adult male mice (C57BL/6N) were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various dietary treatments (i) cHF+F, cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids; (ii) cHF+ROSI, cHF with 10 mg rosiglitazone/kg diet; (iii) cHF+F+ROSI; (iv) cHF+PIO, cHF with 50 mg pioglitazone/kg diet; and (v) cHF+F+PIO, or chow-fed. Plasma concentrations of 163 metabolites were evaluated using a targeted metabolomics approach. Both TZDs preserved glucose homeostasis and normal plasma lipid levels while inducing adiponectin, with pioglitazone showing better effectiveness. The beneficial effects of TZDs were further augmented by the combination treatments. cHF+F+ROSI but not cHF+F+PIO counteracted development of obesity, in correlation with inducibility of fatty acid β-oxidation, as revealed by the metabolomic analysis. By contrast, only cHF+F+PIO eliminated hepatic steatosis and this treatment also reversed insulin resistance in dietary obese mice. Our results reveal differential effects of rosiglitazone and pioglitazone, unmasked in the combination treatment with n-3 LC-PUFA, and support the notion that n-3 LC-PUFA could be used as add-on treatment to TZDs in order to improve diabetic patient's therapy

Reduced Number of Adipose Lineage and Endothelial Cells in Epididymal fat in Response to Omega-3 PUFA in Mice Fed High-Fat Diet

We found previously that white adipose tissue (WAT) hyperplasia in obese mice was limited by dietary omega-3 polyunsaturated fatty acids (omega-3 PUFA). Here we aimed to characterize the underlying mechanism. C57BL/6N mice were fed a high-fat diet supplemented or not with omega-3 PUFA for one week or eight weeks; mice fed a standard chow diet were also used. In epididymal WAT (eWAT), DNA content was quantified, immunohistochemical analysis was used to reveal the size of adipocytes and macrophage content, and lipidomic analysis and a gene expression screen were performed to assess inflammatory status. The stromal-vascular fraction of eWAT, which contained most of the eWAT cells, except for adipocytes, was characterized using flow cytometry. Omega-3 PUFA supplementation limited the high-fat diet-induced increase in eWAT weight, cell number (DNA content), inflammation, and adipocyte growth. eWAT hyperplasia was compromised due to the limited increase in the number of preadipocytes and a decrease in the number of endothelial cells. The number of leukocytes and macrophages was unaffected, but a shift in macrophage polarization towards a less inflammatory phenotype was observed. Our results document that the counteraction of eWAT hyperplasia by omega-3 PUFA in dietary-obese mice reflects an effect on the number of adipose lineage and endothelial cells

Postnatal induction of muscle fatty acid oxidation in mice differing in propensity to obesity: a role of pyruvate dehydrogenase

Background/objective: Adaptation to the extrauterine environment depends on a switch from glycolysis to catabolism of fatty acids (FA) provided as milk lipids. We sought to learn whether the postnatal induction of muscle FA oxidation in mice could reflect propensity to obesity and to characterize the mechanisms controlling this induction. Methods: Experiments were conducted using obesity-resistant A/J and obesity-prone C57BL/6J (B6) mice maintained at 30 °C, from 5 to 28 days after birth. At day 10, both A/J and B6 mice with genetic ablation (KO) of α2 subunit of AMP-activated protein kinase (AMPK) were also used. In skeletal muscle, expression of selected genes was determined using quantitative real-time PCR, and AMPK subunits content was evaluated using Western blotting. Activities of both AMPK and pyruvate dehydrogenase (PDH), as well as acylcarnitine levels in the muscle were measured. Results: Acylcarnitine levels and gene expression indicated transient increase in FA oxidation during the first 2 weeks after birth, with a stronger increase in A/J mice. These data correlated with (i) the surge in plasma leptin levels, which peaked at day 10 and was higher in A/J mice, and (ii) relatively low activity of PDH linked with up-regulation of PDH kinase 4 gene (Pdk4) expression in the 10-day-old A/J mice. In contrast with the Pdk4 expression, transient up-regulation of uncoupling protein 3 gene was observed in B6 but not A/J mice. AMPK activity changed during the development, without major differences between A/J and B6 mice. Expression of neither Pdk4 nor other muscle genes was affected by AMPK-KO. Conclusions: Our results indicate a relatively strong postnatal induction of FA oxidation in skeletal muscle of the obesity-resistant A/J mice. This induction is transient and probably results from suppression of PDH activity, linked with a postnatal surge in plasma leptin levels, independent of AMPK.</p

Raw data: Potential of different common (Fagopyrum esculentum Moench) and Tartary (Fagopyrum tataricum (L.) Gaertn.) buckwheat accessions to sustainably manage surrounding weeds

&lt;p&gt;Twenty-nine accessions of two buckwheat species (&lt;em&gt;Fagopyrum esculentum&lt;/em&gt; Moench (common buckwheat) and &lt;em&gt;Fagopyrum tataricum&lt;/em&gt; (L.) Gaertn. (Tartary buckwheat) were evaluated for their allelopathic potential against two resistant weeds, i.e. the monocot &lt;em&gt;Lolium rigidum&lt;/em&gt; Gaud. and the dicot &lt;em&gt;Portulaca oleracea&lt;/em&gt; L. The bulking use of synthetic herbicides and their consequent contamination of the environment and resulting increment of resistant weeds, imminently requires a solution to achieve sustainable weed management without the use of chemical inputs. The results obtained in this study suggest that buckwheat accessions can sustainably manage weeds through plant interference as competition or allelopathy. This research showed that accessions differ in their potential for sustainably manage both weeds, with &lt;em&gt;F. esculentum&lt;/em&gt; accessions being more effective against &lt;em&gt;L. rigidum&lt;/em&gt; and &lt;em&gt;F. tataricum&lt;/em&gt; accessions against both, monocot and dicot weeds. The chemical profile of buckwheat accessions was evaluated to know the content of polyphenols in common and Tartary buckwheat accessions and to know more about their ability to sustainably manage weeds. Differences in the chemical profile between the two buckwheat species were clear. While common buckwheat accessions showed more orientin, vitexin and hyperoside, Tartary buckwheat accessions had higher amounts of rutin, quercetin and kaempferol. We propose that the screening and selection of accessions with strong polyphenol content and vigorous growth can be a step towards organic farming due to its relation to the weed management.&lt;/p&gt

Potential of different common (Fagopyrum esculentum Moench) and Tartary (Fagopyrum tataricum (L.) Gaertn.) buckwheat accessions to sustainably manage surrounding weeds

&lt;p&gt;Twenty-nine accessions of two buckwheat species (&lt;i&gt;Fagopyrum esculentum&lt;/i&gt; Moench (common buckwheat) and &lt;i&gt;Fagopyrum tataricum&lt;/i&gt; (L.) Gaertn. (Tartary buckwheat) were evaluated for their allelopathic potential against two resistant weeds, the monocot &lt;i&gt;Lolium rigidum&lt;/i&gt; Gaud. and the dicot &lt;i&gt;Portulaca oleracea&lt;/i&gt; L. The bulking use of synthetic herbicides and their consequent contamination of the environment and resulting increment of herbicide-resistant weeds, imminently requires a solution to achieve sustainable weed management without chemical inputs. The results obtained in this study suggest that buckwheat accessions can sustainably manage weeds through plant interference as competition or allelopathy. This research showed that accessions differ in their potential for sustainably managing both weeds with &lt;i&gt;F. esculentum&lt;/i&gt; accessions being more effective against &lt;i&gt;L. rigidum&lt;/i&gt; and &lt;i&gt;F. tataricum&lt;/i&gt; accessions against both, monocot and dicot weeds. The chemical profile of buckwheat accessions was evaluated to know the content of polyphenols in common and Tartary buckwheat accessions and to know more about their ability to manage weeds sustainably. Differences in the chemical profile between the two buckwheat species were clear. While common buckwheat accessions showed more orientin, vitexin and hyperoside, Tartary buckwheat accessions had higher amounts of rutin, quercetin and kaempferol. We propose that the screening and selection of accessions with strong polyphenol content and vigorous growth can be a step towards organic farming due to its relation to the weed management.&lt;/p&gt