Short-term activation of peroxisome proliferator-activated receptors α and γ induces tissue-specific effects on lipid metabolism and fatty acid composition in male Wistar rats

Dietary fatty acids (FAs) affect certain metabolic routes, including pathways controlled by the peroxisome proliferator-activated receptors (PPARs), but tissue-specific effects are not well-defined. Thus, the aim was to compare the metabolic response in hepatic, adipose, and cardiac tissues after treatment with specific PPAR agonists. Male Wistar rats were randomized into three groups: a control group receiving placebo (n=8); a PPARα agonist group receiving WY-14,643 (n=6); and a PPARγ agonist group receiving rosiglitazone (n=6) for 12 days. All animals received a low-fat standard chow diet and were given a daily dose of placebo or agonist orally. Lipids and FA methyl esters were measured in plasma, liver, and heart and gene expression was measured in liver and adipose tissue, while enzyme activities were measured in liver. Treatment with the PPARα agonist was associated with higher liver mass relative to body weight (liver index), lower plasma, and hepatic total cholesterol, as well as lower plasma carnitine and acylcarnitines, compared with control. In heart, PPARα activation leads to overall lower levels of free FAs and specific changes in certain FAs, compared with control. Furthermore, β-oxidation in liver and the enzymatic activities of well-known PPARα targeted genes were higher following PPARα administration. Overall, rats treated with the PPARα agonist had higher hepatic saturated FAs (SFAs) and monounsaturated FAs (MUFAs) and lower n-6 and n-3 PUFAs, compared to control. Treatment with the PPARγ agonist was associated with a lower liver index, lower plasma triglycerides (TAG) and phospholipids, and higher hepatic phospholipids, compared with control. PPARγ target genes were increased specifically in adipose tissue. Moreover, lower total cardiac FAs and SFA and higher cardiac n-6 PUFA were also associated with PPARγ activation. Altogether, there were characteristic effects of PPARα activation in liver and heart, as well as in plasma. PPARγ effects were not only confined to adipose tissue, but specific effects were also seen in liver, heart, and plasma. In conclusion, short-term treatment with PPAR agonists induced tissue-specific effects on FA composition in liver and heart. Moreover, both PPARα and PPARγ activation lowered plasma TAG and phospholipids, most likely through effects on liver and adipose tissue, respectively. In future studies we aim to reveal whether similar patterns can be found through diet-induced activation of specific pathways.publishedVersio

Hepatic Energy Metabolism Underlying Differential Lipidomic Responses to High-Carbohydrate and High-Fat Diets in Male Wistar Rats

Background Low-carbohydrate diets are suggested to exert metabolic benefits by reducing circulating triacylglycerol (TG) concentrations, possibly by enhancing mitochondrial activity. Objective We aimed to elucidate mechanisms by which dietary carbohydrate and fat differentially affect hepatic and circulating TG, and how these mechanisms relate to fatty acid composition. Methods Six-week-old, ∼300 g male Wistar rats were fed a high-carbohydrate, low-fat [HC; 61.3% of energy (E%) carbohydrate] or a low-carbohydrate, high-fat (HF; 63.5 E% fat) diet for 4 wk. Parameters of lipid metabolism and mitochondrial function were measured in plasma and liver, with fatty acid composition (GC), high-energy phosphates (HPLC), carnitine metabolites (HPLC-MS/MS), and hepatic gene expression (qPCR) as main outcomes. Results In HC-fed rats, plasma TG was double and hepatic TG 27% of that in HF-fed rats. The proportion of oleic acid (18:1n–9) was 60% higher after HF vs. HC feeding while the proportion of palmitoleic acid (16:1n–7) and vaccenic acid (18:1n–7), and estimated activities of stearoyl-CoA desaturase, SCD-16 (16:1n–7/16:0), and de novo lipogenesis (16:0/18:2n–6) were 1.5–7.5-fold in HC vs. HF-fed rats. Accordingly, hepatic expression of fatty acid synthase (Fasn) and acetyl-CoA carboxylase (Acaca/Acc) was strongly upregulated after HC feeding, accompanied with 8-fold higher FAS activity and doubled ACC activity. There were no differences in expression of liver-specific biomarkers of mitochondrial biogenesis and activity (Cytc, Tfam, Cpt1, Cpt2, Ucp2, Hmgcs2); concentrations of ATP, AMP, and energy charge; plasma carnitine/acylcarnitine metabolites; or peroxisomal fatty acid oxidation. Conclusions In male Wistar rats, dietary carbohydrate was converted into specific fatty acids via hepatic lipogenesis, contributing to higher plasma TG and total fatty acids compared with high-fat feeding. In contrast, the high-fat, low-carbohydrate feeding increased hepatic fatty acid content, without affecting hepatic mitochondrial fatty acid oxidation.publishedVersio

Short-term activation of peroxisome proliferator-activated receptors α and γ induces tissue-specific effects on lipid metabolism and fatty acid composition in male Wistar rats

Dietary fatty acids (FAs) affect certain metabolic routes, including pathways controlled by the peroxisome proliferator-activated receptors (PPARs), but tissue-specific effects are not well-defined. Thus, the aim was to compare the metabolic response in hepatic, adipose, and cardiac tissues after treatment with specific PPAR agonists. Male Wistar rats were randomized into three groups: a control group receiving placebo (n=8); a PPARα agonist group receiving WY-14,643 (n=6); and a PPARγ agonist group receiving rosiglitazone (n=6) for 12 days. All animals received a low-fat standard chow diet and were given a daily dose of placebo or agonist orally. Lipids and FA methyl esters were measured in plasma, liver, and heart and gene expression was measured in liver and adipose tissue, while enzyme activities were measured in liver. Treatment with the PPARα agonist was associated with higher liver mass relative to body weight (liver index), lower plasma, and hepatic total cholesterol, as well as lower plasma carnitine and acylcarnitines, compared with control. In heart, PPARα activation leads to overall lower levels of free FAs and specific changes in certain FAs, compared with control. Furthermore, β-oxidation in liver and the enzymatic activities of well-known PPARα targeted genes were higher following PPARα administration. Overall, rats treated with the PPARα agonist had higher hepatic saturated FAs (SFAs) and monounsaturated FAs (MUFAs) and lower n-6 and n-3 PUFAs, compared to control. Treatment with the PPARγ agonist was associated with a lower liver index, lower plasma triglycerides (TAG) and phospholipids, and higher hepatic phospholipids, compared with control. PPARγ target genes were increased specifically in adipose tissue. Moreover, lower total cardiac FAs and SFA and higher cardiac n-6 PUFA were also associated with PPARγ activation. Altogether, there were characteristic effects of PPARα activation in liver and heart, as well as in plasma. PPARγ effects were not only confined to adipose tissue, but specific effects were also seen in liver, heart, and plasma. In conclusion, short-term treatment with PPAR agonists induced tissue-specific effects on FA composition in liver and heart. Moreover, both PPARα and PPARγ activation lowered plasma TAG and phospholipids, most likely through effects on liver and adipose tissue, respectively. In future studies we aim to reveal whether similar patterns can be found through diet-induced activation of specific pathways

Short-term treatment with a peroxisome proliferator-activated receptor α agonist influences plasma one-carbon metabolites and B-vitamin status in rats

Introduction: Peroxisome proliferator-activated receptors (PPARs) have been suggested to be involved in the regulation of one-carbon metabolism. Previously we have reported effects on plasma concentrations of metabolites along these pathways as well as markers of B-vitamin status in rats following treatment with a pan-PPAR agonist. Here we aimed to investigate the effect on these metabolites after specific activation of the PPARα and PPARγ subtypes. Methods: For a period of 12 days, Male Wistar rats (n = 20) were randomly allocated to receive treatment with the PPARα agonist WY-14.643 (n = 6), the PPARγ agonist rosiglitazone (n = 6) or placebo (n = 8). The animals were sacrificed under fasting conditions, and plasma concentration of metabolites were determined. Group differences were assessed by one-way ANOVA, and planned comparisons were performed for both active treatment groups towards the control group. Results: Treatment with a PPARα agonist was associated with increased plasma concentrations of most biomarkers, with the most pronounced differences observed for betaine, dimethylglycine, glycine, nicotinamide, methylnicotinamide, pyridoxal and methylmalonic acid. Lower levels were observed for flavin mononucleotide. Fewer associations were observed after treatment with a PPARγ agonist, and the most notable was increased plasma serine. Conclusion: Treatment with a PPARα agonist influenced plasma concentration of one-carbon metabolites and markers of B-vitamin status. This confirms previous findings, suggesting specific involvement of PPARα in the regulation of these metabolic pathways as well as the status of closely related B-vitamins

Short-term treatment with a peroxisome proliferator-activated receptor α agonist influences plasma one-carbon metabolites and B-vitamin status in rats

Introduction: Peroxisome proliferator-activated receptors (PPARs) have been suggested to be involved in the regulation of one-carbon metabolism. Previously we have reported effects on plasma concentrations of metabolites along these pathways as well as markers of B-vitamin status in rats following treatment with a pan-PPAR agonist. Here we aimed to investigate the effect on these metabolites after specific activation of the PPARα and PPARγ subtypes. Methods: For a period of 12 days, Male Wistar rats (n = 20) were randomly allocated to receive treatment with the PPARα agonist WY-14.643 (n = 6), the PPARγ agonist rosiglitazone (n = 6) or placebo (n = 8). The animals were sacrificed under fasting conditions, and plasma concentration of metabolites were determined. Group differences were assessed by one-way ANOVA, and planned comparisons were performed for both active treatment groups towards the control group. Results: Treatment with a PPARα agonist was associated with increased plasma concentrations of most biomarkers, with the most pronounced differences observed for betaine, dimethylglycine, glycine, nicotinamide, methylnicotinamide, pyridoxal and methylmalonic acid. Lower levels were observed for flavin mononucleotide. Fewer associations were observed after treatment with a PPARγ agonist, and the most notable was increased plasma serine. Conclusion: Treatment with a PPARα agonist influenced plasma concentration of one-carbon metabolites and markers of B-vitamin status. This confirms previous findings, suggesting specific involvement of PPARα in the regulation of these metabolic pathways as well as the status of closely related B-vitamins

Hepatic Energy Metabolism Underlying Differential Lipidomic Responses to High-Carbohydrate and High-Fat Diets in Male Wistar Rats

Background Low-carbohydrate diets are suggested to exert metabolic benefits by reducing circulating triacylglycerol (TG) concentrations, possibly by enhancing mitochondrial activity. Objective We aimed to elucidate mechanisms by which dietary carbohydrate and fat differentially affect hepatic and circulating TG, and how these mechanisms relate to fatty acid composition. Methods Six-week-old, ∼300 g male Wistar rats were fed a high-carbohydrate, low-fat [HC; 61.3% of energy (E%) carbohydrate] or a low-carbohydrate, high-fat (HF; 63.5 E% fat) diet for 4 wk. Parameters of lipid metabolism and mitochondrial function were measured in plasma and liver, with fatty acid composition (GC), high-energy phosphates (HPLC), carnitine metabolites (HPLC-MS/MS), and hepatic gene expression (qPCR) as main outcomes. Results In HC-fed rats, plasma TG was double and hepatic TG 27% of that in HF-fed rats. The proportion of oleic acid (18:1n–9) was 60% higher after HF vs. HC feeding while the proportion of palmitoleic acid (16:1n–7) and vaccenic acid (18:1n–7), and estimated activities of stearoyl-CoA desaturase, SCD-16 (16:1n–7/16:0), and de novo lipogenesis (16:0/18:2n–6) were 1.5–7.5-fold in HC vs. HF-fed rats. Accordingly, hepatic expression of fatty acid synthase (Fasn) and acetyl-CoA carboxylase (Acaca/Acc) was strongly upregulated after HC feeding, accompanied with 8-fold higher FAS activity and doubled ACC activity. There were no differences in expression of liver-specific biomarkers of mitochondrial biogenesis and activity (Cytc, Tfam, Cpt1, Cpt2, Ucp2, Hmgcs2); concentrations of ATP, AMP, and energy charge; plasma carnitine/acylcarnitine metabolites; or peroxisomal fatty acid oxidation. Conclusions In male Wistar rats, dietary carbohydrate was converted into specific fatty acids via hepatic lipogenesis, contributing to higher plasma TG and total fatty acids compared with high-fat feeding. In contrast, the high-fat, low-carbohydrate feeding increased hepatic fatty acid content, without affecting hepatic mitochondrial fatty acid oxidation