The Role of PPARα Activation in Liver and Muscle

PPARα is one of three members of the soluble nuclear receptor family called peroxisome proliferator-activated receptor (PPAR). It is a sensor for changes in levels of fatty acids and their derivatives that responds to ligand binding with PPAR target gene transcription, inasmuch as it can influence physiological homeostasis, including lipid and carbohydrate metabolism in various tissues. In this paper we summarize the involvement of PPARα in the metabolically active tissues liver and skeletal muscle and provide an overview of the risks and benefits of ligand activation of PPARα, with particular consideration to interspecies differences

Comparison of Fish, Krill and Flaxseed as Omega-3 Sources to Increase the Omega-3 Index in Dogs

Simple Summary For pets, as for humans, dietary inclusion of long-chain omega-3 fatty acids is recommended for disease prevention and improved health. However, many diets for dogs do not contain sufficient amounts of these fatty acids and fall short of achieving high blood omega-3 levels. This is reflected in the diagnostic health tool called Omega-3 Index (O3I). In this study, O3I levels were measured at baseline in 45 dogs fed a commercial premium diet and compared to O3I levels reached when the dogs were fed with diets containing different omega-3 sources at low inclusion levels, i.e., fish meal/oil, flaxseed cake and krill meal. After four weeks of treatment, the data showed that the highest O3I increase was observed in the 3% krill meal group, accompanied by the lowest arachidonic acid to eicosapentaenoic acid ratio as a measure for immunomodulatory effects. Hence, by using the O3I, this study provides an option for dog owners to measure the impact their pet food has on their dogs' health and if needed, how to adjust it with the right omega-3 supplement. (1) Background: it is only the longer chain omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (20:5n-3, EPA), and docosahexaenoic acid (22:6n-3, DHA) and not the shorter chain alpha-linolenic acid (ALA, 18:3n-3) that have been linked to health benefits. (2) Methods: 45 dogs divided into three groups were first given premium dry food for 38 days (baseline). The O3I was then used as a diagnostic tool to provide a measure of the sum of EPA + DHA in red blood cell membranes given as a percentage of all fatty acids. The dogs were subsequently fed with either krill meal (krill), fishmeal/oil (fish) or flaxseed cake (flax) included in raw food providing daily 416 mg EPA + DHA (971 mg ALA), 513 mg EPA + DHA (1027 mg ALA) and 1465 mg ALA (122 mg EPA + DHA), respectively. (3) Results: the average baseline O3I level of all dogs was low (1.36%), warranting n-3 supplementation. After four weeks, O3I levels were significantly increased in the krill (from 1.36 +/- 0.44 to 2.36 +/- 0.39%) and fish (from 1.35 +/- 0.22 to 1.9 +/- 0.35%) groups (p < 0.001). No significant modification of the O3I was detected in the flax animals. (4) Conclusions: only marine n-3 PUFAs resulted in a significantly increased O3I, with dietary krill meal providing the highest increase

Different Adipose Depots: Their Role in the Development of Metabolic Syndrome and Mitochondrial Response to Hypolipidemic Agents

Adipose tissue metabolism is closely linked to insulin resistance, and differential fat distributions are associated with disorders like hypertension, diabetes, and cardiovascular disease. Adipose tissues vary in their impact on metabolic risk due to diverse gene expression profiles, leading to differences in lipolysis and in the production and release of adipokines and cytokines, thereby affecting the function of other tissues. In this paper, the roles of the various adipose tissues in obesity are summarized, with particular focus on mitochondrial function. In addition, we discuss how a functionally mitochondrial-targeted compound, the modified fatty acid tetradecylthioacetic acid (TTA), can influence mitochondrial function and decrease the size of specific fat depots

Differential Effects of Krill Oil and Fish Oil on the Hepatic Transcriptome in Mice

Dietary supplementation with ω-3 polyunsaturated fatty acids (ω-3 PUFAs), specifically the fatty acids docosahexaenoic acid (DHA; 22:6 ω-3) and eicosapentaenoic acid (EPA; 20:5 ω-3), is known to have beneficial health effects including improvements in glucose and lipid homeostasis and modulation of inflammation. To evaluate the efficacy of two different sources of ω-3 PUFAs, we performed gene expression profiling in the liver of mice fed diets supplemented with either fish oil (FO) or krill oil (KO). We found that ω-3 PUFA supplements derived from a phospholipid krill fraction (KO) downregulated the activity of pathways involved in hepatic glucose production as well as lipid and cholesterol synthesis. The data also suggested that KO-supplementation increases the activity of the mitochondrial respiratory chain. Surprisingly, an equimolar dose of EPA and DHA derived from FO modulated fewer pathways than a KO-supplemented diet and did not modulate key metabolic pathways regulated by KO, including glucose metabolism, lipid metabolism and the mitochondrial respiratory chain. Moreover, FO upregulated the cholesterol synthesis pathway, which was the opposite effect of krill-supplementation. Neither diet elicited changes in plasma levels of lipids, glucose, or insulin, probably because the mice used in this study were young and were fed a low-fat diet. Further studies of KO-supplementation using animal models of metabolic disorders and/or diets with a higher level of fat may be required to observe these effects

Effects of dietary supplementation with krill meal on serum pro-inflammatory markers after the iditarod sled dog race

A seafood-based supplement from krill, rich in omega-3 phospholipids and proteins was tested on a group of dogs competing in the 2016 Iditarod dog sled race to investigate the effects of krill meal on exercise-induced inflammation and muscle damage in comparison to a control group. A single team of 16 dogs received 8% krill meal for 5 weeks prior to the start of race, while another team of 16 dogs received no supplementation. Ten dogs of the treatment and 11 dogs of the control group finished the race and their blood was analyzed for omega-3 index, inflammation (CRP) and muscle damage (CK). The omega-3 index of the krill meal-fed dogs was significantly higher at the beginning of the race (mean 6.2% in the supplemented vs 5.2% in the control group, p &lt; .001). CRP concentrations increased from 7.05 ± 2.27 to 37.04 ± 9.16 μg/ml in the control and from 4.26 ± 0.69 to 16.56 ± 3.03 μg/ml in the treatment group, with a significant difference between the groups (p &lt; .001). CK activity was increased from 90.75 ± 8.15 IU/l to 715.90 ± 218.9 IU/l in the control group and from 99.55 ± 12.15 to 515.69 ± 98.98 in the supplemented group, but there were no differences between groups (p = .266). The results showed that krill meal supplementation led to significantly higher omega-3 index, which correlated with lower inflammation and a tendency for reduced muscle damage after this long-distance sled dog competition. However, these results need to be confirmed by more controlled studies, since it was a field study and effects of race speed or other performance-related factors such as fitness and musher skill on the results cannot be excluded

Tissue-Specific Effects of Bariatric Surgery Including Mitochondrial Function

A better understanding of the molecular links between obesity and disease is potentially of great benefit for society. In this paper we discuss proposed mechanisms whereby bariatric surgery improves metabolic health, including acute effects on glucose metabolism and long-term effects on metabolic tissues (adipose tissue, skeletal muscle, and liver) and mitochondrial function. More short-term randomized controlled trials should be performed that include simultaneous measurement of metabolic parameters in different tissues, such as tissue gene expression, protein profile, and lipid content. By directly comparing different surgical procedures using a wider array of metabolic parameters, one may further unravel the mechanisms of aberrant metabolic regulation in obesity and related disorders

Induction of mitochondrial biogenesis and respiration is associated with mTOR regulation in hepatocytes of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA)

The hypolipidemic effect of peroxisome proliferator-activated receptor (PPAR) activators has been explained by increasing mitochondrial fatty acid oxidation, as observed in livers of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA). PPAR-activation does, however, not fully explain the metabolic adaptations observed in hepatocytes after treatment with TTA. We therefore characterized the mitochondrial effects, and linked this to signalling by the metabolic sensor, the mammalian target of rapamycin (mTOR). In hepatocytes isolated from TTA-treated rats, the changes in cellular content and morphology were consistent with hypertrophy. This was associated with induction of multiple mitochondrial biomarkers, including mitochondrial DNA, citrate synthase and mRNAs of mitochondrial proteins. Transcription analysis further confirmed activation of PPARα-associated genes, in addition to genes related to mitochondrial biogenesis and function. Analysis of mitochondrial respiration revealed that the capacity of both electron transport and oxidative phosphorylation were increased. These effects coincided with activation of the stress related factor, ERK1/2, and mTOR. The protein level and phosphorylation of the downstream mTOR actors eIF4G and 4E-BP1 were induced. In summary, TTA increases mitochondrial respiration by inducing hypertrophy and mitochondrial biogenesis in rat hepatocytes, via adaptive regulation of PPARs as well as mTOR.acceptedVersio

Fish oil and krill oil supplementations differentially regulate lipid catabolic and synthetic pathways in mice

Background: Marine derived oils are rich in long-chain polyunsaturated omega-3 fatty acids, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have long been associated with health promoting effects such as reduced plasma lipid levels and anti-inflammatory effects. Krill oil (KO) is a novel marine oil on the market and is also rich in EPA and DHA, but the fatty acids are incorporated mainly into phospholipids (PLs) rather than triacylglycerols (TAG). This study compares the effects of fish oil (FO) and KO on gene regulation that influences plasma and liver lipids in a high fat diet mouse model. Methods: Male C57BL/6J mice were fed either a high-fat diet (HF) containing 24% (wt/wt) fat (21.3% lard and 2.3% soy oil), or the HF diet supplemented with FO (15.7% lard, 2.3% soy oil and 5.8% FO) or KO (15.6% lard, 2.3% soy oil and 5.7% KO) for 6 weeks. Total levels of cholesterol, TAG, PLs, and fatty acid composition were measured in plasma and liver. Gene regulation was investigated using quantitative PCR in liver and intestinal epithelium. Results: Plasma cholesterol (esterified and unesterified), TAG and PLs were significantly decreased with FO. Analysis of the plasma lipoprotein particles indicated that the lipid lowering effect by FO is at least in part due to decreased very low density lipoprotein (VLDL) content in plasma with subsequent liver lipid accumulation. KO lowered plasma non-esterified fatty acids (NEFA) with a minor effect on fatty acid accumulation in the liver. In spite of a lower omega-3 fatty acid content in the KO supplemented diet, plasma and liver PLs omega-3 levels were similar in the two groups, indicating a higher bioavailability of omega-3 fatty acids from KO. KO more efficiently decreased arachidonic acid and its elongation/desaturation products in plasma and liver. FO mainly increased the expression of several genes involved in fatty acid metabolism, while KO specifically decreased the expression of genes involved in the early steps of isoprenoid/ cholesterol and lipid synthesis. Conclusions: The data show that both FO and KO promote lowering of plasma lipids and regulate lipid homeostasis, but with different efficiency and partially via different mechanisms

Krill-Oil-Dependent Increases in HS-Omega-3 Index, Plasma Choline and Antioxidant Capacity in Well-Conditioned Power Training Athletes

There is evidence that both omega-3 polyunsaturated fatty acids (n-3 PUFAs) and choline can influence sports performance, but information establishing their combined effects when given in the form of krill oil during power training protocols is missing. The purpose of this study was therefore to characterize n-3 PUFA and choline profiles after a one-hour period of high-intensity physical workout after 12 weeks of supplementation. Thirty-five healthy power training athletes received either 2.5 g/day of Neptune krill oilTM (550 mg EPA/DHA and 150 mg choline) or olive oil (placebo) in a randomized double-blind design. After 12 weeks, only the krill oil group showed a significant HS-Omega-3 Index increase from 4.82 to 6.77% and a reduction in the ARA/EPA ratio (from 50.72 to 13.61%) (p < 0.001). The krill oil group showed significantly higher recovery of choline concentrations relative to the placebo group from the end of the first to the beginning of the second exercise test (p = 0.04) and an 8% decrease in total antioxidant capacity post-exercise versus 21% in the placebo group (p = 0.35). In conclusion, krill oil can be used as a nutritional strategy for increasing the HS-Omega-3 Index, recover choline concentrations and address oxidative stress after intense power trainings