Exercise Induces an Augmented Skeletal Muscle Mitochondrial Unfolded Protein Response in a Mouse Model of Obesity Produced by a High-Fat Diet.

Increase in body fat contributes to loss of function and changes in skeletal muscle, accelerating sarcopenia, a phenomenon known as sarco-obesity or sarcopenic obesity. Studies suggest that obesity decreases the skeletal muscle (SM)'s ability to oxidize glucose, increases fatty acid oxidation and reactive oxygen species production, due to mitochondrial dysfunction. Exercise improves mitochondrial dysfunction in obesity; however, it is not known if exercise regulates the mitochondrial unfolded protein response (UPRmt) in the SM. Our study aimed to determine the mito-nuclear UPRmt in response to exercise in a model of obesity, and how this response is associated with the improvement in SM functioning after exercise training. C57BL/6 mice were fed a normal diet and high-fat diet (HFD) for 12 weeks. After 8 weeks, animals were subdivided into sedentary and exercised for the remaining 4 weeks. Grip strength and maximal velocity of mice submitted to HFD improved after training. Our results show an increase in the activation of UPRmt after exercise while in obese mice, proteostasis is basally decreased but shows a more pronounced increase with exercise. These results correlate with improvement in the circulating triglycerides, suggesting mitochondrial proteostasis could be protective and could be related to mitochondrial fuel utilization in SM.

Skeletal muscle type-specific mitochondrial adaptation to high-fat diet relies on differential autophagy modulation.

In obesity, skeletal muscle mitochondrial activity changes to cope with increased nutrient availability. Autophagy has been proposed as an essential mechanism involved in the regulation of mitochondrial metabolism. Still, the contribution of autophagy to mitochondrial adaptations in skeletal muscle during obesity is unknown. Here, we show that in response to high-fat diet (HFD) feeding, distinct skeletal muscles in mice exhibit differentially regulated autophagy that may modulate mitochondrial activity. We observed that after 4 and 40 weeks of high-fat diet feeding, OXPHOS subunits and mitochondrial DNA content increased in the oxidative soleus muscle. However, in gastrocnemius muscle, which has a mixed fiber-type composition, the mitochondrial mass increased only after 40 weeks of HFD feeding. Interestingly, fatty acid-supported mitochondrial respiration was enhanced in gastrocnemius, but not in soleus muscle after a 4-week HFD feeding. This increased metabolic profile in gastrocnemius was paralleled by preserving autophagy flux, while autophagy flux in soleus was reduced. To determine the role of autophagy in this differential response, we used an autophagy-deficient mouse model with partial deletion of Atg7 specifically in skeletal muscle (SkM-Atg7+/- mice). We observed that Atg7 reduction resulted in diminished autophagic flux in skeletal muscle, alongside blunting the HFD-induced increase in fatty acid-supported mitochondrial respiration observed in gastrocnemius. Remarkably, SkM-Atg7+/- mice did not present increased mitochondria accumulation. Altogether, our results show that HFD triggers specific mitochondrial adaptations in skeletal muscles with different fiber type compositions, and that Atg7-mediated autophagy modulates mitochondrial respiratory capacity but not its content in response to an obesogenic diet.

Effect of Structured Phenolic Lipids with EPA/DHA and Gallic Acid against Metabolic-Associated Fatty Liver Disease (MAFLD) in Mice.

Obesity is the leading risk factor for developing metabolic (dysfunction)-associated fatty liver disease (MAFLD). The food industry has an essential role in searching for new strategies to improve primary food sources to revert some of the metabolic alterations induced by obesity. There is consistent evidence that long-chain polyunsaturated fatty acids (n-3 LCPUFA) belonging to the n-3 series, i.e., eicosapentaenoic (20:5n-3, EPA) and docosahexaenoic (22:6n-3, DHA) acids, could revert some alterations associated with obesity-induced metabolic diseases. A relevant tool is the synthesis of structured acylglycerols (sAG), which include EPA or DHA at the sn-2 position. On the other hand, it has been reported that a crucial role of antioxidants is the reversion of MAFLD. In this work, we studied the effects of new molecules incorporating gallic acid (GA) into EPA/DHA-rich structured lipids. Mice were fed with a high-fat diet (60%) for three months and were then divided into five groups for supplementation with sAG and sAG structured with gallic acid (structured phenolic acylglycerols, sPAG). sPAG synthesis was optimized using a 2²-screening factorial design based on the response surface methodology (RSM). Our results show that treatment of sPAG was effective in decreasing visceral fat, fasting glycemia, fasting insulin, suggesting that this new molecule has a potential use in the reversal of MAFLD-associated alterations.

Synthesis of EPA- and DHA-Enriched Structured Acylglycerols at the sn-2 Position Starting from Commercial Salmon Oil by Enzymatic Lipase Catalysis under Supercritical Conditions.

There is consistent evidence that long-chain polyunsaturated fatty acids (LCPUFA) belonging to the n-3 series, i.e., eicosapentaenoic (20:5n-3, EPA) and docosahexaenoic (22:6n-3, DHA) acids, decrease the risk of heart, circulatory and inflammatory diseases. Furthermore, the bioavailability of such fatty acids has been shown to depend on their location in triacylglycerol (TG) molecules at the sn-2 position. Consequently, great attention has been accorded to the synthesis of structured acylglycerols (sAG), which include EPA or DHA at the sn-2 position. The aim of this work was to synthesize sAG starting from deodorized refined commercial salmon oil. For this, immobilized lipase B from Candida antarctica (nonspecific) was used as a catalyst for the intra-interesterification process under CO2 supercritical conditions (CO2SC). According to the CO2SC reaction time, three different fractions including sAG compounds were obtained. The location of EPA and DHA at the sn-2 position in the resulting glycerol backbone was identified by mass spectrometry (MALDI-TOF) analysis. In all fractions obtained, a marked decrease in the starting TG content was observed, while an increase in the DHA content at the sn-2 position was detected. The fraction obtained after the longest reaction time period (2 h) led to the highest yield of sn-2 position DHA in the resulting sAG molecule.

Moderate Aerobic Exercise Training Prevents the Augmented Hepatic Glucocorticoid Response Induced by High-Fat Diet in Mice.

Glucocorticoids (GCs) are critical regulators of energy balance. Their deregulation is associated with the development of obesity and metabolic syndrome. However, it is not understood if obesity alters the tissue glucocorticoid receptor (GR) response, and moreover whether a moderate aerobic exercise prevents the alteration in GR response induced by obesity. METHODS: To evaluate the GR response in obese mice, we fed C57BL6J mice with a high-fat diet (HFD) for 12 weeks. Before mice were sacrificed, we injected them with dexamethasone. To assess the exercise role in GR response, we fed mice an HFD and subjected them to moderate aerobic exercise three times a week. RESULTS: We found that mice fed a high-fat diet for 12 weeks developed hepatic GC hypersensitivity without changes in the gastrocnemius or epididymal fat GR response. Therefore, moderate aerobic exercise improved glucose tolerance, increased the corticosterone plasma levels, and prevented hepatic GR hypersensitivity with an increase in epididymal fat GR response. CONCLUSION: Collectively, our results suggest that mice with HFD-induced obesity develop hepatic GR sensitivity, which could enhance the metabolic effects of HFD in the liver. Moreover, exercise was found to be a feasible non-pharmacological strategy to prevent the deregulation of GR response in obesity.

Protective Effects of Eicosapentaenoic Acid Plus Hydroxytyrosol Supplementation Against White Adipose Tissue Abnormalities in Mice Fed a High-Fat Diet.

OBJECTIVE: Obesity induced by high-fat diet (HFD) elicits white adipose tissue dysfunction. In this study, we have hypothesized that the metabolic modulator eicosapentaenoic acid (EPA) combined with the antioxidant hydroxytyrosol (HT) attenuates HFD-induced white adipose tissue (WAT) alterations. METHODS: C57BL/6J mice were administered with a HFD (60% fat, 20% protein, 20% carbohydrates) or control diet (CD; 10% fat, 20% protein, 70% carbohydrates), with or without EPA (50 mg/kg/day), HT (5 mg/kg/day), or both for 12 weeks. Determinations in WAT include morphological parameters, EPA and docosahexaenoic acid content in phospholipids (gas chromatography), lipogenesis, oxidative stress (OS) and inflammation markers, and gene expression and activities of transcription factors, such as sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor-gamma (PPAR-γ), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (p65 subunit) and nuclear factor erythroid 2-related factor 2 (Nrf2) (quantitative polymerase chain reaction and enzyme linked immunosorbent assay). RESULTS: HFD led to WAT hypertrophy in relation to PPAR-γ downregulation. WAT metabolic dysfunction was characterized by upregulation of lipogenic SREBP-1c system, mitochondrial energy metabolism depression, loss of the antioxidant Nrf2 signaling with OS enhancement, n-3 long-chain polyunsaturated fatty acids depletion and activation of the pro-inflammatory NF-κB system. EPA and HT co-supplementation diminished HFD-dependent effects additively, reaching values close or similar to controls. CONCLUSION: Data presented strengthen the importance of combined protocols such as EPA plus HT to attenuate metabolic-inflammatory states triggered by obesity.

EPA/DHA Concentrate by Urea Complexation Decreases Hyperinsulinemia and Increases Plin5 in the Liver of Mice Fed a High-Fat Diet.

Dietary intake of eicosapentaenoic/docosahexaenoic acid (EPA/DHA) reduces insulin resistance and hepatic manifestations through the regulation of metabolism in the liver. Obese mice present insulin resistance and lipid accumulation in intracellular lipid droplets (LDs). LD-associated proteins perilipin (Plin) have an essential role in both adipogenesis and lipolysis; Plin5 regulates lipolysis and thus contributes to fat oxidation. The purpose of this study was to compare the effects of deodorized refined salmon oil (DSO) and its polyunsaturated fatty acids concentrate (CPUFA) containing EPA and DHA, obtained by complexing with urea, on obesity-induced metabolic alteration. CPUFA maximum content was determined using the Box-Behnken experimental design based on Surface Response Methodology. The optimized CPUFA was administered to high-fat diet (HFD)-fed mice (200 mg/kg/day of EPA + DHA) for 8 weeks. No significant differences (p > 0.05) in cholesterol, glycemia, LDs or transaminase content were found. Fasting insulin and hepatic Plin5 protein level increased in the group supplemented with the EPA + DHA optimized product (38.35 g/100 g total fatty acids) compared to obese mice without fish oil supplementation. The results suggest that processing salmon oil by urea concentration can generate an EPA+DHA dose useful to prevent the increase of fasting insulin and the decrease of Plin5 in the liver of insulin-resistant mice.

Composition and biological effects of goldenberry byproducts: an overview.

Goldenberry is a wild fruit that has been widely used for centuries, mainly in folk medicine. Most studies of goldenberry have focused on the fruit, but new research has studied its byproducts, which were considered to be waste until recently. The main objective of our study was to systematize the published information regarding the composition of goldenberry byproducts (calyces, leaves, seeds, and pomace) and their effects on biological systems. Goldenberry byproducts contain minerals, amino acids, withanolides, flavonoids, and essential fatty acids, thus representing good sources of these compounds. Some of their major biological effects include anti-inflammatory, antioxidant, antidiabetic, and antiproliferative effects. Information regarding their toxicity is also presented here. To determine the optimal dosage, further safety studies would be recommended to ensure the best health benefits of these compounds. The available evidence has demonstrated the nutritional value of different byproducts of goldenberry, suggesting them to be potential candidates for use in the cosmetic industry, in the preparation of functional foods, and in phytomedicine for the prevention and adjuvant treatment of some diseases. © 2020 Society of Chemical Industry.

Concentration of EPA and DHA from Refined Salmon Oil by Optimizing the Urea⁻Fatty Acid Adduction Reaction Conditions Using Response Surface Methodology.

This research focused on obtaining eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3) (EPA+DHA) concentrates from refined commercial salmon oil (RCSO). Independent variables of the complexation process were optimized by means of the application of response surface methodology (RSM) in order to obtain the maximum content of such fatty acids (FAs). As a result of employing the optimized conditions for all the variables (6.0, urea:FA content ratio; -18.0 °C, crystallization temperature; 14.80 h, crystallization time; 500 rpm, stirring speed), high contents of EPA and DHA could be obtained from RCSO, achieving increases of 4.1 and 7.9 times in the concentrate, with values of 31.20 and 49.31 g/100 g total FA, respectively. Furthermore, a 5.8-time increase was observed for the EPA + DHA content, which increased from 13.78 to 80.51 g/100 g total FA. It is concluded that RCSO can be transformed into a profitable source of EPA and DHA (EPA+DHA), thus leading to a product with higher commercial value.

I. THE ROLE OF RESEARCH ETHICS COMMITTEES IN OBSERVATIONAL STUDIES: EPIDEMIOLOGICAL REGISTRIES, CASE REPORTS, INTERVIEWS, AND RETROSPECTIVE STUDIES.

It is often unclear to the clinical investigator whether observational studies should be submitted to a research ethics committee (REC), mostly because, in general, no active or additional interventions are performed. Moreover, obtaining an informed consent under these circumstances may be challenging, either because these are very large epidemiological registries, or the subject may no longer be alive, is too ill to consent, or is impossible to contact after being discharged. Although observational studies do not involve interventions, they entail ethical concerns, including threats such as breaches in confidentiality and autonomy, and respect for basic rights of the research subjects according to the good clinical practices. In this context, in addition to their main function as evaluators from an ethical, methodological, and regulatory point of view, the RECs serve as mediators between the research subjects, looking after their basic rights, and the investigator or institution, safeguarding them from both legal and unethical perils that the investigation could engage, by ensuring that all procedures are performed following the international standards of care for research. The aim of this manuscript is to provide information on each type of study and its risks, along with actions to prevent such risks, and the function of RECs in each type of study.

Global Study of Social Odor Awareness.

Olfaction plays an important role in human social communication, including multiple domains in which people often rely on their sense of smell in the social context. The importance of the sense of smell and its role can however vary inter-individually and culturally. Despite the growing body of literature on differences in olfactory performance or hedonic preferences across the globe, the aspects of a given culture as well as culturally universal individual differences affecting odor awareness in human social life remain unknown. Here, we conducted a large-scale analysis of data collected from 10 794 participants from 52 study sites from 44 countries all over the world. The aim of our research was to explore the potential individual and country-level correlates of odor awareness in the social context. The results show that the individual characteristics were more strongly related than country-level factors to self-reported odor awareness in different social contexts. A model including individual-level predictors (gender, age, material situation, education, and preferred social distance) provided a relatively good fit to the data, but adding country-level predictors (Human Development Index, population density, and average temperature) did not improve model parameters. Although there were some cross-cultural differences in social odor awareness, the main differentiating role was played by the individual differences. This suggests that people living in different cultures and different climate conditions may still share some similar patterns of odor awareness if they share other individual-level characteristics.

Catching up with wonderful women: The women-are-wonderful effect is smaller in more gender egalitarian societies.

Inequalities between men and women are common and well-documented. Objective indexes show that men are better positioned than women in societal hierarchies-there is no single country in the world without a gender gap. In contrast, researchers have found that the women-are-wonderful effect-that women are evaluated more positively than men overall-is also common. Cross-cultural studies on gender equality reveal that the more gender egalitarian the society is, the less prevalent explicit gender stereotypes are. Yet, because self-reported gender stereotypes may differ from implicit attitudes towards each gender, we reanalysed data collected across 44 cultures, and (a) confirmed that societal gender egalitarianism reduces the women-are-wonderful effect when it is measured more implicitly (i.e. rating the personality of men and women presented in images) and (b) documented that the social perception of men benefits more from gender egalitarianism than that of women.

Hydroxytyrosol prevents reduction in liver activity of Δ-5 and Δ-6 desaturases, oxidative stress, and depletion in long chain polyunsaturated fatty acid content in different tissues of high-fat diet fed mice.

BACKGROUND: Eicosapentaenoic acid (EPA, C20:5n-3), docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, C20:4n-6) are long-chain polyunsaturated fatty acids (LCPUFAs) with relevant roles in the organism. EPA and DHA are synthesized from the precursor alpha-linolenic acid (ALA, C18:3n-3), whereas AA is produced from linoleic acid (LA, C18:2n-6) through the action of Δ5 and Δ6-desaturases. High-fat diet (HFD) decreases the activity of both desaturases and LCPUFA accretion in liver and other tissues. Hydroxytyrosol (HT), a natural antioxidant, has an important cytoprotective effects in different cells and tissues. METHODS: Male mice C57BL/6 J were fed a control diet (CD) (10% fat, 20% protein, 70% carbohydrates) or a HFD (60% fat, 20% protein, 20% carbohydrates) for 12 weeks. Animals were daily supplemented with saline (CD) or 5 mg HT (HFD), and blood and the studied tissues were analyzed after the HT intervention. Parameters studied included liver histology (optical microscopy), activity of hepatic desaturases 5 and 6 (gas-liquid chromatography of methyl esters derivatives) and antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase by spectrophotometry), oxidative stress indicators (glutathione, thiobarbituric acid reactants, and the antioxidant capacity of plasma), gene expression assays for sterol regulatory element-binding protein 1c (SREBP-1c) (qPCR and ELISA), and LCPUFA profiles in liver, erythrocyte, brain, heart, and testicle (gas-liquid chromatography). RESULTS: HFD led to insulin resistance and liver steatosis associated with SREBP-1c upregulation, with enhancement in plasma and liver oxidative stress status and diminution in the synthesis and storage of n-6 and n-3 LCPUFAs in the studied tissues, compared to animals given control diet. HT supplementation significantly reduced fat accumulation in liver and plasma as well as tissue metabolic alterations induced by HFD. Furthermore, a normalization of desaturase activities, oxidative stress-related parameters, and tissue n-3 LCPUFA content was observed in HT-treated rats over control animals. CONCLUSIONS: HT supplementation prevents metabolic alterations in desaturase activities, oxidative stress status, and n-3 LCPUFA content in the liver and extrahepatic tissues of mice fed HFD.

Insulin elicits a ROS-activated and an IP3-dependent Ca²âº release, which both impinge on GLUT4 translocation.

Insulin signaling includes generation of low levels of H2O2; however, its origin and contribution to insulin-stimulated glucose transport are unknown. We tested the impact of H2O2 on insulin-dependent glucose transport and GLUT4 translocation in skeletal muscle cells. H2O2 increased the translocation of GLUT4 with an exofacial Myc-epitope tag between the first and second transmembrane domains (GLUT4myc), an effect additive to that of insulin. The anti-oxidants N-acetyl L-cysteine and Trolox, the p47(phox)-NOX2 NADPH oxidase inhibitory peptide gp91-ds-tat or p47(phox) knockdown each reduced insulin-dependent GLUT4myc translocation. Importantly, gp91-ds-tat suppressed insulin-dependent H2O2 production. A ryanodine receptor (RyR) channel agonist stimulated GLUT4myc translocation and insulin stimulated RyR1-mediated Ca(2+) release by promoting RyR1 S-glutathionylation. This pathway acts in parallel to insulin-mediated stimulation of inositol-1,4,5-trisphosphate (IP3)-activated Ca(2+) channels, in response to activation of phosphatidylinositol 3-kinase and its downstream target phospholipase C, resulting in Ca(2+) transfer to the mitochondria. An inhibitor of IP3 receptors, Xestospongin B, reduced both insulin-dependent IP3 production and GLUT4myc translocation. We propose that, in addition to the canonical α,ß phosphatidylinositol 3-kinase to Akt pathway, insulin engages both RyR-mediated Ca(2+) release and IP3-receptor-mediated mitochondrial Ca(2+) uptake, and that these signals jointly stimulate glucose uptake.

The cholesterol-lowering agent methyl-ß-cyclodextrin promotes glucose uptake via GLUT4 in adult muscle fibers and reduces insulin resistance in obese mice.

Insulin stimulates glucose uptake in adult skeletal muscle by promoting the translocation of GLUT4 glucose transporters to the transverse tubule (T-tubule) membranes, which have particularly high cholesterol levels. We investigated whether T-tubule cholesterol content affects insulin-induced glucose transport. Feeding mice a high-fat diet (HFD) for 8 wk increased by 30% the T-tubule cholesterol content of triad-enriched vesicular fractions from muscle tissue compared with triads from control mice. Additionally, isolated muscle fibers (flexor digitorum brevis) from HFD-fed mice showed a 40% decrease in insulin-stimulated glucose uptake rates compared with fibers from control mice. In HFD-fed mice, four subcutaneous injections of MßCD, an agent reported to extract membrane cholesterol, improved their defective glucose tolerance test and normalized their high fasting glucose levels. The preincubation of isolated muscle fibers with relatively low concentrations of MßCD increased both basal and insulin-induced glucose uptake in fibers from controls or HFD-fed mice and decreased Akt phosphorylation without altering AMPK-mediated signaling. In fibers from HFD-fed mice, MßCD improved insulin sensitivity even after Akt or CaMK II inhibition and increased membrane GLUT4 content. Indinavir, a GLUT4 antagonist, prevented the stimulatory effects of MßCD on glucose uptake. Addition of MßCD elicited ryanodine receptor-mediated calcium signals in isolated fibers, which were essential for glucose uptake. Our findings suggest that T-tubule cholesterol content exerts a critical regulatory role on insulin-stimulated GLUT4 translocation and glucose transport and that partial cholesterol removal from muscle fibers may represent a useful strategy to counteract insulin resistance.

It is better to smile to women: gender modifies perception of honesty of smiling individuals across cultures.

Social perception studies have revealed that smiling individuals are perceived more favourably on many communion dimensions in comparison to nonsmiling individuals. Research on gender differences in smiling habits showed that women smile more than men. In our study, we investigated this phenomena further and hypothesised that women perceive smiling individuals as more honest than men. An experiment conducted in seven countries (China, Germany, Mexico, Norway, Poland, Republic of South Africa and USA) revealed that gender may influence the perception of honesty in smiling individuals. We compared ratings of honesty made by male and female participants who viewed photos of smiling and nonsmiling people. While men and women did not differ on ratings of honesty in nonsmiling individuals, women assessed smiling individuals as more honest than men did. We discuss these results from a social norms perspective.

Optimization of Oil and Tocopherol Extraction from Maqui (Aristotelia chilensis (Mol.) Stuntz) by Supercritical CO2 Procedure.

This study focused on the oil extraction from freeze-dried maqui (Aristotelia chilensis) by supercritical fluid extraction with carbon dioxide (SFE-CO2). The basic objective was to optimize the oil yield and the tocopherol concentration. A Box/Behnken experimental design was developed with three processing variables: supercritical pressure (74, 187, and 300 bar), temperature (35, 48, and 60 °C), and extracting time (30, 135, and 240 min). Multiple optimizations, based on the combination of factor levels at 274 bar, 240 min, and 60 °C, led to the highest oil yield and tocopherol values. The validation of the optimized conditions of maqui oil extraction led to an oil yield of 8% and values of 735, 53, and 97 (mg·kg-1 oil) for α-tocopherol, α-tocotrienol, and γ-tocopherol, respectively. A higher concentration of tocopherol compounds was observed when compared to the employment of the conventional extracting method. The optimized SFE-CO2 method led to an oil extract exhibiting higher Hydrophilic-Oxygen Radical Absorbance Capacity (H-ORAC) assay and total phenol content (22 µmol Trolox equivalents·g-1 oil and 28 mg gallic acid equivalents·g-1 oil) than the oil obtained by the conventional procedure. A practical and accurate oil extraction is proposed for obtaining tocopherol-enriched oil including high concentrations of valuable lipophilic antioxidants.

Mitofusin-2 induced by exercise modifies lipid droplet-mitochondria communication, promoting fatty acid oxidation in male mice with NAFLD.

BACKGROUND AND AIM: The excessive accumulation of lipid droplets (LDs) is a defining characteristic of nonalcoholic fatty liver disease (NAFLD). The interaction between LDs and mitochondria is functionally important for lipid metabolism homeostasis. Exercise improves NAFLD, but it is not known if it has an effect on hepatic LD-mitochondria interactions. Here, we investigated the influence of exercise on LD-mitochondria interactions and its significance in the context of NAFLD. APPROACH AND RESULTS: Mice were fed high-fat diet (HFD) or HFD-0.1 % methionine and choline-deficient diet (MCD) to emulate simple hepatic steatosis or non-alcoholic steatohepatitis, respectively. In both models, aerobic exercise decreased the size of LDs bound to mitochondria and the number of LD-mitochondria contacts. Analysis showed that the effects of exercise on HOMA-IR and liver triglyceride levels were independent of changes in body weight, and a positive correlation was observed between the number of LD-mitochondria contacts and NAFLD severity and with the lipid droplet size bound to mitochondria. Cellular fractionation studies revealed that ATP-coupled respiration and fatty acid oxidation (FAO) were greater in hepatic peridroplet mitochondria (PDM) from HFD-fed exercised mice than from equivalent sedentary mice. Finally, exercise increased FAO and mitofusin-2 abundance exclusively in PDM through a mechanism involving the curvature of mitochondrial membranes and the abundance of saturated lipids. Accordingly, hepatic mitofusin-2 ablation prevented exercise-induced FAO in PDM. CONCLUSIONS: This study demonstrates that aerobic exercise has beneficial effects in murine NAFLD models by lessening the interactions between hepatic LDs and mitochondria, and by decreasing LD size, correlating with a reduced severity of NAFLD. Additionally, aerobic exercise increases FAO in PDM and this process is reliant on Mfn-2 enrichment, which modifies LD-mitochondria communication.

Happiness Maximization Is a WEIRD Way of Living.

Psychological science tends to treat subjective well-being and happiness synonymously. We start from the assumption that subjective well-being is more than being happy to ask the fundamental question: What is the ideal level of happiness? From a cross-cultural perspective, we propose that the idealization of attaining maximum levels of happiness may be especially characteristic of Western, educated, industrial, rich, and democratic (WEIRD) societies but less so for others. Searching for an explanation for why "happiness maximization" might have emerged in these societies, we turn to studies linking cultures to their eco-environmental habitat. We discuss the premise that WEIRD cultures emerged in an exceptionally benign ecological habitat (i.e., faced relatively light existential pressures compared with other regions). We review the influence of the Gulf Stream on the Northwestern European climate as a source of these comparatively benign geographical conditions. We propose that the ecological conditions in which WEIRD societies emerged afforded them a basis to endorse happiness as a value and to idealize attaining its maximum level. To provide a nomological network for happiness maximization, we also studied some of its potential side effects, namely alcohol and drug consumption and abuse and the prevalence of mania. To evaluate our hypothesis, we reanalyze data from two large-scale studies on ideal levels of personal life satisfaction-the most common operationalization of happiness in psychology-involving respondents from 61 countries. We conclude that societies whose members seek to maximize happiness tend to be characterized as WEIRD, and generalizing this across societies can prove problematic if adopted at the ideological and policy level.

Insulin-dependent H2O2 production is higher in muscle fibers of mice fed with a high-fat diet.

Insulin resistance is defined as a reduced ability of insulin to stimulate glucose utilization. C57BL/6 mice fed with a high-fat diet (HFD) are a model of insulin resistance. In skeletal muscle, hydrogen peroxide (H2O2) produced by NADPH oxidase 2 (NOX2) is involved in signaling pathways triggered by insulin. We evaluated oxidative status in skeletal muscle fibers from insulin-resistant and control mice by determining H2O2 generation (HyPer probe), reduced-to-oxidized glutathione ratio and NOX2 expression. After eight weeks of HFD, insulin-dependent glucose uptake was impaired in skeletal muscle fibers when compared with control muscle fibers. Insulin-resistant mice showed increased insulin-stimulated H2O2 release and decreased reduced-to-oxidized glutathione ratio (GSH/GSSG). In addition, p47phox and gp91phox (NOX2 subunits) mRNA levels were also high (~3-fold in HFD mice compared to controls), while protein levels were 6.8- and 1.6-fold higher, respectively. Using apocynin (NOX2 inhibitor) during the HFD feeding period, the oxidative intracellular environment was diminished and skeletal muscle insulin-dependent glucose uptake restored. Our results indicate that insulin-resistant mice have increased H2O2 release upon insulin stimulation when compared with control animals, which appears to be mediated by an increase in NOX2 expression.