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Aging is characterized by a loss in muscle mass and function, which is defined as sarcopenia. It weakens individuals by increasing the risk of falls and altering their quality of life. The loss of muscle mass results from the age-related impairment of the anabolic effect of nutrients and insulin, which normally increase and decrease muscle protein synthesis and degradation rates respectively. Alterations in muscle protein metabolism have been related to the accumulation of body fat and intramyocellular lipids. In particular, some lipid species such as ceramides or diacylglycerols have been described as inhibitors of the insulin signaling pathway in different models. Accumulation of these molecules in skeletal muscle could result from a lowered buffering capacity of circulating fatty acids by adipose tissue in response to the meal, a reduction of mitochondrial oxidative capacities or chronic inflammation. However, some nutritional strategies have been identified to limit or prevent the accumulation of lipotoxic metabolites and to improve the sensitivity of muscle to nutrients or insulin.

Non-alcoholic steatohepatitis (NASH), one of the deleterious stages of non-alcoholic fatty liver disease, remains a significant cause of liver-related morbidity and mortality worldwide. In the current work, we used an exploratory data analysis to investigate time-dependent cellular and mitochondrial effects of different supra-physiological fatty acids (FA) overload strategies, in the presence or absence of fructose (F), on human hepatoma-derived HepG2 cells. We measured intracellular neutral lipid content and reactive oxygen species (ROS) levels, mitochondrial respiration and morphology, and caspases activity and cell death. FA-treatments induced a time-dependent increase in neutral lipid content, which was paralleled by an increase in ROS. Fructose, by itself, did not increase intracellular lipid content nor aggravated the effects of palmitic acid (PA) or free fatty acids mixture (FFA), although it led to an up-expression of hepatic fructokinase. Instead, F decreased mitochondrial phospholipid content, as well as OXPHOS subunits levels. Increased lipid accumulation and ROS in FA-treatments preceded mitochondrial dysfunction, comprising altered mitochondrial membrane potential (ΔΨm) and morphology, and decreased oxygen consumption rates, especially with PA. Consequently, supra-physiological PA alone or combined with F prompted the activation of caspase pathways leading to a time-dependent decrease in cell viability. Exploratory data analysis methods support this conclusion by clearly identifying the effects of FA treatments. In fact, unsupervised learning algorithms created homogeneous and cohesive clusters, with a clear separation between PA and FFA treated samples to identify a minimal subset of critical mitochondrial markers in order to attain a feasible model to predict cell death in NAFLD or for high throughput screening of possible therapeutic agents, with particular focus in measuring mitochondrial function. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the effect of different types of high-fat diets (HFDs) on the proteomic profile of mouse liver. The analysis included four dietary groups of mice fed a standard diet (STD group), a high-fat diet rich in SFAs (SFA group), and high-fat diets dominated by PUFAs with linoleic acid (LA, C18:2n–6) to α-linolenic acid (ALA, C18:3n–3) ratios of 14:1 (14:1 group) and 5:1 (5:1 group). After three months of diets, liver proteins were resolved by two-dimensional gel electrophoresis (2DE) using 17 cm non-linear 3–10 pH gradient strips. Protein spots with different expression were identified by MALDI-TOF/TOF. The expression of 13 liver proteins was changed in the SFA group compared to the STD group (↓: ALB, APOA1, IVD, MAT1A, OAT and PHB; ↑: ALDH1L1, UniProtKB—Q91V76, GALK1, GPD1, HMGCS2, KHK and TKFC). Eleven proteins with altered expression were recorded in the 14:1 group compared to the SFA group (↓: ARG1, FTL1, GPD1, HGD, HMGCS2 and MAT1A; ↑: APOA1, CA3, GLO1, HDHD3 and IVD). The expression of 11 proteins was altered in the 5:1 group compared to the SFA group (↓: ATP5F1B, FTL1, GALK1, HGD, HSPA9, HSPD1, PC and TKFC; ↑: ACAT2, CA3 and GSTP1). High-PUFA diets significantly affected the expression of proteins involved in, e.g., carbohydrate metabolism, and had varying effects on plasma total cholesterol and glucose levels. The outcomes of this study revealed crucial liver proteins affected by different high-fat diets. [ABSTRACT FROM AUTHOR]

Vegetable oils such as palm oil (enriched in saturated fatty acids, SFA) and high-oleic-acid sunflower oil (HOSO, containing mainly monounsaturated fatty acids, MUFA) have emerged as the most common replacements for trans-fats in the food industry. The aim of this study is to analyze the impact of SFA and MUFA-enriched high-fat (HF) diets on endothelial function, vascular remodeling, and arterial stiffness compared to commercial HF diets. Five-week-old male C57BL6J mice were fed a standard (SD), a HF diet enriched with SFA (saturated oil-enriched Food, SOLF), a HF diet enriched with MUFA (unsaturated oil-enriched Food, UOLF), or a commercial HF diet for 8 weeks. Vascular function was analyzed in the thoracic aorta. Structural and mechanical parameters were assessed in mesenteric arteries by pressure myography. SOLF, UOLF, and HF diet reduced contractile responses to phenylephrine and induced endothelial dysfunction in the thoracic aorta. A significant increase in the β-index, and thus in arterial stiffness, was also detected in mesenteric arteries from the three HF groups, due to enhanced deposition of collagen in the vascular wall. SOLF also induced hypotrophic inward remodeling. In conclusion, these data demonstrate a deleterious effect of HF feeding on obesity-related vascular alterations that is exacerbated by SFA. [ABSTRACT FROM AUTHOR]

Increased circulating levels of free fatty acids, especially saturated ones, are involved in disease progression in the non-alcoholic fatty liver. Although the mechanism of saturated fatty acid-induced toxicity in the liver is not fully understood, oxidative stress may be deeply involved. We examined the effect of increased palmitic acid, the most common saturated fatty acid in the blood, on the liver of BALB/c mice via tail vein injection with palmitate. After 24 h, among several anti-oxidative stress response genes, only heme oxygenase-1 (HO-1) was significantly upregulated in palmitate-injected mice compared with that in vehicle-injected mice. Elevation of HO-1 mRNA was also observed in the fatty liver of high-fat-diet-fed mice. To further investigate the role of HO-1 on palmitic acid-induced oxidative stress, in vitro experiments were performed to expose palmitate to HepG2 cells. SiRNA-mediated knockdown of HO-1 significantly increased the oxidative stress induced by palmitate, whereas pre-treatment with SnCl2, a well-known HO-1 inducer, significantly decreased it. Moreover, SB203580, a selective p38 inhibitor, reduced HO-1 mRNA expression and increased palmitate-induced oxidative stress in HepG2 cells. These results suggest that the HO-1-mediated anti-oxidative stress compensatory reaction plays an essential role against saturated fatty acid-induced lipotoxicity in the liver. [ABSTRACT FROM AUTHOR]

Trilobatin was identified as the primary bioactive component in the Lithocarpus polystachyus Rehd (LPR) leaves. This study explored the antiobesity effect of trilobatin from LPR leaves and its influence on gut microbiota in obese rats. Results showed that trilobatin could significantly reduce body and liver weight gain induced by a high-fat diet, and the accumulation of perirenal fat, epididymal fat, and brown fat of SD (Male Sprague–Dawley) obese rats in a dose-independent manner. Short-chain fatty acids (SCFAs) concentrations increased, especially the concentration of butyrate. Trilobatin supplementation could significantly increase the relative abundance of Lactobacillus, Prevotella, CF231, Bacteroides, and Oscillospira, and decrease greatly the abundance of Blautia, Allobaculum, Phascolarctobacterium, and Coprococcus, resulting in an increase of the ratio of Bacteroidetes to Firmicutes (except the genera of Lactobacillus and Oscillospira). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway predicted by the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) indicated the different relative metabolic pathways after trilobatin supplementation. This study may reveal the contribution of gut microbiota to the antiobesity effect of trilobatin from LPR leaves and predict the potential regulatory mechanism for obesity induced by a high-fat diet. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to examine the anti-inflammatory and anti-apoptotic patterns of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during methotrexate (MTX) induced intestinal damage in cell culture and in a rat model. Methods: Non-treated and treated with MTX HT 29 and HCT116cells were exposed to increasing doses of n-3 PUFAs and cell viability was evaluated using PrestoBlue® assay. Male Sprague-Dawley rats were divided into 4 experimental groups: Control rats, CONTR+n-3 PUFA rats that were treated with oral n-3 PUFA, MTX rats were treated with MTX given IP, and MTX+n-3 PUFA rats were treated with oral n-3 PUFA before and following injection of MTX. Intestinal mucosal parameters and mucosal inflammation, enterocyte proliferation and apoptosis, TNF-α in mucosal tissue and plasma (ELISA), NF-κB, COX-2, TNF-α, Fas, FasL, Fadd, Bid, Bax and Bcl-2gene and protein levels were determined 72 h following MTX injection. Results: Exposure of HT 29 and HCT116cells to n-3 PUFA attenuated inhibiting effects of MTX on cell viability. MTX-n-3 PUFA rats demonstrated a lower intestinal injury score and enhanced intestinal repair. A significant decrease in enterocyte apoptosis in MTX+n-3 PUFA rats was accompanied by decreased TNF-α, FAS, FasL, FADD and BID mRNA levels. Decreased NF-κB, COX-2 and TNF-α levels in mucosa was accompanied by a decreased number of IELs and macrophages. Conclusions: n-3 PUFAs inhibit NF-κB/COX-2 induced production of pro-inflammatory cytokines and inhibit cell apoptosis mainly by extrinsic pathway in rats with MTX-induced intestinal damage. [ABSTRACT FROM AUTHOR]

The increasing impact of obesity on global human health intensifies the importance of studies focusing on agents interfering with the metabolism and remodeling not only of the white adipose tissue (WAT) but also of the liver. In the present study, we have addressed the impact of n-3 PUFA in adipose cells' proliferation and adipogenesis, as well as in the hepatic lipid profile and morphology. Mice were induced to obesity by the consumption of a high-fat diet (HFD) for 16 weeks. At the 9th week, the treatment with fish oil (FO) was initiated and maintained until the end of the period. The FO treatment reduced the animals' body mass, plasma lipids, glucose, plasma transaminases, liver mass, triacylglycerol, and cholesterol liver content when compared to animals consuming only HFD. FO also decreased the inguinal (ing) WAT mass, reduced adipocyte volume, increased adipose cellularity (hyperplasia), and increased the proliferation of adipose-derived stromal cells (AdSCs) which corroborates the increment in the proliferation of 3T3-L1 pre-adipocytes or AdSCs treated in vitro with n-3 PUFA. After submitting the in vitro treated (n-3 PUFA) cells, 3T3-L1 and AdSCs, to an adipogenic cocktail, there was an increase in the mRNA expression of adipogenic transcriptional factors and other late adipocyte markers, as well as an increase in lipid accumulation when compared to not treated cells. Finally, the expression of browning-related genes was also higher in the n-3 PUFA treated group. We conclude that n-3 PUFA exerts an attenuating effect on body mass, dyslipidemia, and hepatic steatosis induced by HFD. FO treatment led to decreasing adiposity and adipocyte hypertrophy in ingWAT while increasing hyperplasia. Data suggest that FO treatment might induce recruitment (by increased proliferation and differentiation) of new adipocytes (white and/or beige) to the ingWAT, which is fundamental for the healthy expansion of WAT. [ABSTRACT FROM AUTHOR]

Westernized diet is characterized by a high content of saturated fatty acids (SFA) and a low level of omega-3 polyunsaturated fatty acids (PUFA), often accompanied by an imbalance in the omega-6/omega-3 PUFA ratio. Since increased intake of SFA and n-6 PUFA is considered as a cardiovascular disease risk factor, this study was conducted to determine whether a three-month dietary supplementation of high-fat diets (HFDs) with saturated fatty acids and a significant proportion of various n-6 and n-3 PUFA ratios would affect the architecture and protein expression patterns of the murine heart. Therefore, three HFD (n = 6) feeding groups: rich in SFA, dominated by PUFA with the n-6/n-3–14:1, and n-6/n-3–5:1, ratios were compared to animals fed standard mouse chow. For this purpose, we performed two-dimensional electrophoresis with MALDI-ToF mass spectrometry-based identification of differentially expressed cardiac proteins, and a histological examination of cardiac morphology. The results indicated that mice fed with all HFDs developed signs of hypertrophy and cardiac fibrosis. Animals fed SFA-rich HFD manifested the most severe cardiac hypertrophy and fibrosis lesions, whereas less pronounced changes were observed in the group of animals that ingested the highest amount of omega-3 FA. In general, all HFDs, regardless of FA composition, evoked a comparable pattern of cardiac protein changes and affected the following biological processes: lipid metabolism and FA β-oxidation, glycolysis, TCA cycle, respiratory chain, myocardium contractility, oxidative stress and PUFA eicosanoid metabolism. However, it should be noted that three proteins, namely IDH3A, LDHB, and AK1, were affected differently by various FA contents. High expression of these myocardial proteins found in the group of animals fed a HFD with the highest n-3 PUFA content could be closely related to the observed development of hypertrophy. [ABSTRACT FROM AUTHOR]

Importance: Sarcopenia and obesity are 2 global concerns associated with adverse health outcomes in older people. Evidence on the population-based prevalence of the combination of sarcopenia with obesity (sarcopenic obesity [SO]) and its association with mortality are still limited., Objective: To investigate the prevalence of sarcopenia and SO and their association with all-cause mortality., Design, Setting, and Participants: This large-scale, population-based cohort study assessed participants from the Rotterdam Study from March 1, 2009, to June 1, 2014. Associations of sarcopenia and SO with all-cause mortality were studied using Kaplan-Meier curves, Cox proportional hazards regression, and accelerated failure time models fitted for sex, age, and body mass index (BMI). Data analysis was performed from January 1 to April 1, 2023., Exposures: The prevalence of sarcopenia and SO, measured based on handgrip strength and body composition (BC) (dual-energy x-ray absorptiometry) as recommended by current consensus criteria, with probable sarcopenia defined as having low handgrip strength and confirmed sarcopenia and SO defined as altered BC (high fat percentage and/or low appendicular skeletal muscle index) in addition to low handgrip strength., Main Outcome and Measure: The primary outcome was all-cause mortality, collected using linked mortality data from general practitioners and the central municipal records, until October 2022., Results: In the total population of 5888 participants (mean [SD] age, 69.5 [9.1] years; mean [SD] BMI, 27.5 [4.3]; 3343 [56.8%] female), 653 (11.1%; 95% CI, 10.3%-11.9%) had probable sarcopenia and 127 (2.2%; 95% CI, 1.8%-2.6%) had confirmed sarcopenia. Sarcopenic obesity with 1 altered component of BC was present in 295 participants (5.0%; 95% CI, 4.4%-5.6%) and with 2 altered components in 44 participants (0.8%; 95% CI, 0.6%-1.0%). An increased risk of all-cause mortality was observed in participants with probable sarcopenia (hazard ratio [HR], 1.29; 95% CI, 1.14-1.47) and confirmed sarcopenia (HR, 1.93; 95% CI, 1.53-2.43). Participants with SO plus 1 altered component of BC (HR, 1.94; 95% CI, 1.60-2.33]) or 2 altered components of BC (HR, 2.84; 95% CI, 1.97-4.11) had a higher risk of mortality than those without SO. Similar results for SO were obtained for participants with a BMI of 27 or greater., Conclusions and Relevance: In this study, sarcopenia and SO were found to be prevalent phenotypes in older people and were associated with all-cause mortality. Additional alterations of BC amplified this risk independently of age, sex, and BMI. The use of low muscle strength as a first step of both diagnoses may allow for early identification of individuals at risk for premature mortality.