Consuming a Linoleate-Rich Diet Increases Concentrations of Tetralinoleoyl Cardiolipin in Mouse Liver and Alters Hepatic Mitochondrial Respiration.

BACKGROUND: Hepatic mitochondrial dysfunction is a major cause of fat accumulation in the liver. Individuals with fatty liver conditions have hepatic mitochondrial structural abnormalities and a switch in the side chain composition of the mitochondrial phospholipid, cardiolipin, from poly- to monounsaturated fatty acids. Linoleic acid (LA), an essential dietary fatty acid, is required to remodel nascent cardiolipin (CL) to its tetralinoleoyl cardiolipin (L4CL, CL with 4 LA side chains) form, which is integral for mitochondrial membrane structure and function to promote fatty acid oxidation. It is unknown, however, whether increasing LA in the diet can increase hepatic L4CL concentrations and improve mitochondrial respiration in the liver compared with a diet rich in monounsaturated and saturated fatty acids. OBJECTIVES: The main aim of this study was to test the ability of a diet fortified with LA-rich safflower oil (SO), compared with the one fortified with lard (LD), to increase concentrations of L4CL and improve mitochondrial respiration in the livers of mice. METHODS: Twenty-four (9-wk-old) C57 BL/J6 male mice were fed either the SO or LD diets for ∼100 d, whereas food intake and body weight, fasting glucose, and glucose tolerance tests were performed to determine any changes in glycemic control. RESULTS: Livers from mice fed SO diet had higher relative concentrations of hepatic L4CL species compared with LD diet-fed mice (P value = 0.004). Uncoupled mitochondria of mice fed the SO diet, compared with LD diet, had an increased baseline oxygen consumption rate (OCR) and succinate-driven respiration (P values = 0.03 and 0.01). SO diet-fed mice had increased LA content in all phospholipid classes compared with LD-fed mice (P < 0.05). CONCLUSIONS: Our findings reveal that maintaining or increasing hepatic L4CL may result in increased OCR in uncoupled hepatic mitochondria in healthy mice whereas higher oleate content of CL reduced mitochondrial function shown by lower OCR in uncoupled mitochondria.

Skeletal muscle adaptations in patients with lung cancer: Longitudinal observations from the whole body to cellular level.

BACKGROUND: Cancer and its treatment can adversely affect skeletal muscle, impacting physical function, treatment response and survival. No studies, however, have comprehensively characterized these muscle adaptations longitudinally in human patients at the cellular level. METHODS: We examined skeletal muscle size and function from the whole body to the sub-cellular level in 11 patients with non-small cell lung cancer (NSCLC; 6 male/5 female, mean age 58 ± 3 years) studied over a 2-month observation period starting during their first cycle of standard of care cancer treatment and in 11 age- and sex-matched healthy controls (HC) without a current or past history of cancer. Biopsies of the vastus lateralis were performed to assess muscle fibre size, contractility and mitochondrial content, along with assessments of physical function, whole muscle size and function, and circulating cytokines. RESULTS: Body weight, composition and thigh muscle area and density were unaltered over time in patients with NSCLC, while muscle density was lower in patients with NSCLC versus HC (P = 0.03). Skeletal muscle fibre size decreased by 18% over time in patients (all P = 0.02) and was lower than HC (P = 0.02). Mitochondrial fractional area and density did not change over time in patients, but fractional area was lower in patients with NSCLC compared with HC (subsarcolemmal, P = 0.04; intermyofibrillar, P = 0.03). Patients with NSCLC had higher plasma concentrations of IL-6 (HC 1.40 ± 0.50; NSCLC 4.71 ± 4.22; P < 0.01), GDF-15 (HC 569 ± 166; NSCLC 2071 ± 1168; P < 0.01) and IL-8/CXCL8 (HC 4.9 ± 1.8; NSCLC 10.1 ± 6.0; P = 0.02) compared with HC, but there were no changes in inflammatory markers in patients with NSCLC over time. No changes were observed in markers of satellite cell activation or DNA damage in patients and no group differences were noted with HC. Whole-muscle strength was preserved over time in patients with NSCLC coincident with improved single fibre contractility. CONCLUSIONS: This study is the first to comprehensively examine longitudinal alterations in skeletal muscle fibre size and function in patients with NSCLC and suggests that muscle fibre atrophy occurs during cancer treatment despite weight stability and no changes in conventional clinical measurements of whole body or thigh muscle size over this period.

Potential Cardioprotective Effects and Lipid Mediator Differences in Long-Chain Omega-3 Polyunsaturated Fatty Acid Supplemented Mice Given Chemotherapy.

Many commonly used chemotherapies induce mitochondrial dysfunction in cardiac muscle, which leads to cardiotoxicity and heart failure later in life. Dietary long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) have demonstrated cardioprotective function in non-chemotherapy models of heart failure, potentially through the formation of LC n-3 PUFA-derived bioactive lipid metabolites. However, it is unknown whether dietary supplementation with LC n-3 PUFA can protect against chemotherapy-induced cardiotoxicity. To test this, 36 female ovariectomized C57BL/6J mice were randomized in a two-by-two factorial design to either a low (0 g/kg EPA + DHA) or high (12.2 g/kg EPA + DHA) LC n-3 PUFA diet, and received either two vehicle or two chemotherapy (9 mg/kg anthracycline + 90 mg/kg cyclophosphamide) tail vein injections separated by two weeks. Body weight and food intake were measured as well as heart gene expression and fatty acid composition. Heart mitochondria were isolated using differential centrifugation. Mitochondrial isolate oxylipin and N-acylethanolamide levels were measured by mass spectrometry after alkaline hydrolysis. LC n-3 PUFA supplementation attenuated some chemotherapy-induced differences (Myh7, Col3a1) in heart gene expression, and significantly altered various lipid species in cardiac mitochondrial preparations including several epoxy fatty acids [17(18)-EpETE] and N-acylethanolamines (arachidonoylethanolamine, AEA), suggesting a possible functional link between heart lipids and cardiotoxicity.

Linoleate-Rich Safflower Oil Diet Increases Linoleate-Derived Bioactive Lipid Mediators in Plasma, and Brown and White Adipose Depots of Healthy Mice.

Polyunsaturated fats are energy substrates and precursors to the biosynthesis of lipid mediators of cellular processes. Adipose tissue not only provides energy storage, but influences whole-body energy metabolism through endocrine functions. How diet influences adipose-lipid mediator balance may have broad impacts on energy metabolism. To determine how dietary lipid sources modulate brown and white adipose tissue and plasma lipid mediators, mice were fed low-fat (15% kcal fat) isocaloric diets, containing either palm oil (POLF) or linoleate-rich safflower oil (SOLF). Baseline and post body weight, adiposity, and 2-week and post fasting blood glucose were measured and lipid mediators were profiled in plasma, and inguinal white and interscapular brown adipose tissues. We identified over 30 species of altered lipid mediators between diets and found that these changes were unique to each tissue. We identified changes to lipid mediators with known functional roles in the regulation of adipose tissue expansion and function, and found that there was a relationship between the average fold difference in lipid mediators between brown adipose tissue and plasma in mice consuming the SOLF diet. Our findings emphasize that even with a low-fat diet, dietary fat quality has a profound effect on lipid mediator profiles in adipose tissues and plasma.

Linoleic Acid-Enriched Diet Increases Mitochondrial Tetralinoleoyl Cardiolipin, OXPHOS Protein Levels, and Uncoupling in Interscapular Brown Adipose Tissue during Diet-Induced Weight Gain.

Cardiolipin (CL) is a phospholipid unique to the inner mitochondrial membrane that supports respiratory chain structure and function and is demonstrated to be influenced by types of dietary fats. However, the influence of dietary fat on CL species and how this best supports mitochondrial function in brown adipose tissue (BAT), which exhibits an alternative method of energy utilization through the uncoupling of the mitochondrial proton gradient to generate heat, is not well understood. Therefore, the aim of our study was to evaluate metabolic parameters, interscapular BAT CL quantity, species, and mitochondrial function in mice consuming isocaloric moderate-fat diets with either lard (LD; similar fatty acid profile to western dietary patterns) or safflower oil high in linoleic acid (SO), shown to be metabolically favorable in large clinical meta-analyses. Mice fed the SO diet exhibited decreased adiposity, improved insulin sensitivity, and enrichment of LA-containing CL species in BAT CL. Furthermore, mice fed the SO diet exhibit higher levels of OXPHOS complex proteins and increased oxygen consumption in BAT. Our findings demonstrate that dietary consumption of LA-rich oil improves metabolic parameters, increases LA-containing CL species, and improves BAT function when compared to the consumption of lard in mice during diet-induced weight gain.

Dietary Naringenin Preserves Insulin Sensitivity and Grip Strength and Attenuates Inflammation but Accelerates Weight Loss in a Mouse Model of Cancer Cachexia.

SCOPE: Cancer cachexia is characterized by the loss of skeletal muscle resulting in functional impairment, reduced quality of life and mortality. Naringenin, a flavonoid found in citrus fruits, improves insulin sensitivity and reduces inflammation and tumor growth in preclinical models. Therefore, the study hypothesizes that dietary supplementation of naringenin will improve insulin sensitivity, decrease inflammation, slow body weight loss, and delay tumor growth in a mouse model of cancer cachexia. METHODS AND RESULTS: Mice are fed 2 wt% dietary naringenin before and during initiation of cancer cachexia using inoculated adenocarcinoma-26 cells (C-26). Food intake, body weight, body composition, muscle function, insulin tolerance, and inflammatory status are assessed. Although naringenin-fed tumor-bearing mice exhibit reductions in body weight and food intake earlier than control diet-fed tumor-bearing mice, dietary naringenin is protective against loss of muscle strength, and attenuates the onset of insulin resistance and markers of inflammation. CONCLUSIONS: Dietary supplementation of naringenin improves multiple aspects of metabolic disturbance and inflammation during cancer cachexia progression in [C-26 tumor-bearing] mice. However, the acceleration of anorexia and weight loss is also observed. These findings emphasize the link between inflammation and insulin resistance as a basis for understanding their roles in the pathogenesis of cancer cachexia.

Linoleic acid, glycemic control and Type 2 diabetes.

Dietary fat quality, especially the intake of specific types of fatty acids, impacts the risk of many chronic diseases, including cardiovascular diseases, certain cancers and type 2 diabetes (T2DM). A recent pooled analysis involving 20 studies from around the world revealed that higher linoleic acid (18:2n-6 LA) biomarker is associated with dose-dependent decreases in the incidence of T2DM. This latest study corroborates earlier cross-sectional studies and intervention trials showing that biomarkers of LA intake are associated with reduced risk of T2DM and better glycemic control and/or insulin sensitivity. This review highlights key clinical trials that have evaluated the role of LA in glycemia and the related condition, insulin sensitivity.