Insulin resistance directly correlates with increased saturated fatty acids in skeletal muscle triglycerides

AbstractThe metabolic impact of circulating fatty acids (FAs) in patients requiring hemodialysis (HD) is unknown. We investigated the associations between plasma triglyceride (TG) FAs and markers of inflammation, insulin resistance, nutritional status and body composition. Plasma TG-FAs were measured using gas chromatography in 341 patients on HD (age = 55.2 ± 14.0 years and 54.3% males). Cross-sectional associations of TG-FAs with 13 markers were examined using multivariate linear regression adjusted for potential confounders. Higher levels of TG saturated fatty acids were associated with greater body mass index (BMI, r = 0.230), waist circumference (r = 0.203), triceps skinfold (r = 0.197), fat tissue index (r = 0.150), serum insulin (r = 0.280), and homeostatic model assessment of insulin resistance (r = 0.276), but lower malnutrition inflammation score (MIS, r = − 0.160). Greater TG monounsaturated fatty acid levels were associated with lower lean tissue index (r = − 0.197) and serum albumin (r = − 0.188), but higher MIS (r = 0.176). Higher levels of TG n-3 polyunsaturated fatty acids (PUFAs) were associated with lower MIS (r = − 0.168) and interleukin-6 concentrations (r = − 0.115). Higher levels of TG n-6 PUFAs were associated with lower BMI (r = − 0.149) but greater serum albumin (r = 0.112). In conclusion, TG monounsaturated fatty acids were associated with poor nutritional status, while TG n-3 PUFAs were associated with good nutritional status. On the other hand, TG saturated fatty acids and TG n-6 PUFAs had both favorable and unfavorable associations with nutritional parameters.

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Palmitic acid promotes resistin-induced insulin resistance and inflammation in SH-SY5Y human neuroblastoma

Scientific Reports ◽

10.1038/s41598-021-85018-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hamza Amine ◽

Yacir Benomar ◽

Mohammed Taouis

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Palmitic Acid ◽

Lipid Rafts ◽

Acid Treatment ◽

Protective Action ◽

Saturated Fatty Acids ◽

Membrane Lipid ◽

Human Neuroblastoma ◽

Peripheral Tissues

AbstractSaturated fatty acids such as palmitic acid promote inflammation and insulin resistance in peripheral tissues, contrasting with the protective action of polyunsaturated fatty acids such docosahexaenoic acid. Palmitic acid effects have been in part attributed to its potential action through Toll-like receptor 4. Beside, resistin, an adipokine, also promotes inflammation and insulin resistance via TLR4. In the brain, palmitic acid and resistin trigger neuroinflammation and insulin resistance, but their link at the neuronal level is unknown. Using human SH-SY5Yneuroblastoma cell line we show that palmitic acid treatment impaired insulin-dependent Akt and Erk phosphorylation whereas DHA preserved insulin action. Palmitic acid up-regulated TLR4 as well as pro-inflammatory cytokines IL6 and TNFα contrasting with DHA effect. Similarly to palmitic acid, resistin treatment induced the up-regulation of IL6 and TNFα as well as NFκB activation. Importantly, palmitic acid potentiated the resistin-dependent NFkB activation whereas DHA abolished it. The recruitment of TLR4 to membrane lipid rafts was increased by palmitic acid treatment; this is concomitant with the augmentation of resistin-induced TLR4/MYD88/TIRAP complex formation mandatory for TLR4 signaling. In conclusion, palmitic acid increased TLR4 expression promoting resistin signaling through TLR4 up-regulation and its recruitment to membrane lipid rafts.

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High Physiological Omega-3 Fatty Acid Supplementation Affects Muscle Fatty Acid Composition and Glucose and Insulin Homeostasis in Obese Adolescents

Journal of Nutrition and Metabolism ◽

10.1155/2012/395757 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 30

Author(s):

Frida Dangardt ◽

Yun Chen ◽

Eva Gronowitz ◽

Jovanna Dahlgren ◽

Peter Friberg ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Fatty Acid ◽

Glucose Tolerance ◽

Saturated Fatty Acids ◽

Fasting Blood Glucose ◽

Omega 3 ◽

Intravenous Glucose ◽

Obese Adolescents ◽

Insulin Homeostasis

Obese adolescents have high concentrations of saturated fatty acids and low omega-3 long-chain polyunsaturated fatty acids (LCUFAs) in plasma phospholipids. We aimed to investigate effects of omega-3 LCPUFA supplementation to obese adolescents on skeletal muscle lipids and glucose and insulin homeostasis. Twenty-five obese adolescents (14–17 years old, 14 females) completed a randomized double-blind crossover study supplying capsules containing either 1.2 g omega-3 LCPUFAs or placebo, for 3 months each with a six-week washout period. Fasting blood glucose, insulin, leptin, adiponectin, and lipids were measured. Intravenous glucose tolerance test (IVGTT) and euglycemic-hyperinsulinemic clamp were performed, and skeletal muscle biopsies were obtained at the end of each period. The concentrations of EPA, DHA, and total omega-3 PUFA in muscle phospholipids increased in both sexes. In the females, omega-3 LCPUFA supplementation improved glucose tolerance by 39% (P=0.04) and restored insulin concentration by 34% (P=0.02) during IVGTT. Insulin sensitivity improved 17% (P=0.07). In males, none of these parameters was influenced by omega-3 supplementation. Thus, three months of supplementation of omega-3 LCPUFA improved glucose and insulin homeostasis in obese girls without influencing body weight.

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Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells-implications for diet-induced insulin resistance

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201200058 ◽

2012 ◽

Vol 56 (8) ◽

pp. 1212-1222 ◽

Cited By ~ 98

Author(s):

Clare M. Reynolds ◽

Fiona C. McGillicuddy ◽

Karen A. Harford ◽

Orla M. Finucane ◽

Kingston H. G. Mills ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Dendritic Cells ◽

Nlrp3 Inflammasome ◽

Saturated Fatty Acids

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Saturated Fatty Acids Promote GDF15 Expression in Human Macrophages through the PERK/eIF2/CHOP Signaling Pathway

Nutrients ◽

10.3390/nu12123771 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3771

Author(s):

Laurent L’homme ◽

Benan Pelin Sermikli ◽

Bart Staels ◽

Jacques Piette ◽

Sylvie Legrand-Poels ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Er Stress ◽

Signaling Pathway ◽

Promoter Region ◽

Unsaturated Fatty Acids ◽

Saturated Fatty Acids ◽

Growth Differentiation Factor 15 ◽

Human Macrophages ◽

Primary Monocyte

Growth differentiation factor-15 (GDF-15) and its receptor GFRAL are both involved in the development of obesity and insulin resistance. Plasmatic GDF-15 level increases with obesity and is positively associated with disease progression. Despite macrophages have been recently suggested as a key source of GDF-15 in obesity, little is known about the regulation of GDF-15 in these cells. In the present work, we sought for potential pathophysiological activators of GDF15 expression in human macrophages and identified saturated fatty acids (SFAs) as strong inducers of GDF15 expression and secretion. SFAs increase GDF15 expression through the induction of an ER stress and the activation of the PERK/eIF2/CHOP signaling pathway in both PMA-differentiated THP-1 cells and in primary monocyte-derived macrophages. The transcription factor CHOP directly binds to the GDF15 promoter region and regulates GDF15 expression. Unlike SFAs, unsaturated fatty acids do not promote GDF15 expression and rather inhibit both SFA-induced GDF15 expression and ER stress. These results suggest that free fatty acids may be involved in the control of GDF-15 and provide new molecular insights about how diet and lipid metabolism may regulate the development of obesity and T2D.

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Ameliorative effects of polyunsaturated fatty acids against palmitic acid-induced insulin resistance in L6 skeletal muscle cells

Lipids in Health and Disease ◽

10.1186/1476-511x-11-36 ◽

2012 ◽

Vol 11 (1) ◽

pp. 36 ◽

Cited By ~ 25

Author(s):

Keisuke Sawada ◽

Kyuichi Kawabata ◽

Takatoshi Yamashita ◽

Kengo Kawasaki ◽

Norio Yamamoto ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Palmitic Acid ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

L6 Skeletal Muscle Cells

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Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00006.2010 ◽

2010 ◽

Vol 298 (6) ◽

pp. E1122-E1130 ◽

Cited By ~ 51

Author(s):

Sun Ju Choi ◽

Francis Kim ◽

Michael W. Schwartz ◽

Brent E. Wisse

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Fatty Acid ◽

Saturated Fatty Acid ◽

Cell Lines ◽

Saturated Fatty Acids ◽

Neuronal Cell ◽

Acid Exposure ◽

Inflammatory Signaling ◽

Hypothalamic Neurons

Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. Since in vitro exposure to saturated fatty acids causes inflammation and insulin resistance in many cultured cell types, we determined how cultured hypothalamic neurons respond to this stimulus. Two murine hypothalamic neuronal cell cultures, N43/5 and GT1–7, were exposed to escalating concentrations of saturated fatty acids for up to 24 h. Harvested cells were evaluated for activation of inflammation by gene expression and protein content. Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNFα, as judged by induction of IκBα (3- to 5-fold) and IL-6 (3- to 7-fold) mRNA and p-IκBα protein, and TNFα pretreatment reduced insulin-mediated p-Akt activation by 30% ( P < 0.05). By comparison, neither mixed saturated fatty acid (100, 250, or 500 μM for ≤6 h) nor palmitate exposure alone (200 μM for ≤24 h) caused inflammatory activation or insulin resistance in cultured hypothalamic neurons, whereas they did in control muscle and endothelial cell lines. Despite the lack of evidence of inflammatory signaling, saturated fatty acid exposure in cultured hypothalamic neurons causes endoplasmic reticulum stress, induces mitogen-activated protein kinase, and causes apoptotic cell death with prolonged exposure. We conclude that saturated fatty acid exposure does not induce inflammatory signaling or insulin resistance in cultured hypothalamic neurons. Therefore, hypothalamic neuronal inflammation in the setting of DIO may involve an indirect mechanism mediated by saturated fatty acids on nonneuronal cells.

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Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites

Journal of Applied Physiology ◽

10.1152/japplphysiol.01438.2005 ◽

2006 ◽

Vol 100 (5) ◽

pp. 1467-1474 ◽

Cited By ~ 203

Author(s):

Jong Sam Lee ◽

Srijan K. Pinnamaneni ◽

Su Ju Eo ◽

In Ho Cho ◽

Jae Hwan Pyo ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acids ◽

Insulin Sensitivity ◽

Polyunsaturated Fatty Acids ◽

Glucose Uptake ◽

High Fat ◽

Insulin Resistant ◽

L6 Myotubes ◽

Lipid Metabolites

Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.

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