In vitro and in vivo evidence of bioenergetic metabolism alteration by mono-(2-ethylhexyl) phthalate

Abstract Background: To better understand the potential alteration of muscle bioenergetic metabolism by the obesogenic toxicant mono-(2ethylhexyl) phthalate (MEHP) the objectives of this research were to determine the: 1) association between urinary MEHP levels and plasma fatty acid levels in women with obesity who participated in National Health and Nutrition Examination Survey (NHANES) studies, and 2) in vitro effects of MEHP on fatty acid, or glucose supported mitochondrial energetics in C2C12 muscle cells.Results: The association between urinary MEHP from NHANES participants with plasma fatty acid levels was studied via secondary data statistical analyses. 14C-palmitic acid oxidation, Seahorse fatty acid oxidation and glycolysis stress tests and western blot analyses were conducted on C2C12 cells exposed to increasing MEHP concentrations. Increased urinary MEHP in women with obesity was associated with increased plasma gamma-linolenic and arachidonic acid levels. C2C12 myotubes exposed to increasing MEHP concentrations, displayed decreased fatty acid oxidation and mitochondrial bioenergetics. Acyl-CoA synthetase long chain 5 (ACSL5) protein level was also upregulated with increasing MEHP exposure in C2C12 myoblasts. Glycolysis was not significantly modified with increased exposure of C2C12 cells to MEHP.Conclusions: MEHP exposure may alter fatty acid utilization at the whole-body level in women with obesity and fatty acid utilization in muscle cells. Our findings are consistent with the idea that women with obesity may be particularly susceptible to the effects of MEHP, which alters fatty acid metabolism in muscle cells.

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Abstract 344: FNDC5, a PGC1-a-Dependent Myokine, Increases Glucose Utilization and Fatty-Acid Oxidation by AMPK Signaling Pathway

Circulation Research ◽

10.1161/res.113.suppl_1.a344 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Ling Tao ◽

Yi Liu ◽

Chao Xin ◽

Weidong Huang ◽

Lijian Zhang ◽

...

Keyword(s):

Fatty Acid ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Glucose Utilization ◽

C2c12 Cells ◽

Time Dependent ◽

Acid Oxidation ◽

Ampk Signaling

FNDC5 is a hormone secreted by myocytes that could reduce obesity and insulin resistance, However, the exact effect of FNDC5 on glucose and lipid metabolism remain poorly identified; More importantly, the signaling pathways that mediate the metabolic effects of FNDC5 is completely unknown. Here we showed that FNDC5 stimulates β-oxidation and glucose uptake in C2C12 cells in a dose- and time-dependent fashion in vitro (n=8, all P<0.01). In vivo study revealed that FNDC5 also enhanced glucose tolerance in diabetic mice and increased the glucose uptake evidenced by increased [18F] FDG accumulation in hearts by PET scan (n=6, all P<0.05). FNDC5 decreased the expression of gluconeogenesis related molecules (PEPCK and G6Pase) and increased the phosphorylation of ACC, a key modulator of fatty-acid oxidation, both in hepatocytes and C2C12 cells (n=3, all P<0.05). In parallel with its stimulation of β-oxidation and glucose uptake, FNDC5 increased the phosphorylation of AMPK both in hepatocytes and C2C12 cells in a dose- and time-dependent fashion in vitro and in vivo. More importantly, the β-oxidation and glucose uptake, the expression of PEPCK and G6Pase and the phosphorylation of ACC induced by FNDC5 were attenuated by AMPK inhibitor in hepatocytes and C2C12 cells (P<0.05). Most importantly, the FNDC5 induced glucose uptake and phosphorylation of ACC were attenuated in AMPK-DN mice (n=6, all P<0.05). The glucose-lowering effect of FNDC5 in diabetic mice was also attenuated by AMPK inhibitor. Our data presents the direct evidence that FNDC5 stimulates glucose utilization and fatty-acid oxidation by AMPK signaling pathway, suggesting that FNDC5 be a novel pharmacological approach for type 2 diabetes.

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Analysis of Direct Effects of the CB1 Receptor Antagonist Rimonabant on Fatty Acid Oxidation and Glycogenolysis in Liver and Muscle Cells in vitro

Biochemistry (Moscow) ◽

10.1134/s000629791908011x ◽

2019 ◽

Vol 84 (8) ◽

pp. 954-962

Author(s):

G. A. Müller ◽

S. Wied ◽

A. W. Herling

Keyword(s):

Fatty Acid ◽

Receptor Antagonist ◽

Fatty Acid Oxidation ◽

Muscle Cells ◽

Cb1 Receptor ◽

Acid Oxidation ◽

Direct Effects ◽

Cb1 Receptor Antagonist

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Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity

Journal of Applied Physiology ◽

10.1152/jappl.2000.89.6.2276 ◽

2000 ◽

Vol 89 (6) ◽

pp. 2276-2282 ◽

Cited By ~ 46

Author(s):

Jeffrey F. Horowitz ◽

Samuel Klein

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Abdominal Obesity ◽

Fat Free Mass ◽

Peak Oxygen Consumption ◽

Whole Body ◽

Acid Oxidation ◽

Plasma Fatty Acid ◽

Obese Women

We evaluated plasma fatty acid availability and plasma and whole body fatty acid oxidation during exercise in five lean and five abdominally obese women (body mass index = 21 ± 1 vs. 38 ± 1 kg/m2), who were matched on aerobic fitness, to test the hypothesis that obesity alters the relative contribution of plasma and nonplasma fatty acids to total energy production during exercise. Subjects exercised on a recumbent cycle ergometer for 90 min at 54% of their peak oxygen consumption. Stable isotope tracer methods ([13C]palmitate) were used to measure fatty acid rate of appearance in plasma and the rate of plasma fatty acid oxidation, and indirect calorimetry was used to measure whole body substrate oxidation. During exercise, palmitate rate of appearance increased progressively and was similar in obese and lean groups between 60 and 90 min of exercise [3.9 ± 0.4 vs. 4.0 ± 0.3 μmol · kg fat free mass (FFM)−1 · min−1]. The rate of plasma fatty acid oxidation was also similar in obese and lean subjects (12.8 ± 1.7 vs. 14.5 ± 1.8 μmol · kg FFM−1 · min−1; P = not significant). However, whole body fatty acid oxidation during exercise was 25% greater in obese than in lean subjects (21.9 ± 1.2 vs. 17.5 ± 1.6 μmol · kg FFM−1 · min−1; P < 0.05). These results demonstrate that, although plasma fatty acid availability and oxidation are similar during exercise in lean and obese women, women with abdominal obesity use more fat as a fuel by oxidizing more nonplasma fatty acids.

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Deletion of nuclear factor-κB p50 upregulates fatty acid utilization and contributes to an anti-obesity and high-endurance phenotype in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00071.2015 ◽

2015 ◽

Vol 309 (6) ◽

pp. E523-E533 ◽

Cited By ~ 5

Author(s):

Yoshihiko Minegishi ◽

Satoshi Haramizu ◽

Koichi Misawa ◽

Akira Shimotoyodome ◽

Tadashi Hase ◽

...

Keyword(s):

Fatty Acid ◽

Nuclear Factor Κb ◽

Whole Body ◽

Acid Oxidation ◽

Endurance Capacity ◽

Peroxisome Proliferator ◽

Primary Role ◽

Nuclear Factor ◽

Oxidation Activity ◽

Fatty Acid Utilization

The transcription factor nuclear factor-κB (NF-κB) plays an important role in regulating physiological processes such as immunity and inflammation. In addition to this primary role, NF-κB interacts physically with peroxisome proliferator-activated receptors regulating lipid metabolism-related gene expression and inhibits their transcriptional activity. Therefore, inhibition of NF-κB may promote fatty acid utilization, which could ameliorate obesity and improve endurance capacity. To test this hypothesis, we attempted to elucidate the energy metabolic status of mice lacking the p50 subunit of NF-κB (p50 KO mice) from the tissue to whole body level. p50 KO mice showed a significantly lower respiratory quotient throughout the day than did wild-type (WT) mice; this decrease was associated with increased fatty acid oxidation activity in liver and gastrocnemius muscle of p50 KO mice. p50 KO mice that were fed a high-fat diet were also resistant to fat accumulation and adipose tissue inflammation. Furthermore, p50 KO mice showed a significantly longer maximum running time compared with WT mice, with a lower respiratory exchange ratio during exercise as well as higher residual muscle glycogen content and lower blood lactate levels after exercise. These results suggest that p50 deletion facilitates fatty acid catabolism, leading to an anti-obesity and high-endurance phenotype of mice and supporting the idea that NF-κB is an important regulator of energy metabolism.

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Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase

Diabetes ◽

10.2337/db05-1404 ◽

2006 ◽

Vol 55 (10) ◽

pp. 2688-2697 ◽

Cited By ~ 473

Author(s):

A. L. Carey ◽

G. R. Steinberg ◽

S. L. Macaulay ◽

W. G. Thomas ◽

A. G. Holmes ◽

...

Keyword(s):

Fatty Acid ◽

Protein Kinase ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Interleukin 6 ◽

Glucose Disposal ◽

Acid Oxidation ◽

Amp Activated Protein Kinase

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Meal composition affects postprandial fatty acid oxidation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.264.6.r1065 ◽

1993 ◽

Vol 264 (6) ◽

pp. R1065-R1070 ◽

Cited By ~ 6

Author(s):

D. M. Surina ◽

W. Langhans ◽

R. Pauli ◽

C. Wenk

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Nutrient Utilization ◽

Whole Body ◽

Acid Oxidation ◽

Plasma Ffa ◽

Hepatic Fatty Acid Oxidation ◽

Beta Hydroxybutyrate ◽

Chain Fatty Acids

The influence of macronutrient content of a meal on postprandial fatty acid oxidation was investigated in 13 Caucasian males after consumption of a high-fat (HF) breakfast (33% carbohydrate, 52% fat, 15% protein) and after an equicaloric high-carbohydrate (HC) breakfast (78% carbohydrate, 6% fat, 15% protein). The HF breakfast contained short- and medium-chain fatty acids, as well as long-chain fatty acids. Respiratory quotient (RQ) and plasma beta-hydroxybutyrate (BHB) were measured during the 3 h after the meal as indicators of whole body substrate oxidation and hepatic fatty acid oxidation, respectively. Plasma levels of free fatty acids (FFA), triglycerides, glucose, insulin, and lactate were also determined because of their relationship to nutrient utilization. RQ was significantly lower and plasma BHB was higher after the HF breakfast than after the HC breakfast, implying that more fat is burned in general and specifically in the liver after an HF meal. As expected, plasma FFA and triglycerides were higher after the HF meal, and insulin and lactate were higher after the HC meal. In sum, oxidation of ingested fat occurred in response to a single HF meal.

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Effect of adipocyte β3-adrenergic receptor activation on the type 2 diabetic MKR mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00344.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. E1227-E1236 ◽

Cited By ~ 34

Author(s):

Hyunsook Kim ◽

Patricia A. Pennisi ◽

Oksana Gavrilova ◽

Stephanie Pack ◽

William Jou ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Receptor Activation ◽

Whole Body ◽

Acid Oxidation ◽

Adrenergic Agonists ◽

Nonobese Diabetic ◽

Type 2 Diabetic

The antiobesity and antidiabetic effects of the β3-adrenergic agonists were investigated on nonobese type 2 diabetic MKR mice after injection with a β3-adrenergic agonist, CL-316243. An intact response to acute CL-316243 treatment was observed in MKR mice. Chronic intraperitoneal CL-316243 treatment of MKR mice reduced blood glucose and serum insulin levels. Hyperinsulinemic euglycemic clamps exhibited improvement of the whole body insulin sensitivity and glucose homeostasis concurrently with enhanced insulin action in liver and adipose tissue. Treating MKR mice with CL-316243 significantly lowered serum and hepatic lipid levels, in part due to increased whole body triglyceride clearance and fatty acid oxidation in adipocytes. A significant reduction in total body fat content and epididymal fat weight was observed along with enhanced metabolic rate in both wild-type and MKR mice after treatment. These data demonstrate that β3-adrenergic activation improves the diabetic state of nonobese diabetic MKR mice by potentiation of free fatty acid oxidation by adipose tissue, suggesting a potential therapeutic role for β3-adrenergic agonists in nonobese diabetic subjects.

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Critical Role for Hepatocyte-Specific eNOS in NAFLD and NASH

10.2337/figshare.15108567.v1 ◽

2021 ◽

Author(s):

Rory P. Cunningham ◽

Mary P. Moore ◽

Ryan J. Daskek ◽

Grace M. Meers ◽

Takamune Takahashi ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Critical Role ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Nonalcoholic Fatty Liver ◽

Mitochondrial Fatty Acid ◽

Endothelial Nitric Oxide

Regulation of endothelial nitric oxide synthase (eNOS) in hepatocytes may be an important target in nonalcoholic fatty liver disease (NAFLD) development and progression to steatohepatitis (NASH). In this study, we show genetic deletion and viral knockdown of hepatocyte-specific eNOS exacerbated hepatic steatosis and inflammation, decreased hepatic mitochondrial fatty acid oxidation and respiration, increased mitochondrial H<sub>2</sub>O<sub>2</sub> emission, and impaired the hepatic mitophagic (BNIP3 and LC3II) response. Conversely, overexpressing eNOS in hepatocytes in vitro and in vivo increased hepatocyte mitochondrial respiration and attenuated western diet induced NASH. Moreover, patients with elevated NAFLD activity score (histology score of worsening steatosis, hepatocyte ballooning, and inflammation) exhibited reduced hepatic eNOS expression which correlated with reduced hepatic mitochondrial fatty acid oxidation and lower hepatic protein expression of mitophagy protein BNIP3. The current study reveals an important molecular role for hepatocyte-specific eNOS as a key regulator of NAFLD/NASH susceptibility and mitochondrial quality control with direct clinical correlation to patients with NASH.

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