A decreased n-6/n-3 ratio in the fat-1 mouse is associated with improved glucose tolerance

2010 ◽  
Vol 35 (5) ◽  
pp. 699-706 ◽  
Author(s):  
Brennan K. Smith ◽  
Graham P. Holloway ◽  
Sandra Reza-Lopez ◽  
Stanley M. Jeram ◽  
Jing X. Kang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Glucose Tolerance ◽  
White Muscle ◽  
Citrate Synthase ◽  
Challenge Test ◽  
Whole Body ◽  
Acid Oxidation ◽  
Mitochondrial Content ◽  
Isolated Mitochondria

A reduction in skeletal muscle fatty acid oxidation (FAO), manifested as a reduction in mitochondrial content and (or) FAO within mitochondria, may contribute to the development of insulin resistance. n-3 polyunsaturated fatty acids (PUFA) have been observed to increase the capacity for FAO and improve insulin sensitivity. We used the fat-1 mouse model, a transgenic animal capable of synthesizing n-3 PUFA from n-6 PUFA, to examine this relationship. Fat-1 mice exhibited a ~20-fold decrease in the n-6/n-3 ratio in skeletal muscle, and plasma glucose and the area under the glucose curve were significantly (p < 0.05) lower in fat-1 mice during a glucose challenge test. The improvement in whole-body glucose tolerance in the fat-1 mouse was associated with a ~21% (p < 0.05) decrease in whole-muscle citrate synthase (CS) activity (in red muscle only), without alterations in CS activity of isolated mitochondria (either red or white muscle; p > 0.05). These data suggest that the fat-1 mouse has decreased skeletal muscle mitochondrial content. However, the intrinsic ability of mitochondria to oxidize fatty acids was not altered in the fat-1 mouse, as rates of palmitate oxidation in isolated mitochondria from both red and white muscle were unchanged. Overall, this study demonstrates that a decrease in the n-6/n-3 ratio can enhance glucose tolerance in healthy animals, independent of changes in mitochondrial content.

Genetically increasing flux through β-oxidation in skeletal muscle increases mitochondrial reductive stress and glucose intolerance

2021 ◽  
Author(s):  
Cody D. Smith ◽  
Chein-Te Lin ◽  
Shawna L. McMillin ◽  
Luke A. Weyrauch ◽  
Cameron Alan Schmidt ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Tolerance ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Whole Body ◽  
Acid Oxidation ◽  
Wild Type ◽  
High Fat ◽  
Redox Environment

Elevated mitochondrial H2O2 emission and an oxidative shift in cytosolic redox environment have been linked to high fat diet-induced insulin resistance in skeletal muscle. To test specifically whether increased flux through mitochondrial fatty acid oxidation, in the absence of elevated energy demand, directly alters mitochondrial function and redox state in muscle, two genetic models characterized by increased muscle β-oxidation flux were studied. In mice overexpressing peroxisome proliferator activated receptor-α in muscle (MCK-PPARα), lipid supported mitochondrial respiration, membrane potential (ΔΨm) and H2O2 production rate (JH2O2) were increased, which coincided with a more oxidized cytosolic redox environment, reduced muscle glucose uptake, and whole-body glucose intolerance despite an increased rate of energy expenditure. Similar results were observed in lipin-1 deficient, fatty-liver dystrophic mice, another model characterized by increased β-oxidation flux and glucose intolerance. Crossing MCAT (mitochondrial-targeted catalase) with MCK-PPARα mice normalized JH2O2 production, redox environment and glucose tolerance, but surprisingly both basal and absolute insulin-stimulated rates of glucose uptake in muscle remained depressed. Also surprising, when placed on a high fat diet MCK-PPARα mice were characterized by much lower whole body, fat and lean mass as well as improved glucose tolerance relative to wild-type mice, providing additional evidence that overexpression of PPARα in muscle imposes more extensive metabolic stress than experienced by wild-type mice on a high fat diet. Overall, the findings suggest that driving an increase in skeletal muscle fatty acid oxidation in the absence of metabolic demand imposes mitochondrial reductive stress and elicits multiple counterbalance metabolic responses in attempt to restore bioenergetic homeostasis.

Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese women

2007 ◽  
Vol 292 (6) ◽  
pp. E1782-E1789 ◽  
Author(s):  
Graham P. Holloway ◽  
A. Brianne Thrush ◽  
George J. F. Heigenhauser ◽  
Narendra N. Tandon ◽  
David J. Dyck ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Citrate Synthase ◽  
Intrinsic Defect ◽  
Acid Oxidation ◽  
Obese Women ◽  
Mitochondrial Content ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid

A reduction in fatty acid oxidation has been associated with lipid accumulation and insulin resistance in the skeletal muscle of obese individuals. We examined whether this decrease in fatty acid oxidation was attributable to a reduction in muscle mitochondrial content and/or a dysfunction in fatty acid oxidation within mitochondria obtained from skeletal muscle of age-matched, lean [body mass index (BMI) = 23.3 ± 0.7 kg/m2] and obese women (BMI = 37.6 ± 2.2 kg/m2). The mitochondrial marker enzymes citrate synthase (−34%), β-hydroxyacyl-CoA dehydrogenase (−17%), and cytochrome c oxidase (−32%) were reduced ( P < 0.05) in obese participants, indicating that mitochondrial content was diminished. Obesity did not alter the ability of isolated mitochondria to oxidize palmitate; however, fatty acid oxidation was reduced at the whole muscle level by 28% ( P < 0.05) in the obese. Mitochondrial fatty acid translocase (FAT/CD36) did not differ in lean and obese individuals, but mitochondrial FAT/CD36 was correlated with mitochondrial fatty acid oxidation ( r = 0.67, P < 0.05). We conclude that the reduction in fatty acid oxidation in obese individuals is attributable to a decrease in mitochondrial content, not to an intrinsic defect in the mitochondria obtained from skeletal muscle of obese individuals. In addition, it appears that mitochondrial FAT/CD36 may be involved in regulating fatty acid oxidation in human skeletal muscle.

scholarly journals Lipid oxidation is reduced in obese human skeletal muscle

2000 ◽  
Vol 279 (5) ◽  
pp. E1039-E1044 ◽  
Author(s):  
Jong-Yeon Kim ◽  
Robert C. Hickner ◽  
Ronald L. Cortright ◽  
G. Lynis Dohm ◽  
Joseph A. Houmard
Keyword(s):  
Skeletal Muscle ◽  
Lipid Oxidation ◽  
Human Skeletal Muscle ◽  
Citrate Synthase ◽  
Acid Oxidation ◽  
Cellular Mechanisms ◽  
Mitochondrial Content ◽  
Palmitoyl Carnitine ◽  
Obese Human ◽  
Carnitine Palmitoyltransferase 1

The purpose of this study was to discern cellular mechanisms that contribute to the suppression of lipid oxidation in the skeletal muscle of obese individuals. Muscle was obtained from obese [body mass index (BMI), 38.3 ± 3.1 kg/m2] and lean (BMI, 23.8 ± 0.9 kg/m2) women, and fatty acid oxidation was studied by measuring 14CO2 production from14C-labeled fatty acids. Palmitate oxidation, which is at least partially dependent on carnitine palmitoyltransferase-1 (CPT-1) activity, was depressed ( P < 0.05) by ≈50% with obesity (6.8 ± 2.2 vs. 13.7 ± 1.4 nmole CO2 · g−1 · h−1). The CPT-1-independent event of palmitoyl carnitine oxidation was also depressed ( P < 0.01) by ≈45%. There were significant negative relationships ( P < 0.05) for adiposity with palmitate ( r = −0.76) and palmitoyl carnitine ( r = −0.82) oxidation. Muscle CPT-1 and citrate synthase activity, an index of mitochondrial content, were also significantly ( P < 0.05) reduced (≈35%) with obesity. CPT-1 ( r = −0.48) and citrate synthase ( r = −0.65) activities were significantly ( P < 0.05) related to adiposity. These data suggest that lesions at CPT-1 and post-CPT-1 events, such as mitochondrial content, contribute to the reduced reliance on fat oxidation evident in human skeletal muscle with obesity.

The effects of apelin treatment on skeletal muscle mitochondrial content

2009 ◽  
Vol 297 (6) ◽  
pp. R1761-R1768 ◽  
Author(s):  
Bruce C. Frier ◽  
Deon B. Williams ◽  
David C. Wright
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Protein Content ◽  
Citrate Synthase ◽  
Uncoupling Protein ◽  
Whole Body ◽  
Mitochondrial Content ◽  
Ampk Signaling ◽  
Male Wistar Rats ◽  
Whole Body Metabolism

Adipose tissue is recognized as a key player in the regulation of whole body metabolism. Apelin, is a recently identified adipokine that when given to mice results in increases in skeletal muscle uncoupling protein 3 (UCP3) content. Similarly, acute apelin treatment has been shown to increase the activity of 5′-AMP-activated protein kinase (AMPK), a reputed mediator of skeletal muscle mitochondrial biogenesis. Given these findings, we sought to determine the effects of apelin on skeletal muscle mitochondrial content. Male Wistar rats were given daily intraperitoneal injections of apelin-13 (100 nmol/kg) for 2 wk. We made the novel observation that the activities of citrate synthase, cytochrome c oxidase, and β-hydroxyacyl coA dehydrogenase (βHAD) were increased in triceps but not heart and soleus muscles from apelin-treated rats. When confirming these results we found that both nuclear and mitochondrial-encoded subunits of the respiratory chain were increased in triceps from apelin-treated rats. Similarly, apelin treatment increased the protein content of components of the mitochondrial import and assembly pathway. The increases in mitochondrial marker proteins were associated with increases in proliferator-activated receptor-γ coactivator-1 (PGC-1β) but not PGC-1α or Pgc-1-related co-activator (PRC) mRNA expression. Chronic and acute apelin treatment did not increase the protein content and/or phosphorylation status of AMPK and its downstream substrate acetyl-CoA carboxylase. These findings are the first to demonstrate that apelin treatment can induce skeletal muscle mitochondrial content. Given the lack of an effect of apelin on AMPK signaling and PGC-1α mRNA expression, these results suggest that apelin increases skeletal muscle mitochondrial content through a mechanism that is distinct from that of more robust physiological stressors.

PGC-1α's relationship with skeletal muscle palmitate oxidation is not present with obesity despite maintained PGC-1α and PGC-1β protein

2008 ◽  
Vol 294 (6) ◽  
pp. E1060-E1069 ◽  
Author(s):  
Graham P. Holloway ◽  
Christopher G. R. Perry ◽  
A. Brianne Thrush ◽  
George J. F. Heigenhauser ◽  
David J. Dyck ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Transcription Factors ◽  
Network Formation ◽  
Citrate Synthase ◽  
Acid Oxidation ◽  
Mitochondrial Content ◽  
Palmitate Oxidation ◽  
Mitofusin 1 ◽  
The Relationship

Reduced skeletal muscle mitochondrial content and fatty acid oxidation are associated with obesity and insulin resistance. Although the exact mechanisms remain elusive, this may result from impaired mitochondrial biogenesis or reductions in the mitochondrial reticulum network. Therefore, the purpose of this study was to determine whether the protein contents of various transcription factors, including PGC-1α and PGC-1β and proteins associated with mitochondrial fusion events, were reduced in skeletal muscle of nine obese (BMI = 37.6 ± 2.2 kg/m−2) compared with nine age-matched lean (BMI = 23.3 ± 0.7 kg/m−2) women. The protein contents of PGC-1α, PGC-1β, PPARα, and tFAM were not reduced with obesity. In contrast, PPARγ was increased (+22%, P < 0.05) with obesity, and there was a trend toward an increase (+31%, P = 0.13) in PPARδ/β. In lean individuals, PGC-1α protein correlated with citrate synthase (CS; r = 0.67) and rates of palmitate oxidation ( r = 0.87), whereas PGC-1β correlated with PPARγ ( r = 0.90), PPARδ/β ( r = 0.63), and cytochrome c oxidase IV (COX-IV; r = 0.63). In obese individuals, the relationship between PGC-1α and CS was maintained ( r = 0.65); however, the associations between PGC-1α and palmitate oxidation ( r = −0.38) and PGC-1β with PPARγ ( r = 0.14), PPARδ/β ( r = 0.21), and COX-IV ( r = 0.01) were lost. In addition, mitofusin-1 (MFN-1), MFN-2, and dynamin-related protein-1 (DRP-1) total protein contents were not altered with obesity ( P > 0.05). These data suggest that altered regulation, and not reductions in the protein contents of transcription factors, is associated with insulin resistance. Also, it does not appear that alterations in the proteins associated with mitochondrial network formation and degradation can account for the observed decrease in mitochondrial content.

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

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
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.

scholarly journals Minimal impact of age and housing temperature on the metabolic phenotype of Acc2−/− mice

2015 ◽  
Vol 228 (3) ◽  
pp. 127-134 ◽  
Author(s):  
Amanda E Brandon ◽  
Ella Stuart ◽  
Simon J Leslie ◽  
Kyle L Hoehn ◽  
David E James ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Composition ◽  
Energy Expenditure ◽  
Glucose Tolerance ◽  
Fat Mass ◽  
Knockout Mice ◽  
Muscle Glycogen ◽  
Insulin Action ◽  
Metabolic Phenotype ◽  
Whole Body

An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 (Acacb) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12–16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29 °C; which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42–54 weeks of age, male WT and Acc2−/− mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2−/− mice, aged Acc2−/− mice showed increased whole-body FAO (24 h average respiratory exchange ratio=0.95±0.02 and 0.92±0.02 for WT and Acc2−/− mice respectively, P<0.05) and skeletal muscle glycogen content (+60%, P<0.05) without any detectable change in whole-body energy expenditure. Hyperinsulinaemic–euglycaemic clamp studies revealed no difference in insulin action between groups with similar glucose infusion rates and tissue glucose uptake. Housing Acc2−/− mice at 29 °C did not alter body composition, glucose tolerance or the effects of fat feeding compared with WT mice. These results confirm that manipulation of Acc2 may alter FAO in mice, but this has little impact on body composition or insulin action.

Meal composition affects postprandial fatty acid oxidation

1993 ◽  
Vol 264 (6) ◽  
pp. R1065-R1070 ◽  
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.

scholarly journals Relationships between urinary inositol excretions and whole-body glucose tolerance and skeletal muscle insulin receptor phosphorylation

Metabolism ◽  
2008 ◽  
Vol 57 (11) ◽  
pp. 1545-1551 ◽  
Author(s):  
April J. Stull ◽  
John P. Thyfault ◽  
Mark D. Haub ◽  
Richard E. Ostlund ◽  
Wayne W. Campbell
Keyword(s):  
Skeletal Muscle ◽  
Glucose Tolerance ◽  
Insulin Receptor ◽  
Whole Body ◽  
Receptor Phosphorylation

scholarly journals Low intrinsic running capacity is associated with reduced skeletal muscle substrate oxidation and lower mitochondrial content in white skeletal muscle

2011 ◽  
Vol 300 (4) ◽  
pp. R835-R843 ◽  
Author(s):  
Donato A. Rivas ◽  
Sarah J. Lessard ◽  
Misato Saito ◽  
Anna M. Friedhuber ◽  
Lauren G. Koch ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Aerobic Capacity ◽  
Artificial Selection ◽  
White Muscle ◽  
Metabolic Diseases ◽  
Metabolic Health ◽  
Mitochondrial Content ◽  
Red Muscle ◽  
Selection For

Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (∼30%; P = 0.04), glucose oxidation (∼50%; P = 0.04), and lipid oxidation (∼40%; P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the divergent aerobic capacity observed in this generation of LCR/HCR.

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