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1.
Med Sci Sports Exerc ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31524824

RESUMO

INTRODUCTION: Long-chain acyl-CoA synthetases (ACSLs) are implicated as regulators of oxidation and storage of fatty acids within skeletal muscle; however, to what extent diet and exercise alter skeletal muscle ACSLs remains poorly understood. PURPOSE: To determine effects of diet and exercise training on skeletal muscle ACSLs and examine relationships between ACSL1 and ACSL6 and fat oxidation and fat storage, respectively. METHODS: Male C57BL/6J mice consumed a 60% high-fat diet (HFD) for 12 weeks to induce obesity compared with low-fat diet (LFD). At week 4, mice began aerobic exercise (EX-Tr) or remained sedentary (SED) for 8 weeks. At week 12, protein abundance of 5 known ACSL isoforms and mRNA expression for ACSL1 and ACSL6 were measured in gastrocnemius muscle, as was skeletal muscle lipid content. Fat oxidation was measured using metabolic cage indirect calorimetry at week 10. RESULTS: Of 5 known ACSL isoforms, 4 were detected at the protein level. HFD resulted in greater, yet non-significant, ACSL1 protein abundance (+18%, P=0.13 vs. LFD), greater ACSL6 (+107%, P<0.01 vs. LFD), and no difference in ACSL4 or ACSL5. Exercise training resulted in greater ACSL6 protein abundance in LFD mice (P=0.05 LFD EX-Tr vs. SED) while ACSL4 was lower following exercise training compared with sedentary, regardless of diet. Under fasted conditions, skeletal muscle ACSL1 protein abundance was not related to measures of whole-body fat oxidation. Conversely, skeletal muscle ACSL6 protein abundance was positively correlated with intramyocellular lipid content (P<0.01, r=0.22).We present evidence that ACSL isoforms 1, 4 and 6 may undergo regulation by HFD and/or exercise training. We further conclude increased skeletal muscle ACSL6 may facilitate increased intramyocellular fat storage during HFD-induced obesity.

2.
J Nutr ; 149(12): 2120-2132, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31495890

RESUMO

BACKGROUND: Dietary nitrate improves exercise performance by reducing the oxygen cost of exercise, although the mechanisms responsible are not fully understood. OBJECTIVES: We tested the hypothesis that nitrate and nitrite treatment would lower the oxygen cost of exercise by improving mitochondrial function and stimulating changes in the availability of metabolic fuels for energy production. METHODS: We treated 9-mo-old zebrafish with nitrate (sodium nitrate, 606.9 mg/L), nitrite (sodium nitrite, 19.5 mg/L), or control (no treatment) water for 21 d. We measured oxygen consumption during a 2-h, strenuous exercise test; assessed the respiration of skeletal muscle mitochondria; and performed untargeted metabolomics on treated fish, with and without exercise. RESULTS: Nitrate and nitrite treatment increased blood nitrate and nitrite levels. Nitrate treatment significantly lowered the oxygen cost of exercise, as compared with pretreatment values. In contrast, nitrite treatment significantly increased oxygen consumption with exercise. Nitrate and nitrite treatments did not change mitochondrial function measured ex vivo, but significantly increased the abundances of ATP, ADP, lactate, glycolytic intermediates (e.g., fructose 1,6-bisphosphate), tricarboxylic acid (TCA) cycle intermediates (e.g., succinate), and ketone bodies (e.g., ß-hydroxybutyrate) by 1.8- to 3.8-fold, relative to controls. Exercise significantly depleted glycolytic and TCA intermediates in nitrate- and nitrite-treated fish, as compared with their rested counterparts, while exercise did not change, or increased, these metabolites in control fish. There was a significant net depletion of fatty acids, acyl carnitines, and ketone bodies in exercised, nitrite-treated fish (2- to 4-fold), while exercise increased net fatty acids and acyl carnitines in nitrate-treated fish (1.5- to 12-fold), relative to their treated and rested counterparts. CONCLUSIONS: Nitrate and nitrite treatment increased the availability of metabolic fuels (ATP, glycolytic and TCA intermediates, lactate, and ketone bodies) in rested zebrafish. Nitrate treatment may improve exercise performance, in part, by stimulating the preferential use of fuels that require less oxygen for energy production.

3.
Am J Physiol Cell Physiol ; 317(2): C339-C347, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31091142

RESUMO

Rat L6 and mouse C2C12 cell lines are commonly used to investigate myocellular metabolism. Mitochondrial characteristics of these cell lines remain poorly understood despite mitochondria being implicated in the development of various metabolic diseases. To address this need, we performed high-resolution respirometry to determine rates of oxygen consumption and H2O2 emission in suspended myoblasts during multiple substrate-uncoupler-inhibitor titration protocols. The capacity for oxidative phosphorylation supported by glutamate and malate, with and without succinate, or supported by palmitoyl-l-carnitine was lower in L6 compared with C2C12 myoblasts (all P < 0.01 for L6 vs. C2C12). Conversely, H2O2 emission during oxidative phosphorylation was greater in L6 than C2C12 myoblasts (P < 0.01 for L6 vs. C2C12). Induction of noncoupled respiration revealed a significantly greater electron transfer capacity in C2C12 compared with L6 myoblasts, regardless of the substrate(s) provided. Mitochondrial metabolism was also investigated in differentiated L6 and C2C12 myotubes. Basal rates of oxygen consumption were not different between intact, adherent L6, and C2C12 myotubes; however, noncoupled respiration was significantly lower in L6 compared with C2C12 myotubes (P = 0.01). In summary, L6 myoblasts had lower respiration rates than C2C12 myoblasts, including lesser capacity for fatty acid oxidation and greater electron leak toward H2O2. L6 cells also retain a lower capacity for electron transfer compared with C2C12 following differentiation to form fused myotubes. Intrinsic differences in mitochondrial metabolism between these cell lines should be considered when modeling and investigating myocellular metabolism.

4.
Am J Physiol Endocrinol Metab ; 316(5): E866-E879, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620635

RESUMO

Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for the ability to induce insulin resistance in vitro and characterize gene expression to uncover how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. RNAseq analysis was performed on IMAT with gene expression compared with skeletal muscle and SAT, and relationships to insulin sensitivity were determined in men and women spanning a wide range of insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Conditioned media from IMAT and VAT decreased insulin sensitivity similarly compared with SAT. Multidimensional scaling analysis revealed distinct gene expression patterns in IMAT compared with SAT and muscle. Pathway analysis revealed that IMAT expression of genes in insulin signaling, oxidative phosphorylation, and peroxisomal metabolism related positively to donor insulin sensitivity, whereas expression of macrophage markers, inflammatory cytokines, and secreted extracellular matrix proteins were negatively related to insulin sensitivity. Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.

5.
Physiol Rep ; 6(24): e13956, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30592185

RESUMO

Ras-related C3 botulinum toxin substrate 1 (Rac1) is required for normal insulin-stimulated glucose transport in skeletal muscle and evidence indicates Rac1 may be negatively regulated by lipids. We investigated if insulin-stimulated activation of Rac1 (i.e., Rac1-GTP binding) is impaired by accumulation of diacylglycerols (DAG) and ceramides in cultured muscle cells. Treating L6 myotubes with 100 nmol/L insulin resulted in increased Rac1-GTP binding that was rapid (occurring within 2 min), relatively modest (+38 ± 19% vs. basal, P < 0.001), and short-lived, returning to near-basal levels within 15 min of continuous treatment. Incubating L6 myotubes overnight in 500 µmol/L palmitate increased the accumulation of DAG and ceramides (P < 0.05 vs. no fatty acid control). Despite significant accumulation of lipids, insulin-stimulated Rac1-GTP binding was not impaired during palmitate treatment (P = 0.39 vs. no fatty acid control). Nevertheless, phosphorylation of Rac1 effector protein p21-activated kinase (PAK) was attenuated in response to palmitate treatment (P = 0.02 vs. no fatty acid control). Palmitate treatment also increased inhibitory phosphorylation of insulin receptor substrate-1 and attenuated insulin-stimulated phosphorylation of Akt at both Thr308 and Ser473 (all P < 0.05 vs. no fatty acid control). Such signaling impairments resulted in near complete inhibition of insulin-stimulated translocation of glucose transporter protein 4 (GLUT4; P = 0.10 vs. basal during palmitate treatment). In summary, our finding suggests that Rac1 may not undergo negative regulation by DAG or ceramides. We instead provide evidence that attenuated PAK phosphorylation and impaired GLUT4 translocation during palmitate-induced insulin resistance can occur independent of defects in insulin-stimulated Rac1-GTP binding.


Assuntos
Guanosina Trifosfato/metabolismo , Insulina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Palmitatos/farmacologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Linhagem Celular , Diglicerídeos/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Insulina/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Ligação Proteica , Ratos , Transdução de Sinais
6.
Physiol Rep ; 6(14): e13810, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30047243

RESUMO

Skeletal muscle autophagy is suppressed by insulin, but it is not clear if such suppression is altered with insulin resistance. We investigated if the inhibitory action of insulin on autophagy remains intact despite insulin resistance to glucose metabolism. C57BL/6J mice consumed either a low-fat (10% fat) diet as control or high-fat (60% fat) diet for 12 weeks to induce insulin resistance. Following a 5-hour fast, mice underwent either hyperinsulinemic-euglycemic, hyperinsulinemic-hyperglycemic, or saline infusion to test the effect of insulin on autophagy markers in the quadriceps muscle (n = 8-10 per diet and clamp condition). Mice were anesthetized by sodium pentobarbital for tissue collection after 2 h of infusion. Despite the high-fat group having lower insulin-stimulated glucose uptake, both low-fat and high-fat groups had similar autophagosome abundance during hyperinsulinemic conditions. The lipidation of microtubule-associated proteins 1A/1B light chain 3B (LC3II/LC3I) was decreased in hyperinsulinemia versus saline control (P < 0.01) in low-fat (-54%) and high-fat groups (-47%), demonstrating similar suppression of autophagy between diet groups. Mitochondrial-associated LC3II was greater in the high-fat compared to the low-fat group (P = 0.045) across clamp conditions, suggesting a greater localization of autophagosomes with mitochondria. L6 myotubes were treated with insulin and rapamycin to determine the role of mechanistic target of rapamycin complex-1 (mTORC1) in insulin-mediated suppression of autophagy. Inhibition of mTORC1 blunted the decline of LC3II/LC3I with insulin by 40%, suggesting mTORC1 partially mediates the insulin action to suppress autophagy. Collectively, autophagy remained responsive to the suppressive effects of insulin in otherwise insulin-resistant and obese mice.

7.
Am J Physiol Endocrinol Metab ; 315(4): E425-E434, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29812987

RESUMO

Excess fat intake can increase lipid oxidation and expression of mitochondrial proteins, indicating remodeling of the mitochondrial proteome. Yet intermediates of lipid oxidation also accumulate, indicating a relative insufficiency to completely oxidize lipids. We investigated remodeling of the mitochondrial proteome to determine mechanisms of changes in lipid oxidation following high-fat feeding. C57BL/6J mice consumed a high-fat diet (HFD, 60% fat from lard) or a low-fat diet (LFD, 10% fat) for 12 wk. Mice were fasted for 4 h and then anesthetized by pentobarbital sodium overdose for tissue collection. A mitochondrial-enriched fraction was prepared from gastrocnemius muscles and underwent proteomic analysis by high-resolution mass spectrometry. Mitochondrial respiratory efficiency was measured as the ratio of ATP production to O2 consumption. Intramuscular acylcarnitines were measured by liquid chromatography-mass spectrometry. A total of 658 mitochondrial proteins were identified: 40 had higher abundance and 14 had lower abundance in mice consuming the HFD than in mice consuming the LFD. Individual proteins that changed with the HFD were primarily related to ß-oxidation; there were fewer changes to the electron transfer system. Gene set enrichment analysis indicated that the HFD increased pathways of lipid metabolism and ß-oxidation. Intramuscular concentrations of select acylcarnitines (C18:0) were greater in the HFD mice and reflected dietary lipid composition. Mitochondrial respiratory ATP production-to-O2 consumption ratio for lipids was not different between LFD and HFD mice. After the 60% fat diet, remodeling of the mitochondrial proteome revealed upregulation of proteins regulating lipid oxidation that was not evident for all mitochondrial pathways. The accumulation of lipid metabolites with obesity may occur without intrinsic dysfunction to mitochondrial lipid oxidation.

8.
JCI Insight ; 3(3)2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29415895

RESUMO

BACKGROUND: Accumulation of diacylglycerol (DAG) and sphingolipids is thought to promote skeletal muscle insulin resistance by altering cellular signaling specific to their location. However,the subcellular localization of bioactive lipids in human skeletal muscle is largely unknown. METHODS: We evaluated subcellular localization of skeletal muscle DAGs and sphingolipids in lean individuals (n = 15), endurance-trained athletes (n = 16), and obese men and women with (n = 12) and without type 2 diabetes (n = 15). Muscle biopsies were fractionated into sarcolemmal, cytosolic, mitochondrial/ER, and nuclear compartments. Lipids were measured using liquid chromatography tandem mass spectrometry, and insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp. RESULTS: Sarcolemmal 1,2-DAGs were not significantly related to insulin sensitivity. Sarcolemmal ceramides were inversely related to insulin sensitivity, with a significant relationship found for the C18:0 species. Sarcolemmal sphingomyelins were also inversely related to insulin sensitivity, with the strongest relationships found for the C18:1, C18:0, and C18:2 species. In the mitochondrial/ER and nuclear fractions, 1,2-DAGs were positively related to, while ceramides were inversely related to, insulin sensitivity. Cytosolic lipids as well as 1,3-DAG, dihydroceramides, and glucosylceramides in any compartment were not related to insulin sensitivity. All sphingolipids but only specific DAGs administered to isolated mitochondria decreased mitochondrial state 3 respiration. CONCLUSION: These data reveal previously unknown differences in subcellular localization of skeletal muscle DAGs and sphingolipids that relate to whole-body insulin sensitivity and mitochondrial function in humans. These data suggest that whole-cell concentrations of lipids obscure meaningful differences in compartmentalization and suggest that subcellular localization of lipids should be considered when developing therapeutic interventions to treat insulin resistance. FUNDING: National Institutes of Health General Clinical Research Center (RR-00036), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK089170), NIDDK (T32 DK07658), and Colorado Nutrition Obesity Research Center (P30DK048520).

9.
Am J Physiol Endocrinol Metab ; 313(5): E552-E562, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28698283

RESUMO

Skeletal muscle mitochondrial protein synthesis is regulated in part by insulin. The development of insulin resistance with diet-induced obesity may therefore contribute to impairments to protein synthesis and decreased mitochondrial respiration. Yet the impact of diet-induced obesity and insulin resistance on mitochondrial energetics is controversial, with reports varying from decreases to increases in mitochondrial respiration. We investigated the impact of changes in insulin sensitivity on long-term rates of mitochondrial protein synthesis as a mechanism for changes to mitochondrial respiration in skeletal muscle. Insulin resistance was induced in C57BL/6J mice using 4 wk of a high-fat compared with a low-fat diet. For 8 additional weeks, diets were enriched with pioglitazone to restore insulin sensitivity compared with nonenriched control low-fat or high-fat diets. Skeletal muscle mitochondrial protein synthesis was measured using deuterium oxide labeling during weeks 10-12 High-resolution respirometry was performed using palmitoyl-l-carnitine, glutamate+malate, and glutamate+malate+succinate as substrates for mitochondria isolated from quadriceps. Mitochondrial protein synthesis and palmitoyl- l-carnitine oxidation were increased in mice consuming a high-fat diet, regardless of differences in insulin sensitivity with pioglitazone treatment. There was no effect of diet or pioglitazone treatment on ADP-stimulated respiration or H2O2 emission using glutamate+malate or glutamate+malate+succinate. The results demonstrate no impairments to mitochondrial protein synthesis or respiration following induction of insulin resistance. Instead, mitochondrial protein synthesis was increased with a high-fat diet and may contribute to remodeling of the mitochondria to increase lipid oxidation capacity. Mitochondrial adaptations with a high-fat diet appear driven by nutrient availability, not intrinsic defects that contribute to insulin resistance.


Assuntos
Dieta Hiperlipídica , Gorduras na Dieta/farmacologia , Hipoglicemiantes/farmacologia , Proteínas Mitocondriais/biossíntese , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Animais , Insulina/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Oxirredução/efeitos dos fármacos , Pioglitazona , Biossíntese de Proteínas/fisiologia , Tiazolidinedionas/farmacologia , Regulação para Cima/efeitos dos fármacos
10.
J Appl Physiol (1985) ; 120(11): 1355-63, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27032901

RESUMO

Several recent reports indicate that the balance of skeletal muscle phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is a key determinant of muscle contractile function and metabolism. The purpose of this study was to determine relationships between skeletal muscle PC, PE and insulin sensitivity, and whether PC and PE are dynamically regulated in response to acute exercise in humans. Insulin sensitivity was measured via intravenous glucose tolerance in sedentary obese adults (OB; n = 14), individuals with type 2 diabetes (T2D; n = 15), and endurance-trained athletes (ATH; n = 15). Vastus lateralis muscle biopsies were obtained at rest, immediately after 90 min of cycle ergometry at 50% maximal oxygen consumption (V̇o2 max), and 2-h postexercise (recovery). Skeletal muscle PC and PE were measured via infusion-based mass spectrometry/mass spectrometry analysis. ATH had greater levels of muscle PC and PE compared with OB and T2D (P < 0.05), with total PC and PE positively relating to insulin sensitivity (both P < 0.05). Skeletal muscle PC:PE ratio was elevated in T2D compared with OB and ATH (P < 0.05), tended to be elevated in OB vs. ATH (P = 0.07), and was inversely related to insulin sensitivity among the entire cohort (r = -0.43, P = 0.01). Muscle PC and PE were altered by exercise, particularly after 2 h of recovery, in a highly group-specific manner. However, muscle PC:PE ratio remained unchanged in all groups. In summary, total muscle PC and PE are positively related to insulin sensitivity while PC:PE ratio is inversely related to insulin sensitivity in humans. A single session of exercise significantly alters skeletal muscle PC and PE levels, but not PC:PE ratio.


Assuntos
Exercício/fisiologia , Resistência à Insulina/fisiologia , Insulina/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Adulto , Atletas , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Teste de Tolerância a Glucose/métodos , Humanos , Masculino , Consumo de Oxigênio/fisiologia
11.
PLoS One ; 10(3): e0120871, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25793412

RESUMO

In vitro examinations of the effect of saturated fatty acids on skeletal muscle insulin action often use only one or two different fatty acid species, which does not resemble the human plasma fatty acid profile. We compared graded concentrations (0.1-0.8 mM) of 3 different lipid mixtures: 1) a physiologic fatty acid mixture (NORM; 40% saturated fatty acids), 2) a physiologic mixture high in saturated fatty acids (HSFA; 60% saturated fatty acids), and 3) 100% palmitate (PALM) on insulin signaling and fatty acid partitioning into triacylglycerol (TAG) and diacylglycerol (DAG) in cultured muscle cells. As expected, PALM readily impaired insulin-stimulated pAktThr308/Akt and markedly increased intracellular DAG content. In contrast, the fatty acid mixtures only modestly impaired insulin-stimulated pAktThr308M/Akt, and we found no differences between NORM and HSFA. Importantly, NORM and HSFA did not increase DAG content, but instead dose-dependently increased TAG accumulation. Therefore, the robust impairment in insulin signaling found with palmitate exposure was attenuated with physiologic mixtures of fatty acids, even with a very high proportion of saturated fatty acids. This may be explained in part by selective partitioning of fatty acids into neutral lipid (i.e., TAG) when muscle cells were exposed to physiologic lipid mixtures.


Assuntos
Ácidos Graxos/metabolismo , Insulina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Transdução de Sinais , Animais , Linhagem Celular , Células Cultivadas , Ácidos Graxos/farmacologia , Humanos , Metabolismo dos Lipídeos , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Med Sport Sci ; 60: 62-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25226801

RESUMO

This chapter summarizes current knowledge regarding the interaction between lipid availability, endurance exercise, and insulin sensitivity. We discuss the role of lipid availability as a key mediator of insulin resistance in obesity, the proposed cellular mechanisms underlying this relationship, recent studies demonstrating that acute exercise protects against lipid-induced insulin resistance, how fatty acid partitioning may contribute to this protective effect of endurance exercise and finally remaining questions and future directions in the field.


Assuntos
Exercício/fisiologia , Ácidos Graxos/sangue , Inflamação/metabolismo , Metabolismo dos Lipídeos/fisiologia , Músculo Esquelético/metabolismo , Obesidade/fisiopatologia , Humanos , Insulina/metabolismo , Resistência à Insulina , Obesidade/sangue , Resistência Física/fisiologia , Transdução de Sinais , Triglicerídeos/metabolismo
13.
Diabetes ; 63(8): 2702-13, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24705404

RESUMO

The origins of nonalcoholic fatty liver disease (NAFLD) may lie in early intrauterine exposures. Here we examined the maternal response to chronic maternal high-fat (HF) diet and the impact of postweaning healthy diet on mechanisms for NAFLD development in juvenile nonhuman primate (NHP) offspring at 1 year of age. Pregnant females on HF diet were segregated as insulin resistant (IR; HF+IR) or insulin sensitive (IS; HF+IS) compared with control (CON)-fed mothers. HF+IR mothers have increased body mass, higher triglycerides, and increased placental cytokines. At weaning, offspring were placed on a CON or HF diet. Only offspring from HF+IR mothers had increased liver triglycerides and upregulated pathways for hepatic de novo lipid synthesis and inflammation that was irreversible upon switching to a healthy diet. These juvenile livers also showed a combination of classical and alternatively activated hepatic macrophages and natural killer T cells, in the absence of obesity or insulin resistance. Our findings suggest that maternal insulin resistance, including elevated triglycerides, insulin, and weight gain, initiates dysregulation of the juvenile hepatic immune system and development of de novo lipogenic pathways that persist in vitro and may be an irreversible "first hit" in the pathogenesis of NAFLD in NHP.


Assuntos
Gorduras na Dieta/efeitos adversos , Fígado Gorduroso/etiologia , Resistência à Insulina , Fígado/metabolismo , Tecido Adiposo , Ração Animal , Animais , Citocinas/genética , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Inflamação/metabolismo , Metabolismo dos Lipídeos , Macaca , Ativação de Macrófagos/fisiologia , Macrófagos/metabolismo , Hepatopatia Gordurosa não Alcoólica , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
14.
Drug Discov Today Dis Mech ; 10(1-2): e35-e40, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23997790

RESUMO

Obesity and obesity-related complications are epidemic issues currently plaguing much of the developed world with increasing associated morbidity, mortality, and economic burden. In this brief review, we discuss emerging evidence and remaining questions regarding the possible role for mitochondrial sirtuin 3 as a therapeutic target for the treatment of obesity-related metabolic diseases.

15.
J Clin Endocrinol Metab ; 98(10): E1601-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23956348

RESUMO

CONTEXT: Insulin resistance and systemic oxidative stress are prominent features of pregnancies complicated by maternal obesity or gestational diabetes mellitus (GDM). The role of skeletal muscle oxidative stress or mitochondrial capacity in obese pregnant women or obese women with GDM is unknown. OBJECTIVE: We investigated whether obese pregnant women, compared with normal weight (NW) pregnant women, demonstrate decreased skeletal muscle mitochondrial enzyme activity and elevated markers of oxidative stress, and if these differences are more severe in obese women diagnosed with GDM. DESIGN: We measured mitochondrial enzyme activity and markers of oxidative stress in skeletal muscle tissue from NW pregnant women (n = 10), obese pregnant women with normal glucose tolerance (NGT; n = 10), and obese pregnant women with GDM (n = 8), undergoing cesarean delivery (∼37 wk gestation). RESULTS: Electron transport complex-II and manganese superoxide dismutase (MnSOD) enzyme activities were decreased in obese-NGT and obese-GDM, compared with NW women. The glutathione redox ratio (GSH:GSSG) was decreased in obese-NGT and obese-GDM, indicative of increased oxidative stress. Mitochondrial sirtuin (SIRT)3 mRNA content and enzyme activity were lower in skeletal muscle of obese-NGT and obese-GDM women. Importantly, acetylation of MnSOD, a SIRT3 target, was increased in obese-NGT and obese-GDM vs NW women and was inversely correlated with SIRT3 activity (r = -0.603), suggesting a mechanism for reduced MnSOD activity. CONCLUSIONS: These data show that obese pregnant women demonstrate decreased skeletal muscle mitochondrial respiratory chain enzyme activity and decreased mitochondrial antioxidant defense. Furthermore, reduced skeletal muscle SIRT3 activity may play a role in the increased oxidative stress associated with pregnancies complicated by obesity.


Assuntos
Diabetes Gestacional/enzimologia , Complexo II de Transporte de Elétrons/metabolismo , Músculo Esquelético/enzimologia , Obesidade/enzimologia , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Feminino , Glutationa/metabolismo , Humanos , Mitocôndrias/enzimologia , Obesidade/complicações , Estresse Oxidativo/fisiologia , Gravidez
16.
Diabetes Care ; 36(9): 2516-22, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23757424

RESUMO

OBJECTIVE: The purpose of this study was to determine the effect of a relatively modest session of exercise on insulin sensitivity and fatty acid uptake the next day in obese adults. RESEARCH DESIGN AND METHODS: Eleven sedentary obese adults (male/female: 3/8; BMI 37 ± 1 kg/m(2); peak oxygen uptake [VO2peak] 20 ± 1 mL/kg/min) completed three experimental trials. On two of these occasions, subjects exercised to expend 350 kcal in the afternoon. These two exercise trials were identical except for the exercise intensity (50% VO2peak [EX50] and 65% VO2peak [EX65]) and the duration of exercise necessary to expend 350 kcal (EX50 = ≈ 70 min; EX65 = ≈ 55 min). Subjects also completed a control trial (CON), without exercise. The next morning, we measured insulin sensitivity (hyperinsulinemic-euglycemic clamp) and whole-body fatty acid uptake (palmitate rate of disappearance from plasma [Rd]). RESULTS: Exercise increased insulin sensitivity the next day, but whereas the 35% improvement after EX50 compared with CON was statistically significant (P = 0.01), the 20% improvement after EX65 was not (P = 0.17). Despite nearly identical values between CON and EX65 (P = 0.88), systemic fatty acid uptake was lower after EX50 compared with EX65 (P = 0.02), but not quite significant compared with CON (P = 0.07). Importantly, the change in fatty acid uptake after exercise compared with CON was negatively correlated with the change in insulin sensitivity for all trials (r = -0.60, P = 0.003). CONCLUSIONS: A relatively modest single session of exercise in obese adults improved insulin sensitivity the next day, and a reduction in systemic fatty acid uptake in the several hours after exercise may be important for this effect.


Assuntos
Exercício/fisiologia , Resistência à Insulina/fisiologia , Obesidade/sangue , Adulto , Glicemia/metabolismo , Terapia por Exercício , Feminino , Técnica Clamp de Glucose , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/terapia , Adulto Jovem
17.
Clin Auton Res ; 21(2): 81-7, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21113641

RESUMO

PURPOSE: Electromagnetic fields have been administered, with mixed success, in order to treat a variety of ailments. Transcranial magnetic stimulation (TMS) elicits brief changes in peripheral sympathetic nervous system (SNS) activity. The purpose of this study was to explore the utility of repetitive trans-spinal magnetic stimulation (rTSMS) for acute and prolonged modulation of SNS in adult humans. METHODS: 23 healthy men and women were randomly assigned to receive either rTSMS (figure-eight coil aligned with the sixth and seventh cervical vertebrae; 10 Hz; n = 14, at 100% intensity of stimulator output) or sham stimulation (n = 13). RESULTS: Compared with sham, rTSMS did not affect skeletal muscle SNS activity (via microneurography) during the 60-s or 10-min period following stimulation. rTSMS also had no effect on R-to-R interval (RR(int)) and standard deviation of RR(int) (a marker of heart rate variability), blood pressure or plasma concentrations of norepinephrine, epinephrine, insulin and glucose (condition/time interaction, all P > 0.10). CONCLUSION: These data suggest that rTSMS does not influence SNS in adults. While rTSMS represents a novel application of TMS technology, further study and perhaps modification of the technique is required before use in clinical studies of peripheral SNS function.


Assuntos
Terapia de Campo Magnético/métodos , Medula Espinal/fisiologia , Sistema Nervoso Simpático/fisiologia , Adulto , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Músculo Esquelético/fisiologia
18.
Metabolism ; 60(6): 852-9, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20870251

RESUMO

We previously reported that a single exercise session protects against fatty acid (FA)-induced insulin resistance, perhaps in part through augmented intramyocellular triacylglycerol (IMTG) synthesis. The aim of this study was to examine the effect of elevated FA availability after exercise on factors regulating IMTG metabolism. After exercise (90 minutes, 65% peak oxygen uptake), 7 healthy women (body mass index, 23 ± 1 kg/m(2)) were infused overnight (16 hours) with either a lipid and heparin solution (LIPID, 0.11 g fat per kilogram per hour) or saline (SALINE). We measured resting FA oxidation (indirect calorimetry) and obtained a skeletal muscle biopsy sample the next morning. The 4-fold increase in overnight plasma FA concentration during LIPID increased IMTG by approximately 30% during LIPID vs SALINE. This was accompanied by an approximately 25% greater membrane-associated abundance of the FA transporter FAT/CD36 (P < .01) and an approximately 8% increase in the activity of the IMTG synthesis enzyme glycerol-3-phosphate acyltransferase (GPAT, P < .01). In contrast, resting FA oxidation was not affected. We also found no difference in the protein abundance of GPAT1 and diacylglycerol acyltransferase-1, diacylglycerol acyltransferase activity, or the abundance of the lipid droplet coat proteins (perilipins 2, 3, 4, and 5) between treatments. Our findings suggest that augmented capacity for FA flux into muscle (ie, via membrane-associated FAT/CD36), perhaps together with a slight yet significant increase in activity of a key IMTG synthesis enzyme (GPAT), may enhance IMTG storage when FA availability is high after exercise. The importance of the absence of a change in perilipin protein abundance despite increased muscle lipid storage remains to be determined.


Assuntos
Exercício/fisiologia , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Músculo Esquelético/fisiologia , Adulto , Limiar Anaeróbio/fisiologia , Western Blotting , Antígenos CD36/metabolismo , Proteínas de Transporte , Ceramidas/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Teste de Esforço , Gorduras/metabolismo , Feminino , Glicerol-3-Fosfato O-Aciltransferase/metabolismo , Humanos , Músculo Esquelético/enzimologia , Oxirredução , Perilipina-1 , Fosfoproteínas/metabolismo , Troca Gasosa Pulmonar/fisiologia , Triglicerídeos/biossíntese
19.
J Endocrinol ; 206(3): 307-15, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20603265

RESUMO

Sedentary behavior is associated with an attenuated thermogenic response to beta-adrenergic receptor (beta-AR) stimulation, an important regulator of energy expenditure (EE) in humans. Chronic stimulation of beta-ARs, via heightened activity of the sympathoadrenal system, leads to diminished beta-AR function. We have investigated the hypothesis that the thermogenic response of sedentary adults to beta-AR stimulation will be increased during short-term sympathoadrenal inhibition. Using a randomly ordered, repeated measures study design, resting EE (REE; indirect calorimetry, ventilated hood technique) and the % increase in EE above REE (%DeltaEE) during acute i.v. isoproterenol administration (nonselective beta-AR agonist; 6, 12, and 24 ng/kg fat-free mass per min) were determined in 16 sedentary adults (nine females and seven males, 25+/-1 years, body mass index: 26.1+/-0.9 kg/m(2), maximal oxygen uptake: 40+/-2 ml/kg per min (mean+/-s.e.m.)) in the basal state and on the 6th day of transdermal clonidine administration (centrally acting alpha2-AR agonist; 0.2 mg/day). Relative to baseline, clonidine inhibited sympathoadrenal activity, as evidenced by decreased plasma norepinephrine concentration (1.04+/-0.13 vs 0.34+/-0.03 nmol/l; P<0.001), skeletal muscle sympathetic nerve activity (22.5+/-3.8 vs 8.5+/-1.9 bursts/min; P=0.003), and resting heart rate (63+/-2 vs 49+/-1 beats/min; P<0.001). Sympathoadrenal inhibition decreased REE (6510+/-243 vs 5857+/-218 kJ/day; P<0.001), increased respiratory exchange ratio (0.84+/-0.01 vs 0.86+/-0.01; P=0.03), and augmented the thermogenic response to beta-AR stimulation (%DeltaEE: 11+/-2, 16+/-2, and 24+/-2 vs 14+/-1, 20+/-2, and 31+/-2; P=0.04). These data demonstrate that in sedentary humans, short-term inhibition of sympathoadrenal activity increases the thermogenic response to beta-AR stimulation, an important determinant of EE and hence energy balance.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Norepinefrina/sangue , Receptores Adrenérgicos beta/metabolismo , Comportamento Sedentário , Sistema Nervoso Simpático/metabolismo , Agonistas alfa-Adrenérgicos/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Adulto , Análise de Variância , Índice de Massa Corporal , Regulação da Temperatura Corporal/efeitos dos fármacos , Calorimetria Indireta , Clonidina/farmacologia , Metabolismo Energético/fisiologia , Feminino , Humanos , Isoproterenol/farmacologia , Masculino , Fatores Sexuais
20.
J Appl Physiol (1985) ; 108(3): 554-60, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20044472

RESUMO

The content of meals consumed after exercise can impact metabolic responses for hours and even days after the exercise session. The purpose of this study was to compare the effect of low dietary carbohydrate (CHO) vs. low energy intake in meals after exercise on insulin sensitivity and lipid metabolism the next day. Nine healthy men participated in four randomized trials. During the control trial (CON) subjects remained sedentary. During the other three trials, subjects exercised [65% peak oxygen consumption (Vo(2 peak)); cycle ergometer and treadmill exercise] until they expended approximately 800 kcal. Dietary intake during CON and one exercise trial (BAL) was designed to provide sufficient energy and carbohydrate to maintain nutrient balance. In contrast, the diets after the other two exercise trials were low in either CHO (LOW-CHO) or energy (LOW-EN). The morning after exercise we obtained a muscle biopsy, assessed insulin sensitivity (S(i); intravenous glucose tolerance test) and measured lipid kinetics (isotope tracers). Although subjects were in energy balance during both LOW-CHO and CON, the lower muscle glycogen concentration during LOW-CHO vs. CON (402 +/- 29 vs. 540 +/- 33 mmol/kg dry wt, P < 0.01) coincided with a significant increase in S(i) [5.2 +/- 0.7 vs. 3.8 +/- 0.7 (mU/l)(-1) x min(-1); P < 0.05]. Conversely, despite ingesting several hundred fewer kilocalories after exercise during LOW-EN compared with BAL, this energy deficit did not affect S(i) the next day [4.9 +/- 0.9, and 5.0 +/- 0.8 (mU/l)(-1) x min(-1)]. Maintaining an energy deficit after exercise had the most potent effect on lipid metabolism, as measured by a higher plasma triacylglycerol concentration, and increased plasma fatty acid mobilization and oxidation compared with when in nutrient balance. Carbohydrate deficit after exercise, but not energy deficit, contributed to the insulin-sensitizing effects of acute aerobic exercise, whereas maintaining an energy deficit after exercise augmented lipid mobilization.


Assuntos
Dieta com Restrição de Carboidratos , Ingestão de Energia , Metabolismo Energético , Exercício , Resistência à Insulina , Insulina/metabolismo , Metabolismo dos Lipídeos , Músculo Esquelético/metabolismo , Adaptação Fisiológica , Adulto , Biópsia , Glicemia/metabolismo , Teste de Tolerância a Glucose , Glicogênio/metabolismo , Humanos , Cinética , Masculino , Músculo Esquelético/fisiopatologia , Oxirredução , Ácido Palmítico/sangue , Triglicerídeos/sangue
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