RESUMEN
Exercise training modifies lipid metabolism in skeletal muscle, but the effect of exercise training on intramyocellular lipid droplet (LD) abundance, size, and intracellular distribution in adults with obesity remains elusive. This study compared high-intensity interval training (HIIT) with more conventional moderate-intensity continuous training (MICT) on intramyocellular lipid content, as well as LD characteristics (size and number) and abundance within the intramyofibrillar (IMF) and subsarcolemmal (SS) regions of type I and type II skeletal muscle fibers in adults with obesity. Thirty-six adults with obesity [body mass index (BMI) = 33 ± 3 kg/m2] completed 12 wk (4 days/wk) of either HIIT (10 × 1 min, 90% HRmax + 1-min active recovery; n = 19) or MICT (45-min steady-state exercise, 70% HRmax; n = 17), while on a weight-maintaining diet throughout training. Skeletal muscle biopsies were collected from the vastus lateralis before and after training, and intramyocellular lipid content and intracellular LD distribution were measured by immunofluorescence microscopy. Both MICT and HIIT increased total intramyocellular lipid content by more than 50% (P < 0.01), which was attributed to a greater LD number per µm2 in the IMF region of both type I and type II muscle fibers (P < 0.01). Our findings also suggest that LD lipophagy (autophagy-mediated LD degradation) may be transiently upregulated the day after the last exercise training session (P < 0.02 for both MICT and HIIT). In summary, exercise programs for adults with obesity involving either MICT or HIIT increased skeletal muscle LD abundance via a greater number of LDs in the IMF region of the myocyte, thereby providing more lipid in close proximity to the site of energy production during exercise.NEW & NOTEWORTHY In this study, 12 wk of either moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) enhanced skeletal muscle lipid abundance by increasing lipid droplet number within the intramyofibrillar (IMF) region of muscle. Because the IMF associates with high energy production during muscle contraction, this adaptation may enhance lipid oxidation during exercise. Despite differences in training intensity and energy expenditure between MICT and HIIT, their effects on muscle lipid abundance and metabolism were remarkably similar.
Asunto(s)
Entrenamiento de Intervalos de Alta Intensidad , Gotas Lipídicas , Adulto , Humanos , Obesidad/terapia , Ejercicio Físico/fisiología , Metabolismo Energético/fisiología , LípidosRESUMEN
Excessive adipose tissue mass underlies much of the metabolic health complications in obesity. Although exercise training is known to improve metabolic health in individuals with obesity, the effects of exercise training without weight loss on adipose tissue structure and metabolic function remain unclear. Thirty-six adults with obesity (body mass index = 33 ± 3 kg · m-2 ) were assigned to 12 weeks (4 days week-1 ) of either moderate-intensity continuous training (MICT; 70% maximal heart rate, 45 min; n = 17) or high-intensity interval training (HIIT; 90% maximal heart rate, 10 × 1 min; n = 19), maintaining their body weight throughout. Abdominal subcutaneous adipose tissue (aSAT) biopsy samples were collected once before and twice after training (1 day after last exercise and again 4 days later). Exercise training modified aSAT morphology (i.e. reduced fat cell size, increased collagen type 5a3, both P ≤ 0.05, increased capillary density, P = 0.05) and altered protein abundance of factors that regulate aSAT remodelling (i.e. reduced matrix metallopeptidase 9; P = 0.02; increased angiopoietin-2; P < 0.01). Exercise training also increased protein abundance of factors that regulate lipid metabolism (e.g. hormone sensitive lipase and fatty acid translocase; P ≤ 0.03) and key proteins involved in the mitogen-activated protein kinase pathway when measured the day after the last exercise session. However, most of these exercise-mediated changes were no longer significant 4 days after exercise. Importantly, MICT and HIIT induced remarkably similar adaptations in aSAT. Collectively, even in the absence of weight loss, 12 weeks of exercise training induced changes in aSAT structure, as well as factors that regulate metabolism and the inflammatory signal pathway in adults with obesity. KEY POINTS: Exercise training is well-known to improve metabolic health in obesity, although how exercise modifies the structure and metabolic function of adipose tissue, in the absence of weight loss, remains unclear. We report that both 12 weeks of moderate-intensity continuous training (MICT) and 12 weeks of high-intensity interval training (HIIT) induced modifications in adipose tissue structure and factors that regulate adipose tissue remodelling, metabolism and the inflammatory signal pathway in adults with obesity, even without weight loss (with no meaningful differences between MICT and HIIT). The modest modifications in adipose tissue structure in response to 12 weeks of MICT or HIIT did not lead to changes in the rate of fatty acid release from adipose tissue. These results expand our understanding about the effects of two commonly used exercise training prescriptions (MICT and HIIT) on adipose tissue remodelling that may lead to advanced strategies for improving metabolic health outcomes in adults with obesity.
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Ejercicio Físico , Obesidad , Tejido Adiposo/metabolismo , Adulto , Ejercicio Físico/fisiología , Ácidos Grasos/metabolismo , Humanos , Obesidad/metabolismo , Grasa Subcutánea/metabolismo , Pérdida de PesoRESUMEN
NEW FINDINGS: What is the central question of this study? Does exercise training modify tissue iron storage in adults with obesity? What is the main finding and its importance? Twelve weeks of moderate-intensity exercise or high-intensity interval training lowered whole-body iron stores, decreased the abundance of the key iron storage protein in skeletal muscle (ferritin) and tended to lower hepatic iron content. These findings show that exercise training can reduce tissue iron storage in adults with obesity and might have important implications for obese individuals with dysregulated iron homeostasis. ABSTRACT: The regulation of iron storage is crucial to human health, because both excess and deficient iron storage have adverse consequences. Recent studies suggest altered iron storage in adults with obesity, with increased iron accumulation in their liver and skeletal muscle. Exercise training increases iron use for processes such as red blood cell production and can lower whole-body iron stores in humans. However, the effects of exercise training on liver and muscle iron stores in adults with obesity have not been assessed. The aim of this study was to determine the effects of 12 weeks of exercise training on whole-body iron stores, liver iron content and the abundance of ferritin (the key iron storage protein) in skeletal muscle in adults with obesity. Twenty-two inactive adults (11 women and 11 men; age, 31 ± 6 years; body mass index, 33 ± 3 kg/m2 ) completed 12 weeks (four sessions/week) of either moderate-intensity continuous training (MICT; 45 min at 70% of maximal heart rate; n = 11) or high-intensity interval training (HIIT; 10 × 1 min at 90% of maximal heart rate, interspersed with 1 min active recovery; n = 11). Whole-body iron stores were lower after training, as indicated by decreased plasma concentrations of ferritin (P = 3 × 10-5 ) and hepcidin (P = 0.02), without any change in C-reactive protein. Hepatic R2*, an index of liver iron content, was 6% lower after training (P = 0.06). Training reduced the skeletal muscle abundance of ferritin by 10% (P = 0.03), suggesting lower muscle iron storage. Interestingly, these adaptations were similar in MICT and HIIT groups. Our findings indicate that exercise training decreased iron storage in adults with obesity, which might have important implications for obese individuals with dysregulated iron homeostasis.
Asunto(s)
Entrenamiento de Intervalos de Alta Intensidad , Hierro , Adaptación Fisiológica , Adulto , Ejercicio Físico/fisiología , Femenino , Humanos , Masculino , Obesidad/metabolismoRESUMEN
NEW FINDINGS: What is the central question of this study? Obesity is associated with complex perturbations to iron homeostasis: is plasma ferritin concentration (a biomarker of whole-body iron stores) related to the abundance of ferritin (the key tissue iron storage protein) in skeletal muscle in adults with obesity? What is the main finding and its importance? Plasma ferritin concentration was tightly correlated with the abundance of ferritin in skeletal muscle, and this relationship persisted when accounting for sex, age, body mass index and plasma C-reactive protein concentration. Our findings suggest that skeletal muscle may be an important iron store. ABSTRACT: Obesity is associated with complex perturbations to whole-body and tissue iron homeostasis. Recent evidence suggests a potentially important influence of iron storage in skeletal muscle on whole-body iron homeostasis, but this association is not clearly resolved. The primary aim of this study was to assess the relationship between whole-body and skeletal muscle iron stores by measuring the abundance of the key iron storage (ferritin) and import (transferrin receptor) proteins in skeletal muscle, as well as markers of whole-body iron homeostasis in men (n = 19) and women (n = 43) with obesity. Plasma ferritin concentration (a marker of whole-body iron stores) was highly correlated with muscle ferritin abundance (r = 0.77, P = 2 × 10-13 ) and negatively associated with muscle transferrin receptor abundance (r = -0.76, P = 1 × 10-12 ). These relationships persisted when accounting for sex, age, BMI and plasma C-reactive protein concentration. In parallel with higher whole-body iron stores in our male versus female participants, men had 2.2-fold higher muscle ferritin abundance (P = 1 × 10-4 ) compared with women. In accordance with lower muscle iron storage, women had 2.7-fold higher transferrin receptor abundance (P = 7 × 10-10 ) compared with men. We conclude that muscle iron storage and import proteins are tightly and independently related to plasma ferritin concentration in adults with obesity, suggesting that skeletal muscle may be an underappreciated iron store.
Asunto(s)
Ferritinas , Obesidad , Adulto , Índice de Masa Corporal , Femenino , Humanos , Hierro , Masculino , Músculo Esquelético/metabolismoRESUMEN
NEW FINDINGS: What is the central question of this study? Do obese women with relatively high whole-body iron stores exhibit elevated in vivo rates of fatty acid (FA) release from adipose tissue compared with a well-matched cohort of obese women with relatively low iron stores? What is the main finding and its importance? Obese women with high plasma [ferritin] (a marker of whole-body iron stores) had greater FA mobilization, lipolytic activation in adipose tissue and insulin resistance (IR) compared with obese women with lower plasma [ferritin]. Given that elevated FA mobilization is intimately linked with the development of IR, these findings suggest that elevated iron stores might contribute to IR in obesity by increasing systemic FA availability. ABSTRACT: High rates of fatty acid (FA) mobilization from adipose tissue are associated with insulin resistance (IR) in obesity. In vitro evidence suggests that iron stimulates lipolysis in adipocytes, but whether iron is related to in vivo FA mobilization is unknown. We hypothesized that plasma ferritin concentration ([ferritin]), a marker of body iron stores, would be positively associated with FA mobilization. We measured [ferritin], the rate of appearance of FA in the systemic circulation (FA Ra; stable isotope dilution), key adipose tissue lipolytic proteins and IR (hyperinsulinaemic-euglycaemic clamp) in 20 obese, premenopausal women. [Ferritin] was correlated with FA Ra (r = 0.65; P = 0.002) and IR (r = 0.57; P = 0.008); these relationships remained significant after controlling for body mass index and plasma [C-reactive protein] (a marker of systemic inflammation) in multiple regression analyses. We then stratified subjects into tertiles based on [ferritin] to compare subjects with 'High-ferritin' versus 'Low-ferritin'. Plasma [hepcidin] was more than fivefold greater (P < 0.05) in the High-ferritin versus Low-ferritin group, but there was no difference in plasma [C-reactive protein] between groups, indicating that the large difference in plasma [ferritin] reflects a difference in iron stores, not systemic inflammation. We found that FA Ra, adipose protein abundance of hormone-sensitive lipase and adipose triglyceride lipase, and IR were significantly greater in subjects with High-ferritin versus Low-ferritin (all P < 0.05). These data provide the first evidence linking iron and in vivo FA mobilization and suggest that elevated iron stores might contribute to IR in obesity by increasing systemic FA availability.
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Ácidos Grasos/sangre , Ferritinas/sangre , Resistencia a la Insulina/fisiología , Obesidad/sangre , Adulto , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
Although the rate of fatty acid release from adipose tissue into the systemic circulation is very high in most obese adults, some obese adults maintain relatively low rates of fatty acid release, which helps protect them against the development of systemic insulin resistance. The primary aim of this study was to identify factors in adipose tissue that may underlie low vs. high rates of fatty acid mobilization in a relatively homogeneous cohort of obese adults. We measured systemic fatty acid rate of appearance (FA Ra) via 13C-palmitate isotope dilution, and we obtained subcutaneous abdominal adipose tissue samples from 30 obese adults (BMI: 38 ± 1 kg/m2, age: 30 ± 2 yr) after an overnight fast. We then measured insulin sensitivity using a hyperinsulinemic-euglycemic clamp. Confirming our previous work, insulin sensitivity was inversely proportional to FA Ra (R2 = 0.50; P < 0.001). Immunoblot analysis of subcutaneous adipose tissue samples revealed that, compared with obese adults with high FA Ra, those with low FA Ra had lower markers of lipase activation and higher abundance of glycerol-3-phosphate acyltransferase, which is a primary enzyme for fatty acid esterification. Microarray and pathway analysis provided evidence of lower fibrosis and lower SAPK/JNK pathway activation in obese adults with low FA Ra compared with those with high FA Ra. Our findings suggest that alterations in factors regulating triglyceride storage in adipose tissue, along with lower fibrosis and inflammatory pathway activation, may underlie maintenance of a relatively low FA Ra in obesity, which may help protect against the development of insulin resistance.
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Ácidos Grasos/metabolismo , Resistencia a la Insulina , Obesidad/metabolismo , Grasa Subcutánea Abdominal/metabolismo , Adulto , Isótopos de Carbono , Femenino , Fibrosis , Técnica de Clampeo de la Glucosa , Glicerol-3-Fosfato O-Aciltransferasa/metabolismo , Humanos , Immunoblotting , Inflamación , Lipasa/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Grasa Subcutánea Abdominal/patologíaRESUMEN
CONTEXT: Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described. OBJECTIVE: The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics. DESIGN: Cross-sectional evaluation. PARTICIPANTS: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD). MEASUREMENTS: Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies. RESULTS: Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization. CONCLUSIONS: Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.
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Composición Corporal , Lipodistrofia Parcial Familiar/diagnóstico , Lipodistrofia/diagnóstico , Adolescente , Adulto , Niño , Estudios Transversales , Femenino , Humanos , Lipodistrofia/genética , Lipodistrofia/metabolismo , Lipodistrofia/fisiopatología , Lipodistrofia Parcial Familiar/genética , Lipodistrofia Parcial Familiar/metabolismo , Lipodistrofia Parcial Familiar/fisiopatología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: This study examined the independent association of objectively measured physical activity on insulin resistance while controlling for confounding variables including: cardiorespiratory fitness, adiposity, sex, age, and smoking status. METHODS: Data were obtained from National Health and Nutrition Examination Survey 2003-2004, a cross-sectional observational study conducted by the National Center for Health Statistics of the Centers for Disease Control that uses a stratified, multistage probability design to obtain a nationally representative sample of the U.S. population. The analysis included 402 healthy U.S. adults with valid accelerometer, cardiorespiratory fitness, and fasting plasma glucose and insulin concentrations. After controlling for relevant confounding variables we performed a multiple linear regression to predict homeostatic model of insulin resistance (HOMA-IR) based on average daily minutes of moderate-to-vigorous physical activity (MVPA). RESULTS: In our bivariate models, MVPA, cardiorespiratory fitness and body fat percentage were all significantly correlated with log HOMA-IR. In the complete model including MVPA and relevant confounding variables, there were strong and significant associations between MVPA and log HOMA-IR (ß= -0.1607, P=0.004). In contrast the association between cardiorespiratory fitness and log HOMA-IR was not significant. CONCLUSION: When using an objective measure of physical activity the amount of time engaged in daily physical activity was associated with lower insulin resistance, whereas higher cardiorespiratory fitness was not. These results suggest that the amount of time engaged in physical activity may be an important determinant for improving glucose metabolism.
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Tejido Adiposo , Composición Corporal , Ejercicio Físico , Conductas Relacionadas con la Salud , Resistencia a la Insulina , Aptitud Física , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Encuestas Nutricionales , Estados Unidos , Adulto JovenRESUMEN
OBJECTIVE: The aims of this study were: 1) to assess relationships among insulin-mediated glucose uptake with standard clinical outcomes and deep-phenotyping measures (including fatty acid [FA] rate of appearance [FA Ra] into the systemic circulation); and 2) to examine the contribution of adipocyte size, fibrosis, and proteomic profile to FA Ra regulation. METHODS: A total of 66 adults with obesity (BMI = 34 [SD 3] kg/m2 ) were assessed for insulin sensitivity (hyperinsulinemic-euglycemic clamp), and stable isotope dilution methods quantified glucose, FA, and glycerol kinetics in vivo. Abdominal subcutaneous adipose tissue (aSAT) and skeletal muscle biopsies were collected, and magnetic resonance imaging quantified liver and visceral fat content. RESULTS: Insulin-mediated FA Ra suppression associated with insulin-mediated glucose uptake (r = 0.51; p < 0.01) and negatively correlated with liver (r = -0.36; p < 0.01) and visceral fat (r = -0.42; p < 0.01). aSAT proteomics from subcohorts of participants with low FA Ra suppression (n = 8) versus high FA Ra suppression (n = 8) demonstrated greater extracellular matrix collagen protein in low versus high FA Ra suppression. Skeletal muscle lipidomics (n = 18) revealed inverse correlations of FA Ra suppression with acyl-chain length of acylcarnitine (r = -0.42; p = 0.02) and triacylglycerol (r = -0.51; p < 0.01), in addition to insulin-mediated glucose uptake (acylcarnitine: r = -0.49; p < 0.01, triacylglycerol: r = -0.40; p < 0.01). CONCLUSIONS: Insulin's ability to suppress FA release from aSAT in obesity is related to enhanced insulin-mediated glucose uptake and metabolic health in peripheral tissues.
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Resistencia a la Insulina , Insulina , Adulto , Humanos , Insulina/metabolismo , Ácidos Grasos/metabolismo , Proteómica , Obesidad/complicaciones , Tejido Adiposo/metabolismo , Resistencia a la Insulina/fisiología , Triglicéridos/metabolismo , Glucosa/metabolismo , Técnica de Clampeo de la GlucosaRESUMEN
Previously, we reported that overeating for only a few days markedly suppressed the secretion of growth hormone (GH). The purpose of the present study was to determine the role of this reduction in GH concentration on key metabolic adaptations that occur during 2 wk of overeating. Nine nonobese, healthy adults were admitted to the hospital for 2 wk, during which time they ate â¼4,000 kcal/day (70 kcal·kg fat-free mass(-1)·day(-1); 50% carbohydrate, 35% fat, and 15% protein), and their plasma GH concentration was allowed to decline naturally (control). An additional eight subjects underwent the same overeating intervention and received exogenous GH treatment (GHT) administered in four daily injections to mimic physiological GH secretion throughout the 2-wk overeating period. We measured plasma insulin and glucose concentrations in the fasting and postprandial state as well as fasting lipolytic rate, proteolytic rate, and fractional synthetic rate (FSR) using stable-isotope tracer methods. GHT prevented the fall in plasma GH concentration, maintaining plasma GH concentration at baseline levels (1.2 ± 0.2 ng/ml), which increased fasting and postprandial assessments of insulin resistance (P < 0.05) and increased fasting lipidemia (all P < 0.05 vs. control). In addition, preventing the suppression in GH with overeating also blunted the increase in systemic proteolysis (P < 0.05 GHT vs. control). However, GHT did not alter lipolysis or FSR in response to overeating. In conclusion, our main findings suggest that the suppression in GH secretion that naturally occurs during the early stages of overeating may help attenuate the insulin resistance and hyperlipidemia that typically accompany overeating.
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Glucemia/metabolismo , Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/sangre , Hiperlipidemias/metabolismo , Hiperfagia/metabolismo , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Absorciometría de Fotón , Adulto , Composición Corporal/fisiología , Estudios de Cohortes , Ácidos Grasos no Esterificados/sangre , Ácidos Grasos no Esterificados/metabolismo , Femenino , Humanos , Insulina/sangre , Masculino , Proteínas Musculares/biosíntesis , Triglicéridos/sangre , Triglicéridos/metabolismo , Adulto JovenRESUMEN
Mammalian skeletal muscle contains heterogenous myofibers with different contractile and metabolic properties that sustain muscle mass and endurance capacity. The transcriptional regulators that govern these myofiber gene programs have been elucidated. However, the hormonal cues that direct the specification of myofiber types and muscle endurance remain largely unknown. Here, we uncover the secreted factor Tsukushi (TSK) as an extracellular signal that is required for maintaining muscle mass, strength, and endurance capacity and that contributes to muscle regeneration. Mice lacking TSK exhibited reduced grip strength and impaired exercise capacity. Muscle transcriptomic analysis revealed that TSK deficiency results in a remarkably selective impairment in the expression of myofibrillar genes, characteristic of slow-twitch muscle fibers, that is associated with abnormal neuromuscular junction formation. AAV-mediated overexpression of TSK failed to rescue these myofiber defects in adult mice, suggesting that the effects of TSK on myofibers are likely restricted to certain developmental stages. Finally, mice lacking TSK exhibited diminished muscle regeneration following cardiotoxin-induced muscle injury. These findings support a crucial role of TSK as a hormonal cue in the regulation of contractile gene expression, endurance capacity, and muscle regeneration.
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Contracción Muscular/fisiología , Músculo Esquelético/metabolismo , Proteoglicanos/genética , Regeneración , Animales , Ratones , Ratones Transgénicos , Modelos Animales , Fibras Musculares de Contracción Lenta/metabolismo , Músculo Esquelético/fisiopatología , Proteoglicanos/biosíntesis , Factores de TranscripciónRESUMEN
Effective storage of excess energy in abdominal subcutaneous adipose tissue during periods of overeating may help attenuate weight-gain-related insulin resistance. The objective of this study was to assess changes in the expression of factors regulating abdominal subcutaneous adipose tissue storage capacity in response to a brief exposure to overeating in nonobese adults. Because exercise can alter the expression of genes involved in regulating adipose tissue storage capacity, we compared the responses to overeating in regular exercisers (EX, n = 11) and nonexercisers (nonEX, n = 11). Abdominal subcutaneous adipose tissue samples and oral glucose tolerance tests were performed before and after participants ate 30% above their estimated daily energy requirements for 1 week. Both EX and nonEX gained â¼1 kg (P < 0.01), and Matsuda insulin sensitivity index was reduced â¼15% (P = 0.04) in both groups. Gene expression of factors involved in lipid metabolism (HSL, ATGL, DGAT, and PPARγ) and angiogenesis (HIF1α and KDR) were increased (P < 0.05), with no differences observed between EX and nonEX. In contrast, protein abundance of these factors did not change. The modest overeating stimulus did not increase markers of inflammation in the systemic circulation or adipose tissue. Overall, our findings indicate that a brief and modest overeating stimulus can impair insulin sensitivity and upregulate genes involved in abdominal adipose tissue storage capacity similarly in exercisers and nonexercisers. ClinicalTrials.gov ID#: NCT02701738.
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Resistencia a la Insulina , Tejido Adiposo/metabolismo , Adulto , Expresión Génica , Humanos , Hiperfagia/genética , Resistencia a la Insulina/fisiología , Insulina Isófana Humana , PPAR gamma/metabolismo , Grasa Subcutánea/metabolismo , Grasa Subcutánea AbdominalRESUMEN
The mechanisms underlying alterations in muscle lipid metabolism in obesity are poorly understood. The primary aim of this study was to compare the abundance and/or activities of key proteins that regulate intramyocellular triglyceride (IMTG) concentration in the skeletal muscle obtained from obese (OB; n = 8, BMI 38 ± 1 kg/m(2)) and nonobese (NOB; n = 9, BMI 23 ± 1 kg/m(2)) women. IMTG concentration was nearly twofold greater in OB vs. NOB subjects (75 ± 15 vs. 40 ± 8 µmol/g dry wt, P < 0.05). In contrast, the activity and protein abundance of key enzymes that regulate the esterification of IMTG (i.e., glycerol-3-phosphate acyltransferase and diacylglycerol acyltransferase) were not elevated. We also found no differences between groups in muscle adipose triglyceride lipase and hormone-sensitive lipase (HSL) protein abundance and no differences in phosphorylation of specific sites known to affect HSL activity. However, we did find the elevated IMTG in obesity to be accompanied by a greater abundance of the fatty acid transporter FAT/CD36 in the membrane fraction of muscle from OB vs. NOB subjects (P < 0.05), suggestive of an elevated fatty acid transport capacity. Additionally, protein abundance of the lipid-trafficking protein perilipin 3 was lower (P < 0.05) in muscle from OB vs. NOB when expressed relative to IMTG content. Our findings indicate that the elevated IMTG content found in obese women was not due to an upregulation of key lipogenic proteins or to the suppression of lipolytic proteins. The impact of a low perilipin protein abundance relative to the amount of IMTG in obesity remains to be clarified.
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Metabolismo de los Lípidos , Lipólisis , Músculo Esquelético/metabolismo , Obesidad/enzimología , Obesidad/metabolismo , Triglicéridos/metabolismo , Adulto , Índice de Masa Corporal , Estudios de Casos y Controles , Regulación hacia Abajo , Activación Enzimática , Esterificación , Femenino , Humanos , Metabolismo de los Lípidos/fisiología , Lípidos/análisis , Músculo Esquelético/química , Músculo Esquelético/enzimología , Concentración Osmolar , Proteínas/metabolismo , Triglicéridos/análisis , Regulación hacia Arriba , Adulto JovenRESUMEN
Fatty acid oversupply is a key mediator of skeletal muscle insulin resistance in obesity, primarily via accumulation of fatty acid metabolites and activation of proinflammatory pathways. Herein, we demonstrate that fatty acid-induced insulin resistance in humans is completely prevented the day after 1 session of endurance exercise. Because skeletal muscle is the primary site for systemic glucose disposal and is highly susceptible to impaired insulin action by elevated fatty acid availability, we obtained skeletal muscle samples to investigate possible mechanisms mediating this protective effect of exercise. Prevention of fatty acid-induced insulin resistance after exercise accompanied enhanced skeletal muscle protein expression of key lipogenic enzymes and an increase in muscle triglyceride synthesis. Partitioning more fatty acids toward triglyceride synthesis within muscle reduced the accumulation of fatty acid metabolites and suppressed the proinflammatory response in skeletal muscle, as evidenced by decreased phosphorylation and activation of JNK and increased abundance of inhibitor of NF-kappaB alpha (I kappa B-alpha) and I kappa B-beta. We believe this is the first study to demonstrate that 1 session of exercise completely reverses fatty acid-induced insulin resistance in humans. Reversal of insulin resistance accompanied enhanced lipogenic capacity within skeletal muscle, reduced accumulation of highly bioactive fatty acid metabolites, and suppressed activation of proinflammatory pathways known to impair insulin action.
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Ejercicio Físico/fisiología , Ácidos Grasos/metabolismo , Resistencia a la Insulina/fisiología , Músculo Esquelético/metabolismo , Triglicéridos/biosíntesis , Adulto , Diacilglicerol O-Acetiltransferasa/metabolismo , Ácidos Grasos/sangre , Femenino , Glicerol-3-Fosfato O-Aciltransferasa/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Oxidación-Reducción , Estearoil-CoA Desaturasa/metabolismoRESUMEN
PURPOSE: This study determined the impact of an exercise-induced energy deficit on postprandial and 24 h glycemic control the day after a session of exercise. METHODS: Fifteen healthy participants (m/f = 5/10, 27 ± 6 yr, body mass index = 24 ± 3 kg·m, peak oxygen consumption [VËO2peak] = 36 ± 9 mL·kg·min) completed two separate 5-d experimental trials performed under "free-living" conditions. On day 1 of each trial, participants were fitted with a continuous glucose monitor and abstained from exercise. Day 2 served as a nonexercise control (NoEx). On day 3, participants exercised at 3:00 PM (65% VËO2peak) until they expended 350 kcals (~45 min). The diet during both experimental trials was identical with the exception of meals after this exercise session. During one trial, the dinner after exercise did not replenish the 350 kcal expended during exercise, thereby establishing an exercise energy deficit (ExDEF). During the other experimental trial, the dinner after exercise contained an additional 350 kcal to compensate for the energy expended during exercise, and thereby maintained energy balance after exercise (ExBAL). Free-living glycemia was measured the day before exercise (NoEx) and the day after exercise under ExDEF and ExBAL conditions. RESULTS: The day after exercise, 3 h postprandial area under the curve was lower after breakfast in ExDEF compared with ExBAL (16.0 ± 1.8 vs 17.0 ± 1.6 mmol·L·h per 3 h, P = 0.01), but did not differ between groups after lunch (P = 0.24), dinner (P = 0.39), or evening snack (P = 0.45). Despite differences in the glycemic response to breakfast, 24 h glycemia did not differ between ExDEF and ExBAL (area under the curve = 128 ± 10 vs 131 ± 10 mmol·L·h per 24 h, respectively; P = 0.54). CONCLUSIONS: An exercise-induced energy deficit lowered the glycemic response to breakfast the next day-but this energy deficit did not impact total 24 h glycemia, the day after exercise in metabolically healthy adults.
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Glucemia/metabolismo , Ingestión de Energía , Ejercicio Físico/fisiología , Periodo Posprandial , Adulto , Índice de Masa Corporal , Metabolismo Energético , Femenino , Humanos , Insulina/sangre , Masculino , Consumo de Oxígeno , Adulto JovenRESUMEN
BACKGROUND: In people with obesity, ß-cell function may adapt to insulin resistance. We describe ß-cell function in people with severe obesity and normal fasting glucose (NFG), impaired fasting glucose (IFG), and type 2 diabetes (T2DM), as assessed before, 3 to 6 months after, and 2 years after medical weight loss to describe its effects on insulin sensitivity, insulin secretion, and ß-cell function. METHODS: Fifty-eight participants with body mass index (BMI) ≥ 35 kg/m2 (14 with NFG, 24 with IFG, and 20 with T2DM) and 13 normal weight participants with NFG underwent mixed meal tolerance tests to estimate insulin sensitivity (S[I]), insulin secretion (Φ), and ß-cell function assessed as model-based Φ adjusted for S(I). All 58 obese participants were restudied at 3 to 6 months and 27 were restudied at 2 years. RESULTS: At 3 to 6 months, after a 20-kg weight loss and a decrease in BMI of 6 kg/m2, S(I) improved in all obese participants, Φ decreased in obese participants with NFG and IFG and tended to decrease in obese participants with T2DM, and ß-cell function improved in obese participants with NFG and tended to improve in obese participants with IFG. At 2 years, ß-cell function deteriorated in participants with NFG and T2DM but remained significantly better in participants with IFG compared to baseline. CONCLUSIONS: Short-term weight loss improves ß-cell function in participants with NFG and IFG, but ß-cell function tends to deteriorate over 2 years. In participants with IFG, weight loss improves longer-term ß-cell function relative to baseline and likely relative to no intervention, suggesting that obese people with IFG are a subpopulation whose ß-cell function is most likely to benefit from weight loss.
Asunto(s)
Intolerancia a la Glucosa/prevención & control , Secreción de Insulina , Células Secretoras de Insulina/fisiología , Obesidad Mórbida/prevención & control , Pérdida de Peso , Biomarcadores/análisis , Estudios de Casos y Controles , Dieta Baja en Carbohidratos , Femenino , Estudios de Seguimiento , Intolerancia a la Glucosa/fisiopatología , Humanos , Células Secretoras de Insulina/citología , Masculino , Persona de Mediana Edad , Obesidad Mórbida/fisiopatología , PronósticoRESUMEN
Adipose tissue pathology in obese patients often features impaired adipogenesis, angiogenesis, and chronic low-grade inflammation, all of which are regulated in large part by adipose tissue stromal vascular cells [SVC; i.e., non-adipocyte cells within adipose tissue including preadipocytes, endothelial cells (ECs), and immune cells]. Exercise is known to increase subcutaneous adipose tissue lipolysis, but the impact of exercise on SVCs in adipose tissue has not been explored. The purpose of this study was to assess the effects of a session of exercise on preadipocyte, EC, macrophage, and T cell content in human subcutaneous adipose tissue. We collected abdominal subcutaneous adipose tissue samples from 10 obese adults (BMI 33 ± 3 kg/m2, body fat 41 ± 7%) 12 h after a 60 min acute session of endurance exercise (80 ± 3%HRpeak) vs. no acute exercise session. SVCs were isolated by collagenase digestion and stained for flow cytometry. We found that acute exercise reduced preadipocyte content (38 ± 7 vs. 30 ± 13%SVC; p = 0.04). The reduction was driven by a decrease in CD34hi preadipocytes (18 ± 5 vs. 13 ± 6%SVC; p = 0.002), a subset of preadipocytes that generates high lipolytic rate adipocytes ex vivo. Acute exercise did not alter EC content. Acute exercise also did not change total immune cell, macrophage, or T cell content, and future work should assess the effects of exercise on subpopulations of these cells. We conclude that exercise may rapidly regulate the subcutaneous adipose tissue preadipocyte pool in ways that may help attenuate the high lipolytic rates that are commonly found in obesity.
RESUMEN
OBJECTIVE: We compared the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on insulin sensitivity and other important metabolic adaptations in adults with obesity. METHODS: Thirty-one inactive adults with obesity (age: 31â ±â 6 years; body mass index: 33â ±â 3 kg/m2) completed 12 weeks (4 sessions/week) of either HIIT (10â ×â 1-minute at 90%HRmax, 1-minute active recovery; nâ =â 16) or MICT (45 minutes at 70%HRmax; nâ =â 15). To assess the direct effects of exercise independent of weight/fat loss, participants were required to maintain body mass. RESULTS: Training increased peak oxygen uptake by ~10% in both HIIT and MICT (Pâ <â 0.0001), and body weight/fat mass were unchanged. Peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) was ~20% greater the day after the final exercise session compared to pretraining (Pâ <â 0.01), with no difference between HIIT and MICT. When trained participants abstained from exercise for 4 days, insulin sensitivity returned to pretraining levels in both groups. HIIT and MICT also induced similar increases in abundance of many skeletal muscle proteins involved in mitochondrial respiration and lipid and carbohydrate metabolism. Training-induced alterations in muscle lipid profile were also similar between groups. CONCLUSION: Despite large differences in training intensity and exercise time, 12 weeks of HIIT and MICT induce similar acute improvements in peripheral insulin sensitivity the day after exercise, and similar longer term metabolic adaptations in skeletal muscle in adults with obesity. These findings support the notion that the insulin-sensitizing effects of both HIIT and MICT are mediated by factors stemming from the most recent exercise session(s) rather than adaptations that accrue with training.
Asunto(s)
Ejercicio Físico/fisiología , Entrenamiento de Intervalos de Alta Intensidad , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Obesidad/rehabilitación , Adaptación Fisiológica , Adulto , Femenino , Humanos , Masculino , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Conducta Sedentaria , Resultado del Tratamiento , Adulto JovenRESUMEN
Obesity is characterized by excessive rates of plasma fatty acid mobilization and uptake, which play a key role in mediating insulin resistance. While weight loss via diet-only or a diet + exercise program clearly improves insulin sensitivity, the precise mechanisms modulating this improvement are not completely understood. The purpose of the present study was to determine the role of the reduced fatty acid mobilization and uptake after weight loss in obese women who were randomly assigned to lifestyle interventions of either weight loss without exercise (WL) (n = 7) or a weight loss + exercise program (WL + EX) (n = 10). Before and after losing 12% of their body weight, we measured insulin sensitivity (S(I)), systemic fatty acid rate of appearance (Ra) and disappearance (Rd), oxidative capacity, and markers for pro-inflammatory pathways in skeletal muscle. Fatty acid Ra and Rd were reduced by 30% after both interventions (P < 0.05). While oxidative capacity increased 25% in WL + EX (compared with no increase after WL), the improvement in S(I) was identical in both groups (60%; P < 0.05), and skeletal muscle pro-inflammatory pathways were reduced (P < 0.05) similarly in both groups. When we artificially increased fatty acid mobilization after weight loss to pre-weight-loss levels via an overnight lipid infusion, the improvement in S(I) was almost completely reversed. Importantly, WL + EX did not protect against this lipid-induced reversal in S(I) despite a significant increase in resting whole-body fat oxidation and a marked increase in skeletal muscle oxidative capacity. In conclusion, reduced fatty acid mobilization and uptake appears to be a primary mediator of improved insulin sensitivity after weight loss. Moreover, enhancing fatty acid oxidative capacity via exercise training is not sufficient to prevent the insulin resistance caused by high fatty acid mobilization, such as that found in obesity.
Asunto(s)
Ejercicio Físico , Ácidos Grasos/sangre , Resistencia a la Insulina , Oxidación-Reducción , Pérdida de Peso , Adulto , Glucemia/metabolismo , Composición Corporal , Femenino , Humanos , Quinasa I-kappa B/metabolismo , Sistema de Señalización de MAP Quinasas , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Triglicéridos/sangre , Quinasa de Factor Nuclear kappa BRESUMEN
The primary goal of this study was to determine the acute glycemic and endocrine responses to the reduction of fat content from a meal. On three separate occasions, nine overweight subjects (body mass index = 30 +/- 1 kg/m(2); 5 men, 4 women) consumed 1) a control meal ( approximately 800 kcal; 100 g of carbohydrate, 31 g of fat, and 30 g of protein), 2) a low-fat meal ( approximately 530 kcal; 100 g of carbohydrate, 1 g of fat, and 30 g of protein), or 3) a low-fat meal plus lipid infusion [same meal as low-fat meal, but the total energy provided was the same as control (800 kcal), with the "missing" fat ( approximately 30 g) provided via an intravenous lipid infusion]. All three meals contained [(13)C]glucose (3 mg/kg body wt) to assess the bioavailability of ingested glucose. During the 5-h period after each meal, we measured the recovery of [(13)C]glucose in plasma, plasma glucose, and insulin concentrations. We also measured plasma concentration of the gastrointestinal peptides: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY(3-36) (PYY(3-36)). The recovery of the ingested [(13)C]glucose in the hour after ingestion was greater (P < 0.05) after the low-fat than after the control meal [area under the curve (AUC): 1,206 +/- 252 and 687 +/- 161 microM.h, respectively]. However, removing dietary fat from the meal did not affect the plasma concentration of glucose or insulin. Importantly, [(13)C]glucose recovery was not different during the low-fat and lipid infusion trials (AUC: 1,206 +/- 252 and 1,134 +/- 247 microM.h, respectively), indicating that the accelerated delivery of exogenous glucose found after removing fat from the meal is due exclusively to the reduction of fat in the gastrointestinal tract. In parallel with these findings, the reduction in fat calories from the meal reduced plasma concentration of GIP, GLP-1, and PYY(3-36). In summary, these data suggest that removing fat from the diet expedited exogenous glucose delivery into the systemic circulation and reduced the concentration of key gastrointestinal peptides, yet maintained plasma glucose concentration at control levels.