RESUMO
Exercise has been shown to be beneficial for individuals with Alzheimer's disease (AD). In rodent models of AD, exercise decreases the amyloidogenic processing of the amyloid precursor protein (APP). Although it remains unclear as to how exercise is promoting this shift away from pathological APP processing, there is emerging evidence that exercise-induced factors released from peripheral tissues may facilitate these alterations in brain APP processing. Interleukin-6 (IL-6) is released from multiple organs into peripheral circulation during exercise and is among the most characterized exerkines. The purpose of this study is to examine whether acute IL-6 can modulate key enzymes responsible for APP processing, namely, a disintegrin and metalloproteinase 10 (ADAM10) and ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which initiate the nonamyloidogenic and amyloidogenic cascades, respectively. Male 10-wk-old C57BL/6J mice underwent acute treadmill exercise bout or were injected with either IL-6 or a PBS control 15 min prior to tissue collection. ADAM10 and BACE1 enzyme activity, mRNA, and protein expression, as well as downstream markers of both cascades, including soluble APPα (sAPPα) and soluble APPß (sAPPß), were examined. Exercise increased circulating IL-6 and brain IL-6 signaling (pSTAT3 and Socs3 mRNA). This occurred alongside a reduction in BACE1 activity and an increase in ADAM10 activity. IL-6 injection reduced BACE1 activity and increased sAPPα protein content in the prefrontal cortex. In the hippocampus, IL-6 injection decreased BACE1 activity and sAPPß protein content. Our results show that acute IL-6 injection increases markers of the nonamyloidogenic cascade and decreases markers of the amyloidogenic cascade in the cortex and hippocampus of the brain.NEW & NOTEWORTHY It is becoming evident that exercise modulates APP processing and can reduce amyloid-beta (Aß) peptide production. Our data help to explain this phenomenon by highlighting IL-6 as an exercise-induced factor that lowers pathological APP processing. These results also highlight brain regional differences in response to acute IL-6.
Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Camundongos , Animais , Masculino , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Interleucina-6/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Camundongos Endogâmicos C57BL , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Córtex Pré-Frontal/metabolismo , RNA MensageiroRESUMO
Ketogenic diets (KDs) are a popular tool used for weight management. Studies in mice have demonstrated that KDs reduce food intake, increase energy expenditure and cause weight loss. These studies were completed at room temperature, a condition below the animal's thermal neutral zone which induces thermal stress. As energy intake and expenditure are sensitive to environmental temperature it is not clear if a KD would exert the same beneficial effects under thermal neutral conditions. Adherence to restrictive diets is poor and consequently it is important to examine the effects, and underlying mechanisms, of cycling from a ketogenic to an obesogenic diet. The purpose of the current study was to determine if housing temperature impacted the effects of a KD in obese mice and to determine if the mechanisms driving KD-induced weight loss reverse when mice are switched to an obesogenic high fat diet. We demonstrate that KD-induced reductions in food intake, increases in energy expenditure, weight loss and improvements in glucose homeostasis are not dependent upon housing temperature. KD-induced weight loss seems to be largely explained by reductions in caloric intake while cycling mice back to an obesogenic diet following a period of KD feeding leads to hyperphagia-induced weight gain. Collectively, our results suggest that prior findings with mice fed a KD at room temperature are likely not an artifact of how mice were housed and that initial changes in weight when transitioning from an obesogenic to a ketogenic diet or back are largely dependent on food intake. KEY POINTS: Ketogenic diets reduce food intake, increase energy expenditure and cause weight loss in rodents Prior preclinical studies have been completed at room temperature, a condition which induces thermal stress and limits clinical translatability Here it is demonstrated that ketogenic diet-induced reductions in food intake, increases in energy expenditure, weight loss and improvements in glucose homeostasis are similar in mice housed at room temperature or thermal neutrality Ketogenic diet-induced reductions in food intake appear to explain a large degree of weight loss. Similarly, switching mice from a ketogenic to an obesogenic diet leads to hyperphagia-mediated weight gain.
Assuntos
Dieta Cetogênica , Camundongos , Animais , Dieta Cetogênica/efeitos adversos , Temperatura , Habitação , Corpos Cetônicos , Redução de Peso , Metabolismo Energético , Camundongos Obesos , Hiperfagia , Aumento de Peso , GlucoseRESUMO
Exercise-induced alterations in adipose tissue insulin and/or ß-adrenergic signaling may contribute to increases in whole-body fat oxidation following acute exercise. Thus, we examined changes in insulin (Akt, AS160) and ß-adrenergic (PKA) signaling proteins in subcutaneous adipose tissue and whole-body fat oxidation in overweight women following acute high-intensity interval exercise (HIIE). Overweight females completed two experimental sessions in a randomized order: 1) control (bed rest) and 2) HIIE (10 × 4 min running intervals at 90% HRmax, 2-min recovery). Subcutaneous abdominal adipose tissue biopsies were obtained from 10 participants before (pre-), immediately (0hr) after (post-), 2hr post-, and 4hr post-exercise. Plasma glucose and insulin levels were assessed in venous blood samples obtained at each biopsy time-point from a different group of 5 participants (BMI-matched to biopsy group). Fat oxidation rates were estimated using the respiratory exchange ratio (RER) in all participants using indirect calorimetry pre-, 2hr post-, and 4hr post-exercise. RER was decreased (p < 0.05) at 2hr post-exercise after HIIE (0.77 ± 0.04) compared to control (0.84 ± 0.04). Despite higher plasma glucose (p < 0.01) and insulin (p < 0.05) levels at 0hr post-exercise versus control, no significant interaction effects were observed for Akt or AS160 phosphorylation (p > 0.05). Phosphorylation of PKA substrates was unaltered in both conditions (p > 0.05). Collectively, altered ß-adrenergic and insulin signaling in subcutaneous adnominal adipose tissue does not appear to explain increased whole-body fat oxidation following acute HIIE.
RESUMO
Interleukin-6 (IL-6) is a pleotropic cytokine, and in this review, we highlight recent studies focusing on the role of IL-6 in health and disease. IL-6 is known as an exercise-inducible myokine, and in rodents it was identified that a lactate-dependent increase in protease activity mediates IL-6 release from skeletal muscle, which acts in both an autocrine and paracrine roles. In humans, a series of publications observed that blocking IL-6 during exercise training prevented beneficial adaptations, such as reductions in visceral and epicardial fat mass. Independent of exercise, IL-6 impacts postprandial physiology, as demonstrated by a slowing of gastric emptying rate and improving glucose homeostasis. Finally, an engineered cytokine harnessing the biology of IL-6, termed IC7Fc, was found to have beneficial impacts on numerous health outcomes. Together, these recent advances indicate that IL-6 has a multifaceted, and perhaps beneficial, role in health and disease.
Assuntos
Exercício Físico/fisiologia , Nível de Saúde , Interleucina-6/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculoesqueléticas/metabolismo , Animais , Glucose/metabolismo , Humanos , Músculo Esquelético/patologia , Doenças Musculoesqueléticas/patologia , Receptores de Interleucina-6/metabolismoRESUMO
The liver is the primary metabolic organ involved in the endogenous production of glucose through glycogenolysis and gluconeogenesis. Hepatic glucose production (HGP) is increased via neural-hormonal mechanisms such as increases in catecholamines. To date, the effects of prior exercise training on the hepatic response to epinephrine have not been fully elucidated. To examine the role of epinephrine signaling on indices of HGP in trained mice, male C57BL/6 mice were either subjected to 12 days of voluntary wheel running or remained sedentary. Epinephrine, or vehicle control, was injected intraperitoneally on day 12 prior to sacrifice with blood glucose being measured 15 min postinjection. Epinephrine caused a larger glucose response in sedentary mice and this was paralleled by a greater reduction in liver glycogen in sedentary compared to trained mice. There was a main effect of epinephrine to increase the phosphorylation of protein kinase-A (p-PKA) substrates in the liver, which was driven by increases in the sedentary, but not trained, mice. Similarly, epinephrine-induced increases in the mRNA expression of hepatic adrenergic receptors (Adra1/2a, Adrb1), and glucose-6-phosphatase (G6pc) were greater in sedentary compared to trained mice. The mRNA expression of cAMP-degrading enzymes phosphodiesterase 3B and 4B (Pde3b, Pde4b) was greater in trained compared to sedentary mice. Taken together, our data suggest that prior exercise training reduces the liver's response to epinephrine. This could be beneficial in the context of training-induced glycogen sparing during exercise.
Assuntos
Agonistas Adrenérgicos/farmacologia , Epinefrina/farmacologia , Fígado/metabolismo , Esforço Físico , Agonistas Adrenérgicos/administração & dosagem , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Epinefrina/administração & dosagem , Gluconeogênese , Glucose-6-Fosfato/metabolismo , Glicogênio/metabolismo , Injeções Intravenosas , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Diester Fosfórico Hidrolases/metabolismo , Receptores Adrenérgicos/metabolismoRESUMO
Reactive oxygen species (ROS) are important signaling molecules mediating the exercise-induced adaptations in skeletal muscle. Acute exercise also drives the expression of genes involved in reesterification and glyceroneogenesis in white adipose tissue (WAT), but whether ROS play any role in this effect has not been explored. We speculated that exercise-induced ROS would regulate acute exercise-induced responses in WAT. To address this question, we utilized various models to alter redox signaling in WAT. We examined basal and exercise-induced gene expression in a genetically modified mouse model of reduced mitochondrial ROS emission [mitochondrial catalase overexpression (MCAT)]. Additionally, H2O2, various antioxidants, and the ß3-adrenergic receptor agonist CL316243 were used to assess gene expression in white adipose tissue culture. MCAT mice have reduced ROS emission from WAT, enlarged WAT depots and adipocytes, and greater pyruvate dehydrogenase kinase-4 (Pdk4) gene expression. In WAT culture, H2O2 reduced glyceroneogenic gene expression. In wild-type mice, acute exercise induced dramatic but transient increases in Pdk4 and phosphoenolpyruvate carboxykinase (Pck1) mRNA in both subcutaneous inguinal WAT and epididymal WAT depots, which was almost completely absent in MCAT mice. Furthermore, the induction of Pdk4 and Pck1 in WAT culture by CL316243 was markedly reduced in the presence of antioxidants N-acetyl-cysteine or vitamin E. Genetic and nutritional approaches that attenuate redox signaling prevent exercise- and ß-agonist-induced gene expression within WAT. Combined, these data suggest that ROS represent important mediators of gene expression within WAT.
Assuntos
Adipócitos/enzimologia , Tecido Adiposo Branco/enzimologia , Metabolismo Energético , Mitocôndrias/enzimologia , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adipócitos/efeitos dos fármacos , Adipogenia , Tecido Adiposo Branco/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Antioxidantes , Catalase/genética , Catalase/metabolismo , Metabolismo Energético/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Oxidantes/farmacologia , Oxirredução , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Esforço Físico , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Transdução de Sinais , Fatores de Tempo , Técnicas de Cultura de TecidosRESUMO
The relationship between liver interleukin-6 (IL-6) resistance following high-fat diet (HFD)-induced obesity and glucose intolerance is unclear. The purpose of this study was to assess the temporal development of hepatic IL-6 resistance and the role of endoplasmic reticulum (ER) stress in this process. We hypothesized that HFD would rapidly induce hepatic IL-6 resistance through a mechanism involving ER stress. Male C57BL/6N mice consumed chow or a HFD (60%) derived from lard (saturated) or olive oil (monounsaturated) for 4 days or 7 weeks before being injected intraperitoneally with IL-6 (6 ng·kg-1). Glucose, insulin, and pyruvate tolerance tests were used as proxies for systemic glucose metabolism and hepatic glucose production, respectively. Primary mouse hepatocytes were incubated with palmitate (saturated) and oleate (unsaturated) overnight, then treated with 20 ng/ml IL-6. ER stress was induced via tunicamycin or prevented by sodium phenylbutyrate (PBA). Seven weeks of a saturated, but not monounsaturated, HFD reduced hepatic IL-6 signaling in conjunction with hepatic ER stress. Palmitate directly impaired IL-6 signaling in hepatocytes along with inducing ER stress. Pharmacologically induced ER stress caused hepatic IL-6 resistance, whereas PBA reversed HFD-induced IL-6 resistance. Chronic HFD-induced obesity is associated with hepatic IL-6 resistance due to saturated FA-induced ER stress.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Interleucina-6/farmacologia , Fígado/metabolismo , Obesidade/induzido quimicamente , Obesidade/metabolismo , Animais , Gorduras na Dieta/efeitos adversos , Estresse do Retículo Endoplasmático , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenilbutiratos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tunicamicina/farmacologiaRESUMO
INTRODUCTION: Follistatin (FST) is a protein with numerous biological roles and was recently identified as an exercise-inducible hepatokine; however, the signals that regulate this are not well understood. The purpose of this study was to delineate potential endocrine factors that may regulate hepatic FST at rest and during exercise. METHODS: This study used four experiments. First, male and female C57BL/6J mice remained sedentary or were subjected to a single bout of exercise at moderate or exhaustive intensity with liver collected immediately post. Second, mice were injected with glucagon (1 mg·kg, 60 min), epinephrine (2 mg·kg, 30 min), glucagon then epinephrine, or saline. Third, mice were pretreated with propranolol (20-60 mg·kg, 30 min) before epinephrine injection. Fourth, glucagon receptor wild type (Gcgr) or knockout (Gcgr) mice were pretreated with saline or propranolol (20 mg·kg, 30 min) and were subjected to a single bout of exhaustive exercise with liver collected immediately post or after 2 h recovery. In all experiments liver FST mRNA expression was measured, and in experiment four FST protein content was measured. RESULTS: A single bout of treadmill exercise performed at an exhaustive but not moderate-intensity increased FST expression, as did injection of glucagon or epinephrine alone and when combined. Pretreatment of mice with propranolol attenuated the epinephrine-induced increase in FST expression. The exercise-induced increase in FST expression was attenuated in Gcgr mice, with no effect of propranolol. Gcgr mice had higher protein content of FST, but there was no effect of exercise or propranolol. CONCLUSIONS: These data suggest that both glucagon and epinephrine regulate hepatic FST expression at rest; however, only glucagon is required for the exercise-induced increase.
Assuntos
Epinefrina/fisiologia , Folistatina/metabolismo , Glucagon/fisiologia , Fígado/metabolismo , Condicionamento Físico Animal , Descanso , Antagonistas Adrenérgicos beta/farmacologia , Animais , Epinefrina/administração & dosagem , Epinefrina/antagonistas & inibidores , Feminino , Expressão Gênica , Glucagon/administração & dosagem , Injeções , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Propranolol/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismoRESUMO
Obesity can lead to impairments in hepatic glucose and insulin homeostasis, and although exercise is an effective treatment, the molecular targets remain incompletely understood. As IL-6 is an exercise-inducible cytokine, we aimed to identify whether IL-6 itself influences hepatic glucose and insulin homeostasis and whether this response differs during obesity. In vivo, male mice were fed a low-fat diet (LFD; 10% kcal) or a high-fat diet (HFD; 60% kcal) for 7 wk, which induced obesity and hepatic lipid accumulation. LFD- and HFD-fed mice were injected with IL-6 (400 ng, 75 min) or PBS and then with insulin (1 U/kg; ~15 min) or saline, at which point livers were collected. In both LFD- and HFD-fed mice, IL-6 decreased blood glucose and mRNA expression of gluconeogenic genes alongside increased phosphorylation of AKT in comparison to PBS controls, and this occurred without changes in circulating insulin. To determine whether this effect of IL-6 was directly on the liver, we completed in vitro isolated primary hepatocyte experiments from chow-fed mice and cultured with or without exposure to free fatty acid (250 µm palmitate and 250 µm oleate, 24 h) to induce lipid accumulation. In both control and free fatty acid-treated hepatocytes, IL-6 (20 ng/ml, 75 min) slightly attenuated insulin-stimulated (10 nM; ~15 min) AKT phosphorylation. Together, these data suggest that IL-6 may lead to improvements in indices of hepatic glucose and insulin homeostasis in vivo; however, this is likely due to an indirect effect on the hepatocyte. NEW & NOTEWORTHY In this study, we used lean and obese mice and found that a single injection of IL-6 improved glucose tolerance, decreased hepatic gluconeogenic gene expression, and increased hepatic phosphorylation of AKT. In primary hepatocytes cultured under control and lipid-laden conditions, IL-6 had a mild, but deleterious, effect on phosphorylation of AKT. Our results show that the beneficial effects of IL-6 on glucose and insulin homeostasis, in vivo, are maintained in obesity.
Assuntos
Glucose/metabolismo , Homeostase/efeitos dos fármacos , Insulina/metabolismo , Interleucina-6/farmacocinética , Animais , Dieta Hiperlipídica , Teste de Tolerância a Glucose , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Resistência à Insulina/fisiologia , Interleucina-6/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismoRESUMO
Olanzapine is a widely prescribed antipsychotic drug. While effective in reducing psychoses, treatment with olanzapine causes rapid increases in blood glucose. We wanted to determine if a single bout of exercise, immediately prior to treatment, would attenuate the olanzapine-induced rise in blood glucose and if this occurred in an IL-6 dependent manner. We found that exhaustive, but not moderate exercise, immediately prior to treatment, prevented olanzapine-induced hyperglycemia and this occurred in parallel with increases in serum IL-6. To determine if IL-6 was involved in the mechanisms through which exhaustive exercise protected against olanzapine-induced hyperglycemia several additional experiments were completed. Treatment with IL-6 (3 ng/g bw, IP) alone did not protect against olanzapine-induced increases in blood glucose. The protective effects of exhaustive exercise against olanzapine-induced increases in blood glucose were intact in whole body IL-6 knockout mice. Similarly, treating mice with an IL-6 neutralizing antibody prior to exhaustive exercise did not negate the protective effect of exercise against olanzapine-induced hyperglycemia. Our findings provide evidence that a single bout of exhaustive exercise protects against acute olanzapine-induced hyperglycemia and that IL-6 is neither sufficient, nor required for exercise to protect against increases in blood glucose with olanzapine treatment.
Assuntos
Antipsicóticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Hiperglicemia/induzido quimicamente , Hiperglicemia/prevenção & controle , Condicionamento Físico Animal , Animais , Antipsicóticos/administração & dosagem , Benzodiazepinas/administração & dosagem , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Interleucina-6/deficiência , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , OlanzapinaRESUMO
Exercise training has robust effects on subcutaneous inguinal white adipose tissue (iWAT), characterized by a shift to a brown adipose tissue (BAT)-like phenotype. Consistent with this, transplantation of exercise-trained iWAT into sedentary rodents activates thermogenesis and improves glucose homeostasis, suggesting that iWAT metabolism may contribute to the beneficial effects of exercise. However, it is yet to be determined if adaptations in iWAT are necessary for the beneficial systemic effects of exercise. To test this, male C57BL/6 mice were provided access to voluntary wheel running (VWR) or remained as a cage control (SED) for 11 nights after iWAT removal via lipectomy (LIPX) or SHAM surgery. We found that SHAM and LIPX mice with access to VWR ran similar distances and had comparable reductions in body mass, increased food intake, and increased respiratory exchange ratio (RER). Further, VWR improved indexes of glucose homeostasis and insulin tolerance in both SHAM and LIPX mice. The lack of effect of LIPX in the response to VWR was not explained by compensatory increases in markers of mitochondrial biogenesis and thermogenesis in skeletal muscle, epididymal white adipose tissue, or interscapular brown adipose tissue. Together, these data demonstrate that mice with and without iWAT have comparable adaptations to VWR, suggesting that iWAT may be dispensable for the metabolic health benefits of exercise.
Assuntos
Tecido Adiposo Branco/metabolismo , Metabolismo Energético/fisiologia , Atividade Motora/fisiologia , Condicionamento Físico Animal/fisiologia , Gordura Subcutânea/metabolismo , Tecido Adiposo Branco/fisiologia , Animais , Composição Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Saúde , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gordura Subcutânea/fisiologia , TermogêneseRESUMO
Obesity is clearly associated with an increased risk of breast cancer in postmenopausal women. The purpose was to determine if obesity alters the adipocyte adipokine secretion profile, thereby altering the adipose-dependent paracrine/endocrine growth microenvironment surrounding breast cancer cells (MCF7). Additionally, we determined whether resveratrol (RSV) supplementation can counteract any obesity-dependent effects on breast cancer tumor growth microenvironment. Obese ZDF rats received standard chow diet or diet supplemented with 200 mg/kg body weight RSV. Chow-fed Zucker rats served as lean controls. After 6 weeks, conditioned media (CM) prepared from inguinal subcutaneous adipose tissue (scAT) was added to MCF7 cells for 24 hrs. Experiments were also conducted using purified isolated adipocytes to determine whether any endocrine effects could be attributed specifically to the adipocyte component of adipose tissue. scAT from ZDF rats promoted cell cycle entry in MCF7 cells which was counteracted by RSV supplementation. RSV-CM had a higher ratio of ADIPO:LEP compared to ZDF-CM. This altered composition of the CM led to increased levels of pAMPKT172, p27, p27T198 and AdipoR1 while decreasing pAktT308 in MCF7 cells grown in RSV-CM compared to ZDF-CM. RSV-CM increased number of cells in G0/G1 and decreased cells in S-phase compared to ZDF-CM. Co-culture experiments revealed that these obesity-dependent effects were driven by the adipocyte component of the adipose tissue. Obesity decreased the ratio of adiponectin:leptin secreted by adipocytes, altering the adipose-dependent growth microenvironment resulting in increased breast cancer cell proliferation. Supplementation with RSV reversed these adipose-dependent effects suggesting a potential for RSV as a nutritional supplementation to improve breast cancer treatment in obese patients.
Assuntos
Adipócitos/citologia , Meios de Cultivo Condicionados/química , Obesidade/complicações , Estilbenos/farmacologia , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Animais , Peso Corporal , Neoplasias da Mama/patologia , Ciclo Celular , Proliferação de Células , Técnicas de Cocultura , Sistema Endócrino , Feminino , Humanos , Células MCF-7 , Masculino , Obesidade/patologia , Ratos , Ratos Zucker , Resveratrol , Fatores de TempoRESUMO
The mechanisms by which estradiol modulates adipose lipolysis are poorly understood. We sought to measure basal and ß3-stimulated indices of lipoysis (FFAs, glycerol) in vivo in E2 deficient or supplemented rats, and ex vivo with direct acute E2 exposure. For 2 weeks, ovariectomized (OVX) and OVX rats treated with a daily oral dose of E2 (OVX E2) were pairfed to SHAM controls (n = 12 per group). Adipocyte size was modestly (â¼40%) increased in OVX rats, but did not reach significance (p = 0.2). After 2 weeks, half of the animals in each group received an in vivo injection of saline or 1 mg/kg of the ß3 agonist CL 316, 243. Serum FFA concentrations, but not glycerol, were lower in OVX and OVX E2 rats compared with SHAM controls (p = 0.02). A significant CL response was present in all groups (p<0.001) and HSL activation was unaffected by OVX or OVX E2 in retroperitoneal (r.p.) or inguinal (iWAT) adipose depots in vivo. Ex vivo, CL increased FFA and glycerol accumulation in the media as well as HSL phosphorylation by several fold in r.p. and iWAT explants, but responses from OVX and OVX E2 rats were comparable to SHAMs. To assess whether E2 can directly affect lipolysis, r.p. and iWAT tissue was treated with E2, CL or E2 + CL for 2, 4 or 8 hours using adipose tissue organ culture. CL stimulated FFA release (p<0.001), but was unaffected by E2. Overall, our results indicate that E2 does not directly regulate adipose tissue lipolysis.
Assuntos
Estradiol/metabolismo , Lipólise/fisiologia , Tecido Adiposo , Adiposidade/fisiologia , Animais , Peso Corporal , Dioxóis , Estradiol/fisiologia , Ácidos Graxos não Esterificados , Feminino , Lipólise/genética , Obesidade , Tamanho do Órgão , Ovariectomia , Ratos , ÚteroRESUMO
The polyphenol compound resveratrol (RSV) has attracted attention due to its reputed beneficial effects on insulin sensitivity. Our lab has previously identified protective effects of RSV against the development of type 2 diabetes in rats. These effects occurred in a manner similar to thiazolidinedione's (TZDs), a class of insulin sensitizing drugs. TZDs are commonly prescribed in combination with metformin (MET) and thus we sought to examine the combined effects of RSV and MET in treating insulin resistance. Male C57BL6 mice were fed a low- (LFD; 10% Kcal from fat) or high-fat diet (HFD; 60% Kcal from fat) for 9 weeks to induce glucose and insulin intolerance. HFD mice were then assigned to control (HFD), MET (231.28 ± 12.24 mg/kg/day), RSV (93.68 ± 3.51 mg/kg/day), or combined (COM; MET 232.01 ± 17.12 mg/kg/day and RSV 92.77 ± 6.92 mg/kg/day) treatment groups. Changes in glucose and insulin tolerance and tissue-specific insulin signaling were measured 4 weeks post-treatment. RSV or MET alone did not have beneficial effects on glucose tolerance, although MET significantly improved insulin tolerance compared to HFD Glucose and insulin tolerance were significantly improved in COM compared to HFD and this was mirrored by enhanced insulin-stimulated AKT phosphorylation in triceps muscle and inguinal subcutaneous adipose tissue in COM compared to HFD mice. Improvements with COM treatment were not explained by differences in body weight, adiposity, or markers of adipose tissue inflammation. In summary, this study provides evidence of beneficial effects of combined RSV and MET therapy in treating impairments in glucose homeostasis.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Metformina/administração & dosagem , Estilbenos/administração & dosagem , Adiposidade , Animais , Glicemia/metabolismo , Quimioterapia Combinada , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Oncogênica v-akt/metabolismo , Especificidade de Órgãos , ResveratrolRESUMO
5'-AMP-activated protein kinase (AMPK) is activated as a consequence of lipolysis and has been shown to play a role in regulation of adipose tissue mitochondrial content. Conversely, the inhibition of lipolysis has been reported to potentiate the induction of protein kinase A (PKA)-targeted genes involved in the regulation of oxidative metabolism. The purpose of the current study was to address these apparent discrepancies and to more fully examine the relationship between lipolysis, AMPK, and the ß-adrenergic-mediated regulation of gene expression. In 3T3-L1 adipocytes, the adipose tissue triglyceride lipase (ATGL) inhibitor ATGListatin attenuated the Thr(172) phosphorylation of AMPK by a ß3-adrenergic agonist (CL 316,243) independent of changes in PKA signaling. Similarly, CL 316,243-induced increases in the Thr(172) phosphorylation of AMPK were reduced in adipose tissue from whole body ATGL-deficient mice. Despite reductions in the activation of AMPK, the induction of PKA-targeted genes was intact or, in some cases, increased. Similarly, markers of mitochondrial content and respiration were increased in adipose tissue from ATGL knockout mice independent of changes in the Thr(172) phosphorylation of AMPK. Taken together, our data provide evidence that AMPK is not required for the regulation of adipose tissue oxidative capacity in conditions of reduced fatty acid release.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Lipase/metabolismo , Lipólise/fisiologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Adrenérgicos/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Linhagem Celular , Ácidos Graxos/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVE: To investigate indices of adipose tissue inflammation and remodeling in high-fat diet (HFD) sarcolipin-knockout (SLN(-) (/-) ) mice. SLN regulates muscle-based nonshivering thermogenesis and is up-regulated with HFD. SLN(-) (/-) mice develop greater diet-induced obesity and glucose intolerance. This is accompanied by increases in circulating catecholamines and fatty acids. Catecholamines and fatty acids play a role in the pathology of adipose tissue inflammation. METHODS: Male mice (wild type and SLN(-) (/-) ) were fed a HFD (42% kcal from fat) for 8 weeks. RESULTS: SLN(-) (/-) mice displayed greater obesity and glucose intolerance. This was accompanied by higher circulating epinephrine and nonesterified fatty acids. Epididymal but not inguinal subcutaneous adipose tissue from SLN(-) (/-) mice displayed higher interleukin-6, suppressor of cytokine signaling 3, interleukin-1ß, and tumor necrosis factor-α mRNA expression, and this was associated with increased markers of macrophage infiltration (F4/80 expression and crown-like structures) and M1 polarization (higher CD11c expression and CD11c/MGL1). Interestingly, this occurred despite SLN(-) (/-) mice having smaller adipocytes. CONCLUSIONS: In conditions of nutrient excess, SLN(-) (/-) mice display depot-specific increases in indices of adipose tissue inflammation and remodeling. This could be a compensatory response to reductions in muscle-based thermogenesis.
Assuntos
Tecido Adiposo/patologia , Dieta Hiperlipídica/efeitos adversos , Proteínas Musculares/fisiologia , Obesidade/patologia , Proteolipídeos/fisiologia , Animais , Epinefrina/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Intolerância à Glucose/etiologia , Intolerância à Glucose/fisiopatologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/fisiopatologia , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Termogênese , Fator de Necrose Tumoral alfa/metabolismoRESUMO
SCOPE: While resveratrol (RSV) is associated with the prevention of high-fat (HF) diet-induced insulin resistance, the effects on bone health combined with an HF-diet is unknown. Therefore, we determined the effect of RSV on bone microarchitecture in the presence of an HF-diet, while also elucidating molecular adaptations within bone that could contribute to bone health status. METHODS AND RESULTS: Male C57BL6 mice were provided control (10% fat) or HF-diet (60% fat) in the presence or absence of RSV for 12 weeks. While RSV prevented HF diet-induced glucose intolerance, HF-RSV compromised tibial microarchitecture, mineral mass, and strength. The compromised outcomes following HF-RSV corresponded with higher markers of osteoclast-activation and bone-resorption (decreased OPG/RANKL ratio; increased cathepsin K), as well as higher markers of tibial mitochondrial content. A molecular model of elevated mitochondrial content (RIP140 knock out (KO) mice) was utilized to determine proof-of-principle that increasing mitochondrial content coincides with decrements in bone health. RIP140 KO mice displayed higher markers of mitochondrial content, and similar to HF-RSV, had compromised bone microarchitecture, lower BMD/strength, and higher markers of osteoclast-activation/bone-resorption. CONCLUSION: These data show that in the presence of an HF-diet, RSV negatively alters bone health, a process associated with increased mitochondrial content and markers of bone resorption.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Estilbenos/farmacologia , Tíbia/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Proteínas Nucleares/genética , Proteína 1 de Interação com Receptor Nuclear , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Ligante RANK/metabolismo , Resveratrol , Tíbia/fisiologia , Tíbia/ultraestruturaRESUMO
INTRODUCTION: Appropriate activation of growth signaling pathways, specifically mammalian target of rapamycin complex 1 (mTORC1), is central to muscle mass and metabolism. The goal of these studies was to examine the effects of metformin on mTORC1 signaling in aged skeletal muscle in an attempt to normalize growth signaling. METHODS: Aged (23m) and young (3m) male mice were fed a low fat diet without or with 0.5% metformin for up to 8 weeks, then mTORC1-related signaling was examined in the plantar flexor complex. RESULTS: Metformin had no significant effect on lowering body weight or muscle mass in aged animals, nor altered p70 S6 Kinase 1 (S6K1) and 4E-binding protein 1 (4E-BP1) phosphorylation. However, it significantly (P < 0.05) reduced body weight and lowered S6K1 and rpS6 phosphorylation in the young. CONCLUSIONS: Collectively, these data suggest metformin is ineffective at normalizing growth signaling in aged skeletal muscle.
Assuntos
Envelhecimento/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Complexos Multiproteicos/metabolismo , Músculo Esquelético/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Fatores Etários , Animais , Teste de Esforço , Antígenos de Histocompatibilidade Classe I/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição/metabolismoRESUMO
The purpose of this investigation was to determine whether exercise-induced increases in adipose tissue interleukin 6 (IL-6) signaling occurred as part of a larger proinflammatory response to exercise and whether the induction of IL-6 signaling with acute exercise was altered in trained mice in parallel with changes in the IL-6 receptor complex. Sedentary and trained C57BL/6J mice were challenged with an acute bout of exercise. Adipose tissue and plasma were collected immediately and 4 h afterward and analyzed for changes in indices of IL-6 signaling, circulating IL-6, markers of adipose tissue inflammation, and expression/content of IL-6 receptor and glycoprotein 130 (gp130). In untrained mice, IL-6 mRNA increased immediately after exercise, and increases in indices of IL-6 signaling were increased 4 h after exercise in epididymal, but not inguinal adipose tissue. This occurred independent of increases in plasma IL-6 and alterations in markers of inflammation. When compared with untrained mice, in trained mice, acute exercise induced the expression of gp130 and IL-6 receptor alpha (IL-6Rα), and training increased the protein content of these. Acute exercise induced the expression, and training increased the protein content, of glycoprotein 130 and IL-6Rα and was associated with a more rapid increase in markers of IL-6 signaling in epididymal adipose tissue from trained compared with untrained mice. The ability of exogenous IL-6 to increase phosphorylation of STAT3 was similar between groups. Our findings demonstrate that acute exercise increases IL-6 signaling in a depot-dependent manner, likely through an autocrine/paracrine mechanism. This response is initiated more rapidly after exercise in trained mice, potentially as a result of increases in IL-6Rα and gp130.
Assuntos
Tecido Adiposo/fisiopatologia , Inflamação/fisiopatologia , Interleucina-6 , Condicionamento Físico Animal , Esforço Físico , Transdução de Sinais , Tecido Adiposo/metabolismo , Animais , Receptor gp130 de Citocina/metabolismo , Epididimo/metabolismo , Ácidos Graxos não Esterificados/sangue , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Receptores de Interleucina-6 , Fator de Transcrição STAT3/metabolismo , Comportamento SedentárioRESUMO
Several gastrointestinal proteins have been identified to have insulinotropic effects, including glucose-dependent insulinotropic polypeptide (GIP); however, the direct effects of incretins on skeletal muscle glucose transport remain largely unknown. Therefore, the purpose of the current study was to examine the role of GIP on skeletal muscle glucose transport and insulin signaling in rats. Relative to a glucose challenge, a mixed glucose+lipid oral challenge increased circulating GIP concentrations, skeletal muscle Akt phosphorylation, and improved glucose clearance by â¼35% (P < 0.05). These responses occurred without alterations in serum insulin concentrations. In an incubated soleus muscle preparation, GIP directly stimulated glucose transport and increased GLUT4 accumulation on the plasma membrane in the absence of insulin. Moreover, the ability of GIP to stimulate glucose transport was mitigated by the addition of the PI 3-kinase (PI3K) inhibitor wortmannin, suggesting that signaling through PI3K is required for these responses. We also provide evidence that the combined stimulatory effects of GIP and insulin on soleus muscle glucose transport are additive. However, the specific GIP receptor antagonist (Pro(3))GIP did not attenuate GIP-stimulated glucose transport, suggesting that GIP is not signaling through its classical receptor. Together, the current data provide evidence that GIP regulates skeletal muscle glucose transport; however, the exact signaling mechanism(s) remain unknown.