RESUMO
Cachexia is a multifactorial syndrome characterized by profound involuntary weight loss, fat depletion, skeletal muscle wasting, and asthenia; all symptoms are not entirely attributable to inadequate nutritional intake. Adipose tissue and skeletal muscle loss during cancer cachexia development has been described systematically. The former was proposed to precede and be more rapid than the latter, which presents a means for the early detection of cachexia in cancer patients. Recently, pioglitazone (PGZ) was proposed to exhibit anti-cancer properties, including a reduction in insulin resistance and adipose tissue loss; nevertheless, few studies have evaluated its effect on survival. For greater insight into a potential anti-cachectic effect due to PGZ, 8-week-old male Wistar rats were subcutaneously inoculated with 1 mL (2×107) of Walker 256 tumor cells. The animals were randomly assigned to two experimental groups: TC (tumor + saline-control) and TP5 (tumor + PGZ/5 mg). Body weight, food ingestion and tumor growth were measured at baseline and after removal of tumor on days 7, 14 and 26. Samples from different visceral adipose tissue (AT) depots were collected on days 7 and 14 and stored at -80o C (5 to 7 animals per day/group). The PGZ treatment showed an increase in the survival average of 27.3% (P< 0.01) when compared to TC. It was also associated with enhanced body mass preservation (40.7 and 56.3%, p< 0.01) on day 14 and 26 compared with the TC group. The treatment also reduced the final tumor mass (53.4%, p<0.05) and anorexia compared with the TC group during late-stage cachexia. The retroperitoneal AT (RPAT) mass was preserved on day 7 compared with the TC group during the same experimental period. Such effect also demonstrates inverse relationship with tumor growth, on day 14. Gene expression of PPAR-γ, adiponectin, LPL and C/EBP-α from cachectic rats was upregulated after PGZ. Glucose uptake from adipocyte cells (RPAT) was entirely re-established due to PGZ treatment. Taken together, the results demonstrate beneficial effects of PGZ treatment at both the early and final stages of cachexia.
Assuntos
Carcinoma 256 de Walker/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Adiponectina/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Caquexia/patologia , Carcinoma 256 de Walker/mortalidade , Carcinoma 256 de Walker/patologia , Linhagem Celular Tumoral , Ingestão de Alimentos/efeitos dos fármacos , Masculino , PPAR gama/metabolismo , Pioglitazona , Ratos , Ratos Wistar , Taxa de Sobrevida , Tiazolidinedionas/farmacologia , Transplante HomólogoRESUMO
Several studies showed that l-leucine supplementation reduces adiposity when provided before the onset of obesity. We studied rats that were exposed to a high-fat diet (HFD) for 10 weeks before they started to receive l-leucine supplementation. Fat mass was increased in l-leucine-supplemented rats consuming the HFD. Accordingly, l-leucine produced a hypothalamic pattern of gene expression that favors fat accumulation. In conclusion, l-leucine supplementation worsened the adiposity of rats previously exposed to HFD possibly by central mechanisms.
Assuntos
Adiposidade/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Hipotálamo/metabolismo , Leucina/efeitos adversos , Obesidade/patologia , Animais , Ingestão de Energia , Expressão Gênica , Leucina/administração & dosagem , Masculino , Ratos , Ratos WistarRESUMO
All of the adaptations acquired through physical training are reversible with inactivity. Although significant reductions in maximal oxygen uptake (Vo2max) can be observed within 2 to 4 wk of detraining, the consequences of detraining on the physiology of adipose tissue are poorly known. Our aim was therefore to investigate the effects of discontinuing training (physical detraining) on the metabolism and adipocyte cellularity of rat periepididymal (PE) adipose tissue. Male Wistar rats, aged 6 wk, were divided into three groups and studied for 12 wk under the following conditions: 1) trained (T) throughout the period; 2) detrained (D), trained during the first 8 wk and detrained during the remaining 4 wk; and 3) age-matched sedentary (S). Training consisted of treadmill running sessions (1 h/day, 5 days/wk, 50-60% Vo2max). The PE adipocyte size analysis revealed significant differences between the groups. The adipocyte cross-sectional area (in µm(2)) was significantly larger in D than in the T and S groups (3,474 ± 68.8; 1,945.7 ± 45.6; 2,492.4 ± 49.08, respectively, P < 0.05). Compared with T, the isolated adipose cells (of the D rats) showed a 48% increase in the ability to perform lipogenesis (both basal and maximally insulin-stimulated) and isoproterenol-stimulated lipolysis. No changes were observed with respect to unstimulated lipolysis. A 15% reduction in the proportion of apoptotic adipocytes was observed in groups T and D compared with group S. The gene expression levels of adiponectin and PPAR-gamma were upregulated by factors of 3 and 2 in D vs. S, respectively. PREF-1 gene expression was 3-fold higher in T vs. S. From these results, we hypothesize that adipogenesis was stimulated in group D and accompanied by significant adipocyte hypertrophy and an increase in the lipogenic capacity of the adipocytes. The occurrence of apoptotic nuclei in PE fat cells was reduced in the D and T rats; these results raise the possibility that the adipose tissue changes after detraining are obesogenic.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Condicionamento Físico Animal/fisiologia , Adiponectina/biossíntese , Animais , Separação Celular , Tamanho Celular , Cromatina/metabolismo , Citrato (si)-Sintase/metabolismo , Ácido Graxo Sintases/metabolismo , Ácidos Graxos não Esterificados/sangue , Glucose/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Insulina/sangue , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Lipólise/fisiologia , Malato Desidrogenase/metabolismo , Masculino , Proteínas de Membrana/biossíntese , Proteínas Mitocondriais/biossíntese , Músculo Esquelético/metabolismo , PPAR gama/biossíntese , Ratos , Ratos Wistar , Testosterona/metabolismo , Fatores de Transcrição/biossínteseRESUMO
Intracellular peptides generated by the proteasome and oligopeptidases have been suggested to function in signal transduction and to improve insulin resistance in mice fed a high-caloric diet. The aim of this study was to identify specific intracellular peptides in the adipose tissue of Wistar rats that could be associated with the physiological and therapeutic control of glucose uptake. Using semiquantitative mass spectrometry and LC/MS/MS analyses, we identified ten peptides in the epididymal adipose tissue of the Wistar rats; three of these peptides were present at increased levels in rats that were fed a high-caloric Western diet (WD) compared with rats fed a control diet (CD). The results of affinity chromatography suggested that in the cytoplasm of epididymal adipose tissue from either WD or CD rats, distinctive proteins bind to these peptides. However, despite the observed increase in the WD animals, the evaluated peptides increased insulin-stimulated glucose uptake in 3T3-L1 adipocytes treated with palmitate. Thus, intracellular peptides from the adipose tissue of Wistar rats can bind to specific proteins and facilitate insulin-induced glucose uptake in 3T3-L1 adipocytes.
Assuntos
Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Glucose/metabolismo , Resistência à Insulina , Peptídeos/análise , Peptídeos/metabolismo , Células 3T3 , Adipócitos/citologia , Adipócitos/metabolismo , Sequência de Aminoácidos , Animais , Cromatografia de Afinidade , Cromatografia Líquida , Ingestão de Energia , Insulina/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Ácido Palmítico/metabolismo , Ligação Proteica , Proteínas/metabolismo , Ratos , Ratos Wistar , Espectrometria de Massas em TandemRESUMO
Diabetes mellitus is a product of low insulin sensibility and pancreatic ß-cell insufficiency. Rats with streptozotocin-induced diabetes during the neonatal period by the fifth day of age develop the classic diabetic picture of hyperglycemia, hypoinsulinemia, polyuria, and polydipsia aggravated by insulin resistance in adulthood. In this study, we investigated whether the effect of long-term treatment with melatonin can improve insulin resistance and other metabolic disorders in these animals. At the fourth week of age, diabetic animals started an 8-wk treatment with melatonin (1 mg/kg body weight) in the drinking water at night. Animals were then killing, and the sc, epididymal (EP), and retroperitoneal (RP) fat pads were excised, weighed, and processed for adipocyte isolation for morphometric analysis as well as for measuring glucose uptake, oxidation, and incorporation of glucose into lipids. Blood samples were collected for biochemical assays. Melatonin treatment reduced hyperglycemia, polydipsia, and polyphagia as well as improved insulin resistance as demonstrated by constant glucose disappearance rate and homeostasis model of assessment-insulin resistance. However, melatonin treatment was unable to recover body weight deficiency, fat mass, and adipocyte size of diabetic animals. Adiponectin and fructosamine levels were completely recovered by melatonin, whereas neither plasma insulin level nor insulin secretion capacity was improved in diabetic animals. Furthermore, melatonin caused a marked delay in the sexual development, leaving genital structures smaller than those of nontreated diabetic animals. Melatonin treatment improved the responsiveness of adipocytes to insulin in diabetic animals measured by tests of glucose uptake (sc, EP, and RP), glucose oxidation, and incorporation of glucose into lipids (EP and RP), an effect that seems partially related to an increased expression of insulin receptor substrate 1, acetyl-coenzyme A carboxylase and fatty acid synthase. In conclusion, melatonin treatment was capable of ameliorating the metabolic abnormalities in this particular diabetes model, including insulin resistance and promoting a better long-term glycemic control.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Resistência à Insulina/fisiologia , Insulina/metabolismo , Melatonina/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Teste de Tolerância a Glucose , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Melatonina/farmacologia , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Ratos , Ratos WistarRESUMO
Weight gain and metabolic abnormalities are serious side effects associated with the use of several second generation antipsychotics (SGA). The adipose tissue has been considered a direct SGA target involved in the development of these adverse effects. Recent studies, mainly using murine cells, have suggested that SGA increase both adipogenesis of preadipocytes and lipid accumulation in mature adipocytes. However, to date there has been little research comparing the effects of antipsychotics with different propensities to induce weight gain on human in vitro models of white adipose tissue neoformation and metabolism. The present study aimed to investigate the effects of antipsychotics either strongly associated with weight gain, such as the SGA clozapine and olanzapine, or not, such as the SGA ziprasidone and the classical antipsychotic haloperidol, on proliferation and adipocyte differentiation of human adipose-derived stem cells (ADSCs) and lipogenesis in human mature adipocytes. Whereas ziprasidone induced elevated levels of cell death during adipogenesis and could not be investigated further, we observed that clozapine, olanzapine and haloperidol had slight stimulatory effects on the transcriptional program of ADSCs adipogenesis. However, the observed changes in adipocyte-specific genes were not accompanied by a significant increase in triglyceride accumulation within differentiated adipocytes. Our data also showed that these three antipsychotics displayed inhibitory effects on the proliferation rates of undifferentiated ADSCs. Regarding mature adipocyte metabolism, we observed that olanzapine slightly inhibited insulin-stimulated lipogenesis at the highest concentration used, and haloperidol exerted the strongest inhibitory effects on both basal and insulin-stimulated lipogenesis. Taken together, our results suggest that a direct and potent effect of clozapine and olanzapine on adipose tissue biology is not an important mechanism by which these SGA induce metabolic disturbances in humans. On the other hand, the haloperidol-mediated downregulation of the lipogenic capacity of human adipose tissue may be a possible mechanism contributing to its lower propensity to induce serious metabolic side effects.
Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Antipsicóticos/farmacologia , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Adulto , Benzodiazepinas/farmacologia , Clozapina/farmacologia , Feminino , Haloperidol/farmacologia , Humanos , Olanzapina , Piperazinas/farmacologia , Tiazóis/farmacologia , Aumento de Peso/efeitos dos fármacosRESUMO
OBJECTIVE: This study investigated the effect of different sodium content diets on rat adipose tissue carbohydrate metabolism and insulin sensitivity. METHODS AND PROCEDURES: Male Wistar rats were fed on normal- (0.5% Na(+); NS), high- (3.12% Na(+); HS),or low-sodium (0.06% Na(+); LS) diets for 3, 6, and 9 weeks after weaning. Blood pressure (BP) was measured using a computerized tail-cuff system. An intravenous insulin tolerance test (ivITT) was performed in fasted animals. At the end of each period, rats were killed and blood samples were collected for glucose and insulin determinations. The white adipose tissue (WAT) from abdominal and inguinal subcutaneous (SC) and periepididymal (PE) depots were weighed and processed for adipocyte isolation and measurement of in vitro rates of insulin-stimulated 2-deoxy-D-[(3)H]-glucose uptake (2DGU) and conversion of -[U-(14)C]-glucose into (14)CO(2). RESULTS: After 6 weeks, HS diet significantly increased the BP, SC and PE WAT masses, PE adipocyte size, and plasma insulin concentration. The sodium dietary content did not influence the whole-body insulin sensitivity. A higher half-maximal effective insulin concentration (EC(50)) from the dose-response curve of 2DGU and an increase in the insulin-stimulated glucose oxidation rate were observed in the isolated PE adipocytes from HS rats. DISCUSSION: The chronic salt overload enhanced the adipocyte insulin sensitivity for glucose uptake and the insulin-induced glucose metabolization, contributing to promote adipocyte hypertrophy and increase the mass of several adipose depots, particularly the PE fat pad.
Assuntos
Tecido Adiposo Branco/metabolismo , Epididimo/metabolismo , Glucose/metabolismo , Insulina/farmacologia , Sódio na Dieta/farmacologia , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Tecido Adiposo/patologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Animais , Transporte Biológico/efeitos dos fármacos , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Epididimo/efeitos dos fármacos , Epididimo/patologia , Glucose/farmacocinética , Frequência Cardíaca/efeitos dos fármacos , Hipertrofia , Insulina/sangue , Masculino , Ratos , Ratos WistarRESUMO
OBJECTIVE: Salt restriction has been reported to increase white adipose tissue (WAT) mass in rodents. The objective of this study was to investigate the effect of different sodium content diets on the lipogenic and lipolytic activities of WAT. RESEARCH METHODS AND PROCEDURES: Male Wistar rats were fed on normal-sodium (NS; 0.5% Na(+)), high-sodium (HS; 3.12% Na(+)), or low-sodium (LS; 0.06% Na(+)) diets for 3, 6, and 9 weeks after weaning. Blood pressure (BP) was measured using a computerized tail-cuff system. At the end of each period, rats were killed and blood samples were collected for leptin determinations. The WAT from abdominal and inguinal subcutaneous (SC), periepididymal (PE) and retroperitoneal (RP) depots was weighed and processed for adipocyte isolation, rate measurement of lipolysis and d-[U-(14)C]-glucose incorporation into lipids, glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme activity evaluation, and determination of G6PDH and leptin mRNA expression. RESULTS: After 6 weeks, HS diet significantly increased BP; SC, PE, and RP WAT masses; PE adipocyte size; plasma leptin concentration; G6PDH activity in SC WAT; and PE depots and malic activity only in SC WAT. The leptin levels correlated positively with WAT masses and adipocyte size. An increase in the basal and isoproterenol-stimulated lipolysis and in the ability to incorporate glucose into lipids was observed in isolated adipocytes from HS rats. DISCUSSION: HS diet induced higher adiposity characterized by high plasma leptin concentration and adipocyte hypertrophy, probably due to an increased lipogenic capacity of WAT.
Assuntos
Tecido Adiposo Branco/metabolismo , Leptina/sangue , Sódio na Dieta/farmacologia , Adipócitos/metabolismo , Ração Animal , Animais , Pressão Sanguínea , Peso Corporal , Glucose/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Leptina/metabolismo , Lipídeos/química , Lipogênese , Lipólise , Masculino , Obesidade/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: Salt restriction is recommended for hypertension treatment to reduce blood pressure, but its effect on some risk factors is still a matter of discussion. The aim of this study was to observe the effect of a long period of salt restriction or overload on blood pressure, left ventricular mass (LVM), kidney mass (KM), glucose tolerance, and plasma insulin. METHODS: Male Wistar rats were fed from weaning with a low-salt diet (LSD) or a high-salt diet (HSD) until 72 weeks of age. After 48 weeks, the diets were changed in half of the rats: HSD until 48 weeks and then LSD (LHSD) and LSD until 48 weeks and then HSD (HLSD). Body weight, blood pressure, electrolyte excretion, creatinine clearance, plasma renin activity, LVM, KM, and intravenous glucose tolerance test with insulin determinations were evaluated. RESULTS: Blood pressure, LVM and KM were higher on the HSD than on the LSD. Blood pressure was lower on the LHSD than on the HLSD. There were no differences in LVM and KM on the LHSD compared with the HLSD. The relationship between area under the curve (AUC) of insulin and glucose during the intravenous glucose tolerance test was higher on the LSD. No differences were detected in AUC between the two groups of rats whose diet were inverted with 48 weeks of age. CONCLUSIONS: A chronic HSD increases blood pressure, LVM, and KM and a chronic LSD increases plasma insulin in response to a glucose challenge in aging rats. The hypotensive effect of salt restriction is not modified by a previous long period on a HSD.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Dieta Hipossódica , Coração/efeitos dos fármacos , Insulina/sangue , Cloreto de Sódio na Dieta/administração & dosagem , Cloreto de Sódio na Dieta/farmacologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Área Sob a Curva , Peso Corporal , Teste de Tolerância a Glucose , Ventrículos do Coração/efeitos dos fármacos , Resistência à Insulina , Rim/efeitos dos fármacos , Masculino , Miocárdio/patologia , Ratos , Ratos Wistar , Renina/sangueRESUMO
The current study investigated the effects of chronic training and pinealectomy on the lipogenic and lipolytic activity of adipose tissue. Pinealectomized and sham-operated adult male Wistar rats were distributed in to four subgroups: pinealectomized untrained, pinealectomized trained, control untrained and control trained. At the end of the training period (8 wk) the rats were killed. Blood samples were collected for glucose, insulin and leptin determinations. Peri-epididymal adipocytes were isolated for measurement of in vitro rates of lipolysis and incorporation of substrates (D-[U-14C]-glucose, L-[U-14C]-lactate, [2-14C]-acetate and [1-14C]-palmitate) into lipids, and samples of epididymal adipose tissue were homogenized for evaluation of glucose-6-phosphate dehydrogenase maximal activity. Pinealectomy resulted in a significantly increased lipolytic capacity in response to isoproterenol and a decrease in circulating leptin levels without affecting the rates of incorporation of different substrates into lipids. However, only in the intact control group did training promote a higher basal and isoproterenol-stimulated lipolysis, increase the incorporation of palmitate (esterification), decrease the incorporation of acetate (lipogenesis) into lipids and diminish circulating leptin levels. These effects of exercise training were not seen in pinealectomized rats. However, pinealectomized trained animals showed a marked reduction in lipolysis and an increased rate of acetate incorporation. In conclusion, we demonstrated for the first time that the pineal gland plays an important role in the regulation of lipid metabolism in such a way that its absence caused a severe alteration in the balance between lipogenesis and lipolysis, which becomes evident with the adaptation to exercise training.