Saturated Fatty Acids Modulate Autophagy's Proteins In The Hypothalamus.

Autophagy is an important process that regulates cellular homeostasis by degrading dysfunctional proteins, organelles and lipids. In this study, the hypothesis that obesity could lead to impairment in hypothalamic autophagy in mice was evaluated by examining the hypothalamic distribution and content of autophagic proteins in animal with obesity induced by 8 or 16 weeks high fat diet to induce obesity and in response to intracerebroventricular injections of palmitic acid. The results showed that chronic exposure to a high fat diet leads to an increased expression of inflammatory markers and downregulation of autophagic proteins. In obese mice, autophagic induction leads to the downregulation of proteins, such as JNK and Bax, which are involved in the stress pathways. In neuron cell- line, palmitate has a direct effect on autophagy even without inflammatory activity. Understanding the cellular and molecular bases of overnutrition is essential for identifying new diagnostic and therapeutic targets for obesity.

A TR beta-selective agonist confers resistance to diet-induced obesity

Thyroid hormone receptor beta (TR beta also listed as THRB oil the MGI Database)-selective agonists activate brown adipose tissue (BAT) thermogenesis, while only minimally affecting cardiac activity or lean body mass. Here, we tested the hypothesis that daily administration of the TR beta agonist GC-24 prevents the metabolic alterations associated with a hypercaloric diet. Rats were placed on a high-fat diet and after a month exhibited increased body weight (BW) and adiposity, fasting hyperglycemia and glucose intolerance, increased plasma levels of triglycerides, cholesterol, nonesterified Fatty acids and interleukin-6. While GC-24 administration to these animals did not affect food ingestion or modified the progression of BW gain, it did increase energy, g the increase in adiposity Without expenditure, eliminating causing cardiac hypertrophy Fasting hyperglycemia remained unchanged, but treatment with GC-24 improved glucose I tolerance by increasing insulin Sensitivity and also normalized plasma triglyceride levels. plasma cholesterol levels were only Partially normalized and liver cholesterol content remained high in the GC-24-treated animals. Gene expression in liver, skeletal muscle, and white adipose tissue was only minimally affected by treatment with GC-24, with the main target being BAT In conclusion, during high-fat feeding treatment with the TR beta-selective agonist, GC-24 only partially improves metabolic control probably as a result Of accelerating the resting metabolic rate. Journal of Endocrinology (2009) 203, 291-299

Involvement of L-type calcium channel and SERCA2a in myocardial dysfunction induced by obesity

Obesity has been shown to impair myocardial performance. Nevertheless, the mechanisms underlying the participation of calcium (Ca(2+)) handling on cardiac dysfunction in obesity models remain unknown. L-type Ca(2+) channels and sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a), may contribute to the cardiac dysfunction induced by obesity. The purpose of this study was to investigate whether myocardial dysfunction in obese rats is related to decreased activity and/or expression of L-type Ca(2+) channels and SERCA2a. Male 30-day-old Wistar rats were fed standard (C) and alternately four palatable high-fat diets (Ob) for 15 weeks. Obesity was determined by adiposity index and comorbidities were evaluated. Myocardial function was evaluated in isolated left ventricle papillary muscles under basal conditions and after inotropic and lusitropic maneuvers. L-type Ca(2+) channels and SERCA2a activity were determined using specific blockers, while changes in the amount of channels were evaluated by Western blot analysis. Phospholamban (PLB) protein expression and the SERCA2a/PLB ratio were also determined. Compared with C rats, the Ob rats had increased body fat, adiposity index and several comorbidities. The Ob muscles developed similar baseline data, but myocardial responsiveness to post-rest contraction stimulus and increased extracellular Ca(2+) was compromised. The diltiazem promoted higher inhibition on developed tension in obese rats. In addition, there were no changes in the L-type Ca(2+) channel protein content and SERCA2a behavior (activity and expression). In conclusion, the myocardial dysfunction caused by obesity is related to L-type Ca(2+) channel activity impairment without significant changes in SERCA2a expression and function as well as L-type Ca(2+) protein levels. J. Cell. Physiol. 226: 2934-2942, 2011. (C) 2011 Wiley-Liss, Inc.

Exercise training and caloric restriction prevent reduction in cardiac Ca(2+)-handling protein profile in obese rats

Previous studies show that exercise training and caloric restriction improve cardiac function in obesity. However, the molecular mechanisms underlying this effect on cardiac function remain unknown. Thus, we studied the effect of exercise training and/or caloric restriction on cardiac function and Ca(2+) handling protein expression in obese rats. To accomplish this goal, male rats fed with a high-fat and sucrose diet for 25 weeks were randomly assigned into 4 groups: high-fat and sucrose diet, high-fat and sucrose diet and exercise training, caloric restriction, and exercise training and caloric restriction. An additional lean group was studied. The study was conducted for 10 weeks. Cardiac function was evaluated by echocardiography and Ca(2+) handling protein expression by Western blotting. Our results showed that visceral fat mass, circulating leptin, epinephrine, and norepinephrine levels were higher in rats on the high-fat and sucrose diet compared with the lean rats. Cardiac nitrate levels, reduced/oxidized glutathione, left ventricular fractional shortening, and protein expression of phosphorylated Ser(2808)-ryanodine receptor and Thr(17-)phospholamban were lower in rats on the high-fat and sucrose diet compared with lean rats. Exercise training and/or caloric restriction prevented increases in visceral fat mass, circulating leptin, epinephrine, and norepinephrine levels and prevented reduction in cardiac nitrate levels and reduced: oxidized glutathione ratio. Exercise training and/or caloric restriction prevented reduction in left ventricular fractional shortening and in phosphorylation of the Ser(2808)-ryanodine receptor and Thr(17)-phospholamban. These findings show that exercise training and/or caloric restriction prevent cardiac dysfunction in high-fat and sucrose diet rats, which seems to be attributed to decreased circulating neurohormone levels. In addition, this nonpharmacological paradigm prevents a reduction in the Ser(2808)-ryanodine receptor and Thr(17-)phospholamban phosphorylation and redox status. (Hypertension. 2010;56:629-635.)

Physiological, performance, and nutritional profile of the Brazilian olympic wushu (kung-fu) team

Artioli, GG, Gualano, B, Franchini, E, Batista, RN, Polacow, VO, and Lancha, AH Jr. Physiological, performance, and nutritional profile of the Brazilian Olympic Wushu (kung-fu) team. J Strength Cond Res 23(1): 20-25, 2009-The purpose of the present study was to determine physiological, nutritional, and performance profiles of elite Olympic Wushu (kung-fu) athletes. Ten men and four women elite athletes took part in the study. They completed the following tests: body composition, nutritional assessment, upper-body Wingate Test, vertical jump, lumbar isometric strength, and flexibility. Blood lactate was determined at rest and after the Wingate Test. Blood lactate was also determined during a training session (combat and Taolu training). We found low body fat (men: 9.5 +/- 6.3%; women: 18.0 +/- 4.8%), high flexibility (sit-and-reach-men: 45.5 +/- 6.1 cm; women: 44.0 +/- 6.3 cm), high leg power (vertical jump-men: 37.7 +/- 8.4 cm; women: 32.3 +/- 1.1 cm), high lumbar isometric strength (men: 159 6 13 cm; women: 94 6 6 cm), moderate arm mean and peak power (Wingate Test-men: 4.1 +/- 0.4 and 5.8 +/- 0.5 W.kg(-1), respectively; women: 2.5 +/- 0.3 and 3.4 +/- 0.3 W.kg(-1), respectively), and elevated blood lactate after the Wingate Test (men: 10.8 +/- 2.0 mmol.L(-1); women: 10.2 +/- 2.0 mmol.L(-1)) and during training (combat: 12.0 +/- 1.8 mmol.L(-1); Taolu: 7.7 +/- 3.3 mmol.L(-1)). Men athletes consume a high-fat, low-carbohydrate diet, whereas women consume a moderate, high-carbohydrate diet. Energy consumption was markedly variable. In conclusion, Olympic Wushu seems to be a highly anaerobic-dependent combat sport. Low body fat, high flexibility, leg anaerobic power, isometric strength, and moderately high arm anaerobic power seem to be important for successful competitive performance.

Endurance exercise training ameliorates insulin resistance and reticulum stress in adipose and hepatic tissue in obese rats

Obesity-induced endoplasmatic reticulum (ER) stress has been demonstrated to underlie the induction of obesity-induced JNK and NF-kappa B activation inflammatory responses, and generation of peripheral insulin resistance. On the other hand, exercise has been used as a crucial tool in obese and diabetic patients, and may reduce inflammatory pathway stimulation. However, the ability of exercise training to reverse endoplasmatic reticulum stress in adipose and hepatic tissue in obesity has not been investigated in the literature. Here, we demonstrate that exercise training ameliorates ER stress and insulin resistance in DIO-induced rats. Rats were fed with standard rodent chow (3,948 kcal kg(-1)) or high-fat diet (5,358 kcal kg(-1)) for 2 months. After that rats were submitted to swimming training (1 h per day, 5 days for week with 5% overload of the body weight for 8 weeks). Samples from epididymal fat and liver were obtained and western blot analysis was performed. Our results showed that swimming protocol reduces pro-inflammatory molecules (JNK, I kappa B and NF-kappa B) in adipose and hepatic tissues. In addition, exercise leads to reduction in ER stress, by reducing PERK and eIF2 alpha phosphorylation in these tissues. In parallel, an increase in insulin pathway signaling was observed, as confirmed by increases in IR, IRSs and Akt phosphorylation following exercise training in DIO rats. Thus, results suggest that exercise can reduce ER stress, improving insulin resistance in adipose and hepatic tissue.

Mitochondrial energy metabolism and redox responses to hypertriglyceridemia

In this work we review recent findings that explain how mitochondrial bioenergetic functions and redox state respond to a hyperlipidemic in vivo environment and may contribute to the maintenance of a normal metabolic phenotype. The experimental model utilized to evidence these adaptive mechanisms is especially useful for these studies since it exhibits genetic hypertriglyceridemia and avoids complications introduced by high fat diets. Liver from hypertrigliceridemic (HTG) mice have a greater content of glycerolipids together with increased mitochondrial free fatty acid oxidation. HTG liver mitochondria have a higher resting respiration rate but normal oxidative phosphorylation efficiency. This is achieved by higher activity of the mitochondrial potassium channel sensitive to ATP (mitoK(ATP)). The mild uncoupling mediated by mitoK(ATP) accelerates respiration rates and reduces reactive oxygen species generation. Although this response is not sufficient to inhibit lipid induced extra-mitochondrial oxidative stress in whole liver cells it avoids amplification of this redox imbalance. Furthermore, higher mitoK(ATP) activity increases liver, brain and whole body metabolic rates. These mitochondrial adaptations may explain why these HTG mice do not develop insulin resistance and obesity even under a severe hyperlipidemic state. On the contrary, when long term high fat diets are employed, insulin resistance, fatty liver and obesity develop and mitochondrial adaptations are inefficient to counteract energy and redox imbalances.

Bioelectrical impedance analysis for the estimation of body composition in rats

Bioelectrical impedance analysis (BIA) was used to assess body composition in rats fed on either standard laboratory diet or on a high-fat diet designed to induce obesity. Bioelectrical impedance analysis predictions of total body water and thus fat-free mass (FFM) for the group mean values were generally within 5% of the measured values by tritiated water ((H2O)-H-3) dilution. The limits of agreement for the procedure were, however, large, approximately +/-25%, limiting the applicability of the technique for measurement of body composition in individual animals.

mRNA differential display of 2-amino-1-methyl-6-phenylinlidazo[4,5-b]pyridine-induced rat mammary gland tumors

The mRNA differential display technique was used to compare mRNAs between normal mammary gland and turner-derived epithelial cells from female Sprague-Dawley rat mammary gland tumors induced by the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by a high-fat diet (23.5% corn oil). Two genes, beta-casein and transferrin, were identified as differentially expressed. The expression of these genes was examined across a bank of rat mammary gland tumors derived from animals on a low-fat diet (5% corn oil) or the high-fat diet. Carcinomas had over a 10- and 50-fold lower expression of beta-casein and transferrin, respectively than normal mammary gland. In addition, carcinomas from animals on the high-fat diet showed on average a 5-fold higher expression of beta-casein, and transferrin than carcinomas from animals on the low-fat diet. The results indicate the process of mammary gland tumorigenesis alters the expression of certain genes in the mammary gland, and that the level of dietary fat further modulates the expression of these genes.

Air pollution and antibodies against modified lipoproteins are associated with atherosclerosis and vascular remodeling in hyperlipemic mice

We analyzed the impact of chronic exposure to urban air pollution on the development of atherosclerosis. Hyperlipemic mice (LDLR(-/-)) were submitted to a high fat diet and air pollution for four months. We measured the susceptibility of LDL to oxidative modifications (TBARS), the presence of anti-oxLDL and an apoB-derived peptide (apoB-D) in blood and the degree of atherosclerosis in the aortic arch. Air pollution increased the susceptibility of LDL to oxidation as well as anti-oxLDL and anti-apo-B levels. These levels were even higher than in mice submitted to a high fat diet and non-polluted air. The lipid content of the atherosclerotic plaques in the aorta was increased in groups with a high cholesterol diet independently of the air quality. However, the thickness of the arterial wall was greater in mice fed a high lipid diet with polluted air. Thus, we conclude that urban air pollution exacerbates the susceptibility of LDL to oxidation, atherogenesis and vascular remodeling in hyperlipemic mice and that an immune response accompanies this process. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Prevention and reversion of nonalcoholic steatohepatitis in ob/ob mice by S-nitroso-N-acetylcysteine treatment

Objective: To evaluate the role oral administration of S-nitroso-N-acetylcysteine (SNAC), a NO donor drug, in the prevention and reversion of NASH in two different animal models. Methods: NASH was induced in male ob/ob mice by methionine-choline deficient (MCD) and high-fat (H) diets. Two animal groups received or not SNAC orally for four weeks since the beginning of the treatment. Two other groups were submitted to MCD and H diets for 60 days receiving SNAC only from the 31(st) to the 60(th) day. Results: SNAC administration inhibited the development of NASH in all groups, leading to a marked decrease in macro and microvacuolar steatosis and in hepatic lipid peroxidation in the MCD group. SNAC treatment reversed the development of NASH in animals treated for 60 days with MCD or H diets, which received SNAC only from the 31(st) to the 60(th) day. Conclusions: Oral administration of SNAC markedly inhibited and reversed NASH induced by MCD and H diets in ob/ob mice.

Impact of obesity on airway and lung parenchyma remodeling in experimental chronic allergic asthma

The impact of obesity on the inflammatory process has been described in asthma, however little is known about the influence of diet-induced obesity on lung remodeling. For this purpose, 56 recently weaned A/J mice were randomly divided into 2 groups. In the C group, mice were fed a standard chow diet, while OB animals received isocaloric high-fat diet to reach 1.5 of the mean body weight of C. After 12 weeks, each group was further randomized to be sensitized and challenged with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, collagen fiber content in airways and lung parenchyma, the volume proportion of smooth muscle-specific actin in alveolar ducts and terminal bronchiole, and the number of eosinophils in bronchoalveolar lavage fluid were higher in OB-OVA than C-OVA. In conclusion, diet-induced obesity enhanced lung remodeling resulting in higher airway responsiveness in the present experimental chronic allergic asthma. (C) 2011 Elsevier B.V. All rights reserved.

Repeated three-dimensional magnetic resonance imaging of atherosclerosis development in innominate arteries of low-density lipoprotein receptor-knockout mice

Background-In vivo methods to evaluate the size and composition of atherosclerotic lesions in animal models of atherosclerosis would assist in the testing of antiatherosclerotic drugs. We have developed an MRI method of detecting atherosclerotic plaque in the major vessels at the base of the heart in low-density lipoprotein (LDL) receptor-knockout (LDLR-/-) mice on a high-fat diet. Methods and Results-Three-dimensional fast spin-echo magnetic resonance images were acquired at 7 T by use of cardiac and respiratory triggering, with approximate to140-mum isotropic resolution, over 30 minutes. Comparison of normal and fat-suppressed images from female LDLR-/- mice I week before and 8 and 12 weeks after the transfer to a high-fat diet allowed visualization and quantification of plaque development in the innominate artery in vivo. Plaque mean cross-sectional area was significantly greater at week 12 in the LDLR-/- mice (0.14+/-0.086 mm(2) [mean+/-SD]) than in wild-type control mice on a normal diet (0.017+/-0.031 mm(2), p

Increased expression of the SNARE accessory protein Munc18c in lipid-mediated insulin resistance

Fatty acids inhibit insulin-mediated glucose metabolism in skeletal muscle, an effect largely attributed to defects in insulin-mediated glucose transport. Insulin-resistant mice transgenic for the overexpression of lipoprotein lipase (LPL) in skeletal muscle were used to examine the molecular mechanism(s) in more detail. Using DNA gene chip array technology, and confirmation by RT-PCR and Western analysis, increases in the yeast Sec1p homolog Munc18c mRNA and protein were found in the gastrocnemius muscle of transgenic mice, but not other tissues. Munc18c has been previously demonstrated to impair insulin-mediated glucose transport in mammalian cells in vitro. Of interest, stably transfected C2C12 cells overexpressing LPL not only demonstrated increases in Munc18c mRNA and protein but also in transcription rates of the Munc18c gene. jlr To confirm the relevance of fatty acid metabolism and insulin resistance to the expression of Munc18c in vivo, a 2-fold increase in Munc18c protein was demonstrated in mice fed a high-fat diet for 4 weeks. Together, these data are the first to implicate in vivo increases in Munc18c as a potential contributing mechanism to fatty acid-induced insulin resistance.

Efeito da jabuticaba (Myrciaria caulifora), do fruto da palmeira juçara (Euterpe edulis Martius) e do jambolão (Syzugium cumini) sobre o perfil lipídico, a glicemia e a endotoxemia em camundongos submetidos à dieta de cafeteria

O excesso de gordura corporal induz a um quadro inflamatório associado à endotoxemia metabólica e aumento da resistência à insulina, bem como altera o perfil lipídico que resulta em prejuízos a função hepática e renal. Estudos sugerem que a ingestão de alimentos antioxidantes, como os polifenóis, proporcionam efeitos benéficos sobre os metabolismos glicídico e lipídico. O objetivo deste estudo foi investigar o efeito da casca de jabuticaba (Myrciaria cauliflora), da polpa do açaí juçara (Euterpe edulis Martius) e do jambolão (Syzygium cumini) sobre o perfil lipídico, a glicemia e a endotoxemia em camundongos Swiss submetidos à dieta de cafeteria. Inicialmente, os frutos foram liofilizados e submetidos à avaliação da composição centesimal. O ensaio biológico contou com 50 camundongos machos adultos da raça Swiss distribuídos em 5 grupos (n=10/grupo), a saber: grupo tratado com dieta comercial padrão (controle negativo), grupo tratado com dieta de cafeteria (controle positivo) e grupos teste que receberam por 14 semanas a dieta de cafeteria suplementada com 2% de casca de jabuticaba, ou polpa do jambolão ou polpa do açaí juçara liofilizados. Na 13ª e 14ª semana foram determinadas a tolerância à insulina e à glicose dos animais. Ao final do período experimental, avaliaram-se o ganho de peso, os parâmetros bioquímicos sanguíneos, histopatológicos e endotoxemia. Os parâmetros bioquímicos avaliados foram: colesterol total (CT) e as frações HDL-c, LDL-c, triacilgliceróis (TAG), bem como proteína C reativa (PCR), aspartato aminotransferase (AST) e alanina aminotransferase (ALT). Na histopatologia foram avaliados os efeitos da dieta hipercalórica sobre a área dos adipócitos, esteatose hepática e função renal a partir do número e área dos glomérulos. A endotoxemia foi avaliada pela concentração de lipopolissacarídeos (LPS) no soro dos animais. Aplicou-se o teste t para comparação dos resultados entre os grupos controle e ANOVA, complementada com teste de Tukey (α=5%), para comparação dos grupos suplementados com os frutos e o controle positivo. A suplementação com 2% de jambolão à dieta de cafeteria resultou em redução significativa (p<0,05) do conteúdo de CT, LDL-c, TAG, da razão CT/HDL, bem como diminuição da área dos adipócitos dos animais tratados com os frutos. A suplementação com açaí juçara também foi capaz de reduzir o conteúdo de CT, TAG e a área dos adipócitos, além de elevar a tolerância à glicose. Por outro lado, a jabuticaba não foi eficaz na melhoria dos parâmetros relacionados ao metabolismo lipídico, ao metabolismo da glicose e dos aspectos histopatológicos. A suplementação com 2% dos frutos liofilizados não promoveu efeitos positivos na redução do ganho de peso, resistência à insulina e endotoxemia provocada pela ingestão da dieta de cafeteria. Além disso, os frutos também não foram eficientes na preservação da histologia renal e infiltração lipídica no fígado. Conclui-se que a inclusão do jambolão e do açaí juçara na dieta pode apresentar efeitos positivos sobre danos causados por dietas hiperlipídicas, especialmente no que se refere à dislipidemia, à tolerância à glicose e à hipertrofia dos adipócitos.