Insulin sensitivity as a predictor of longitudinal changes on body mass index in Brazilian adolescents.

OBJECTIVES: We aimed to investigate the effect of insulin sensitivity and insulin resistance status at baseline on longitudinal body mass index, and the possible effect modification by sex. METHODS: This is a secondary analysis of a randomized intervention community trial, in which a subgroup of 84 adolescents, aged between 10 and 12 years, were analyzed. Body weight, height, and body mass index (BMI) were determined before and after 8 months of follow-up. Glucose and serum insulin were examined at baseline and IR was defined based on the homeostasis model assessment-insulin resistance (HOMA-IR), with a cutoff >2.5 for both genders. Linear mixed-effects models were performed to evaluate the influence of HOMA-IR at baseline on BMI changes over time. Models were adjusted for age, pubertal stage, and stratified by sex. RESULTS: The sample comprised 65.4% of girls and the prevalence of overweight/obesity was 54.7% among girls and 50.0% among boys. The overall prevalence of IR was 75.3%, of which 60.7% for boys and 83.0% for girls. We found an interaction effect by sex (p = .004) for HOMA-IR as a continuous variable, with a decreased BMI rate of change among boys (ß = -0.13; p = .03) but not for girls (ß = +0.03; p = .36). Longitudinal BMI changes considering IR status at baseline (IR vs. non-IR) did not demonstrate any statistically significant difference for both boys (-0.1 vs. +0.4; p = .28) and girls (+0.7 vs. +1.0; p = .44). CONCLUSION: Increased HOMA-IR values at baseline were associated with greater BMI reduction over time among boys but not girls, with no influence of IR status.

Insulin-like growth factor-1 short-period therapy stimulates bone marrow cells in obese swiss mice.

Bone marrow cells (BMCs) from obese Swiss mice fed with Western diet show mitochondrial dysfunction. Obesity interferes with BMCs disrupting energetic metabolism, stimulating apoptosis, and reducing cell proliferation since adipose tissue releases inflammatory adipokines into the medullar microenvironment. These changes lead to reduction of BMC differentiation capacity and hematopoiesis impairment, a process responsible for blood cell continuous production through hematopoietic stem cells (HSCs). This work aimed to analyze the effects of IGF-1 therapy on BMC viability in Western diet-induced obesity, in vivo. We observed that after only 1 week of treatment, obese Swiss mice presented reduced body weight and visceral fat and increased mitochondrial oxidative capacity and coupling, indicating mitochondrial function improvement. In addition, IGF-1 was able to reduce apoptosis of total BMCs, stem cell subpopulations (hematopoietic and mesenchymal), and leukocytes, restoring all progenitor hematopoietic lineages. The treatment also contributed to increase proliferative capacity of hematopoietic stem cells and leukocytes, keeping the hematopoietic and immune systems balanced. Therefore, we conclude that IGF-1 short period therapy improved BMC survival, proliferation, and differentiation capacity in obese Swiss mice.

Vitis vinifera L. Grape Skin Extract Prevents Development of Hypertension and Altered Lipid Profile in Spontaneously Hypertensive Rats: Role of Oxidative Stress.

This study investigated the protective effect of a Vitis vinifera L. grape skin extract (ACH09) on blood pressure, lipid profile, and oxidative status in spontaneously hypertensive rats (SHR). Systolic blood pressure (SBP), total cholesterol, triglyceride, and glucose levels, as well as oxidative damage and antioxidant activity in the plasma and kidney, were evaluated in four experimental groups: control Wistar rats (W-C) and SHR-C that received water, and Wistar rats and SHR treated with ACH09 (200 mg/kg/d) in drinking water for 12 weeks (W-ACH09 and SHR-ACH09, respectively). SBP increased in the SHR group compared with the W groups and the treatment with ACH09 prevented the development of hypertension. Plasma triglyceride and total cholesterol levels increased in SHR compared with W-C rats; these changes prevented by treatment with ACH09. Glucose levels did not differ between the groups. The SHR group had increased oxidative damage in plasma, as expressed by 2-thiobarbituric acid reactive substances (TBARS) levels, and this prevented by ACH09. Levels of TBARS in the kidneys were lower in the SHR-ACH09 group than in the SHR-C group. Further, ACH09 increased the superoxide dismutase activity in both the plasma and kidneys of both SHR and Wistar rats. These results suggest that ACH09 is protective against disruption of blood pressures, oxidant status, and lipid profile in SHR, and provide important evidence on the benefits of ACH09 on hypertension and associated cardiovascular complications.

Insulin-like growth factor-1 short-period therapy improves cardiomyopathy stimulating cardiac progenitor cells survival in obese mice.

BACKGROUND AND AIMS: Cardiovascular diseases are the main cause of mortality in obesity. Despite advanced understanding, the mechanisms that regulate cardiac progenitor cells (CPC) survival in pathological conditions are not clear. Low IGF-1 plasma levels are correlated to obesity, cardiomyopathy and CPC death, so this work aimed to investigate IGF-1 therapeutic potential on cardiomyopathy and its relationship with the survival, proliferation and differentiation of CPC in Western diet-induced obesity. METHODS AND RESULTS: Male Swiss mice were divided into control group (CG, n = 8), fed with standard diet; and obese group (OG, n = 16), fed with Western diet, for 12 weeks. At 11th week, OG was subdivided to receive a daily subcutaneous injection of human recombinant IGF-1 (100 µg.Kg-1) for seven consecutive days (OG + IGF1, n = 8). Results showed that IGF-1 therapy improved the metabolic parameters negatively impacted by western diet in OG, reaching levels similar to CG. OG + IGF-1 also demonstrated restored heart energetic metabolism, fibrosis resolution, decreased apoptosis level, restored cardiac gap junctions and intracellular calcium balance. Cardiomyopathy improvement was accompanied by increased CPC survival, proliferation and newly cardiomyocytes formation related to increased pAkt/Akt ratio. CONCLUSION: These results suggest that only one week of IGF-1 therapy has cardioprotective effects through Akt pathway upregulation, ensuring CPC survival and differentiation, contributing to heart failure rescue.

Capybara Oil Improves Hepatic Mitochondrial Dysfunction, Steatosis, and Inflammation in a Murine Model of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of liver dysfunction worldwide and is commonly associated with obesity. Evidences suggest that NAFLD might be a mitochondrial disease, which contributes to the hepatic steatosis, oxidative stress, cytokine release, and cell death. Capybara oil (CO) is a rich source of polyunsaturated fatty acids (PUFA), which is known to improve inflammation and oxidative stress. In order to determine the effects of CO on NAFLD, C57Bl/6 mice were divided into 3 groups and fed a high-fat diet (HFD) (NAFLD group and NAFLD + CO group) or a control diet (CG group) during 16 weeks. The CO (1.5 g/kg/daily) was administered by gavage during the last 4 weeks of the diet protocol. We evaluated plasma liver enzymes, hepatic steatosis, and cytokine expression in liver as well as hepatocyte ultrastructural morphology and mitochondrial function. CO treatment suppressed hepatic steatosis, attenuated inflammatory response, and decreased plasma alanine aminotransferase (ALT) in mice with NAFLD. CO was also capable of restoring mitochondrial ultrastructure and function as well as balance superoxide dismutase and catalase levels. Our findings indicate that CO treatment has positive effects on NAFLD improving mitochondrial dysfunction, steatosis, acute inflammation, and oxidative stress.

Effect of physical exercise on spontaneous physical activity energy expenditure and energy intake in overweight adults (the EFECT study): a study protocol for a randomized controlled trial.

BACKGROUND: Physical exercise interventions have been extensively advocated for the treatment of obesity; however, clinical trials evaluating the effectiveness of exercise interventions on weight control show controversial results. Compensatory mechanisms through a decrease in energy expenditure and/or an increase in caloric consumption is a possible explanation. Several physiological mechanisms involved in the energy balance could explain compensatory mechanisms, but the influences of physical exercise on these adjustments are still unclear. Therefore, the present trial aims to evaluate the effects of exercise on non-exercise physical activity energy expenditure, energy intake and appetite sensations among active overweight/obese adults, as well as, to investigate hormonal changes associated with physical exercise. METHODS: This study is a randomized controlled trial with parallel, three-group experimental arms. Eighty-one overweight/obese adults will be randomly allocated (1:1:1 ratio) to a vigorous exercise group, moderate exercise group or control group. The trial will be conducted at a military institution and the intervention groups will be submitted to exercise sessions in the evening, three times a week for 65 min, during a 2-week period. The primary outcome will be total spontaneous physical activity energy expenditure during a 2-week period. Secondary outcomes will be caloric intake, appetite sensations and laboratorial biomarkers. Intention-to-treat analysis will be performed using linear mixed-effects models to evaluate the effect of treatment-by-time interaction on primary and secondary outcomes. Data analysis will be performed using SAS 9.3 and statistical significance will be set at p < 0.05. DISCUSSION: The results of the present study will help to understand the effect of physical exercise training on subsequent non-exercise physical activity, appetite and energy intake as well as understand the physiological mechanisms underlying a possible compensatory phenomenon, supporting the development of more effective interventions for prevention and treatment of obesity. TRIAL REGISTRATION: Physical Exercise and Energy Balance trial registry, trial registration number: NCT 03138187 . Registered on 30 April 2017.

Discouraging soft drink consumption reduces blood glucose and cholesterol of Brazilian elementary students: Secondary analysis of a randomized controlled trial.

The objective of this study was to evaluate the effect of an educational program aimed at discouraging sugar-sweetened carbonated beverages intake on blood fasting glucose and total cholesterol. Forty-seven fourth grade classes in twenty-two schools have participated in a randomized controlled trial aimed at discouraging soft drink intake in order to prevent excessive weight gain during a school year, in the city of Niterói, Rio de Janeiro. Of 1140 randomized students, 478 (238 in intervention group and 240 in control group) aged 9-12years old had at least one result on biochemical data and were analyzed to evaluate the effect of the intervention on changes in fasting glucose and total cholesterol at the end of follow-up. Intention-to-treat analysis was performed taking into account the cluster (classes) effect. Statistically significant decrease in fasting glucose (-9.12mg/dL vs. +0.51mg/dL, p<0.001) and total cholesterol (-10.34mg/dL vs. +2.14mg/dL, p<0.001) were observed among students in the intervention group in comparison with controls. In addition, the prevalence of impaired fasting glucose and hypercholesterolemia decreased in interventions and increased in controls (-2.4% vs. +8.8%, p=0.04 and -10.0% vs. +2.7%, p=0.03, respectively). Discouraging soft drink consumption among children has led to a reduction in fasting glucose and total cholesterol, suggesting that these beverages may play a role in the development of cardiometabolic risk in childhood.

Overnutrition during lactation leads to impairment in insulin signaling, up-regulation of GLUT1 and increased mitochondrial carbohydrate oxidation in heart of weaned mice.

Several studies have demonstrated that overnutrition during early postnatal period can increase the long-term risk of developing obesity and cardiac disorders, yet the short-term effects of postnatal overfeeding in cardiac metabolism remains unknown. The aim of our study was to investigate the cardiac metabolism of weaned mice submitted to overnutrition during lactation, particularly as to mitochondrial function, substrate preference and insulin signaling. Postnatal overfeeding was induced by litter size reduction in mice at postnatal day 3. At 21 days of age (weaning), mice in the overfed group (OG) presented biometric and biochemical parameters of obesity, including increased body weight, visceral fat, liver weight and increased left ventricle weight/tibia length ratio; indicating cardiac hypertrophy, hyperglycemia, hyperinsulinemia and increased liver glycogen content compared to control group. In the heart, we detected impaired insulin signaling, mainly due to decreased IRß, pTyr-IRS1, PI3K, GLUT4 and pAkt/Akt and increased PTP1B, GLUT1 and pAMPKα/AMPKα content. Activities of lactate dehydrogenase and citrate synthase were increased, accompanied by enhanced carbohydrate oxidation, as observed by high-resolution respirometry. Moreover, OG hearts had lower CPT1, PPARα and increased UCP2 mRNA expression, associated with increased oxidative stress (4-HNE content), BAX/BCL2 ratio and cardiac fibrosis. Ultrastructural analysis of OG hearts demonstrated mild mitochondrial damage without alterations in OXPHOS complexes. In conclusion, overnutrition during early life induces short-term metabolic disturbances, impairment in heart insulin signaling, up-regulates GLUT-1 and switch cardiac fuel preference in juvenile mice.

Effect of remote ischemic preconditioning in the expression of IL-6 and IL-10 in a rat model of liver ischemia-reperfusion injury.

PURPOSE: To study the effect of remote ischemic preconditioning (RIPC) in ischemia-reperfusion (I/R) liver injury and in the expression of IL-6 and IL-10 in a rat model. METHODS: Thirty-six male rats were divided in three groups: Sham; I/R injury, a 45 minutes lobar liver ischemia and reperfusion; and RIPC, six cycles of four minutes of ischemia and four minutes of reperfusion on the right hindlimb followed by a 45 minutes lobar liver ischemia and reperfusion. Tissue and blood samples were collected after 1h and 3h of reperfusion for histopathological study, plasma cytokines and alanine aminotransferase (ALT) measurement. RESULTS: The histopathological study demonstrated a significant reduction in liver necrosis in the RIPC group (p<0,001). The ALT levels were also significant lower in the RIPC group (p<0.01). The cytokines assessment showed that IL-6 levels were increased in the RIPC group after 1h of reperfusion, in comparison to the I/R group (p<0.05). Interleukin-10 levels in RIPC groups did not differ significantly from I/R group. CONCLUSIONS: Remote ischemic preconditioning is effective in decreasing liver necrosis in a rat model of ischemia-reperfusion. The IL-6 expression is up-regulated and peaked at 60 min of reperfusion. There was no difference in IL-10 expression between the groups.

Effect of remote ischemic preconditioning in the expression of IL-6 and IL-10 in a rat model of liver ischemia-reperfusion injury

PURPOSE: To study the effect of remote ischemic preconditioning (RIPC) in ischemia-reperfusion (I/R) liver injury and in the expression of IL-6 and IL-10 in a rat model. METHODS: Thirty-six male rats were divided in three groups: Sham; I/R injury, a 45 minutes lobar liver ischemia and reperfusion; and RIPC, six cycles of four minutes of ischemia and four minutes of reperfusion on the right hindlimb followed by a 45 minutes lobar liver ischemia and reperfusion. Tissue and blood samples were collected after 1h and 3h of reperfusion for histopathological study, plasma cytokines and alanine aminotransferase (ALT) measurement. RESULTS: The histopathological study demonstrated a significant reduction in liver necrosis in the RIPC group (p<0,001). The ALT levels were also significant lower in the RIPC group (p<0.01). The cytokines assessment showed that IL-6 levels were increased in the RIPC group after 1h of reperfusion, in comparison to the I/R group (p<0.05). Interleukin-10 levels in RIPC groups did not differ significantly from I/R group. CONCLUSIONS: Remote ischemic preconditioning is effective in decreasing liver necrosis in a rat model of ischemia-reperfusion. The IL-6 expression is up-regulated and peaked at 60 min of reperfusion. There was no difference in IL-10 expression between the groups. .

Bone marrow mononuclear cell transplantation improves mitochondrial bioenergetics in the liver of cholestatic rats.

Mitochondrial dysfunction has been associated with liver cholestatis. Toxic bile salt accumulation leads to chronic injury with mitochondrial damage, ROS increase and apoptosis, resulting in liver dysfunction. This study aimed to analyze mitochondrial bioenergetics in rats with hepatic fibrosis induced by bile duct ligation (BDL) after BMMNC transplantation. Livers were collected from normal rats, fibrotic rats after 14 and 21 days of BDL (F14d and F21d) and rats that received BMMNC at 14 days of BDL, analyzed after 7 days. F21d demonstrated increased collagen I content and consequently decrease after BMMNC transplantation. Both F14d and F21d had significantly reduced mitochondrial oxidation capacity and increased mitochondrial uncoupling, which were restored to levels similar to those of normal group after BMMNC transplantation. In addition, F21d had a significantly increase of UCP2, and reduced PGC-1α content. However, after BMMNC transplantation both proteins returned to levels similar to normal group. Moreover, F14d had a significantly increase in 4-HNE content compared to normal group, but after BMMNC transplantation 4-HNE content significantly reduced, suggesting oxidative stress reduction. Therefore, BMMNC transplantation has a positive effect on hepatic mitochondrial bioenergetics of cholestatic rats, increasing oxidative capacity and reducing oxidative stress, which, in turn, contribute to liver function recover.

Impaired mitochondrial function and reduced viability in bone marrow cells of obese mice.

Bone marrow cells (BMCs) are the main type of cells used for transplantation therapies. Obesity, a major world health problem, has been demonstrated to affect various tissues, including bone marrow. This could compromise the success of such therapies. One of the main mechanisms underlying the pathogenesis of obesity is mitochondrial dysfunction, and recent data have suggested an important role for mitochondrial metabolism in the regulation of stem cell proliferation and differentiation. Since the potential use of BMCs for clinical therapies depends on their viability and capacity to proliferate and/or differentiate properly, the analysis of mitochondrial function and cell viability could be important approaches for evaluating BMC quality in the context of obesity. We therefore compared BMCs from a control group (CG) and an obese group (OG) of mice and evaluated their mitochondrial function, proliferation capacity, apoptosis, and levels of proteins involved in energy metabolism. BMCs from OG had increased apoptosis and decreased proliferation rates compared with CG. Mitochondrial respiratory capacity, biogenesis, and the coupling between oxidative phosphorylation and ATP synthesis were significantly decreased in OG compared with CG, in correlation with increased levels of uncoupling protein 2 and reduced peroxisome proliferator-activated receptor-coactivator 1α content. OG also had decreased amounts of the glucose transporter GLUT-1 and insulin receptor (IRß). Thus, Western-diet-induced obesity leads to mitochondrial dysfunction and reduced proliferative capacity in BMCs, changes that, in turn, might compromise the success of therapies utilizing these cells.

Heart energy metabolism impairment in Western-diet induced obese mice.

Nutritional transition has contributed to growing obesity, mainly by changing eating habits of the population. The mechanisms by which diet-induced obesity leads to cardiac injury are not completely understood, but it is known that obesity is associated to impaired cardiac function and energy metabolism, increasing morbidity and mortality. Therefore, our study aimed to investigate the mechanisms underlying cardiac metabolism impairment related to Western diet-induced obesity. After weaning, male Swiss mice were fed a Western diet for 16 weeks in order to induce obesity. After this period, the content of proteins involved in heart energy metabolism GLUT1, cytosolic lysate and plasma membrane GLUT4, AMPK, pAMPK, IRß, IRS-1, PGC-1α, CPT1 and UCP2 was evaluated. Also, the oxidative phosphorylation of myocardial fibers was measured by high-resolution respirometry. Mice in the Western diet group (WG) presented altered biometric parameters compared to those in control group, including higher body weight, increased myocardial lipid deposition and glucose intolerance, which demonstrate the obesogenic role of Western diet. WG presented increased CPT1 and UCP2 contents and decreased IRS-1, plasma membrane GLUT4 and PGC-1α contents. In addition, WG presented cardiac mitochondrial dysfunction and reduced biogenesis, demonstrating a lower capacity of carbohydrates and fatty acid oxidation and also decreased coupling between oxidative phosphorylation and adenosine triphosphate synthesis. Cardiac metabolism impairment related to Western diet-induced obesity is probably due to damaged myocardial oxidative capacity, reduced mitochondrial biogenesis and mitochondria uncoupling, which compromise the bioenergetic metabolism of heart.

Changes in body weight, C-reactive protein, and total adiponectin in non-obese women after 12 months of a small-volume, home-based exercise program.

OBJECTIVE: Our objective was to evaluate the effects of small-volume, home-based exercise combined with slight caloric restriction on the inflammatory markers C-reactive protein and adiponectin. METHODS: In total, 54 women were randomly assigned to one of two groups for exercise intervention: the control or home-based exercise groups. Weight, waist and hip circumferences, and inflammatory markers were measured at baseline and after 6 and 12 months. Women allocated to the home-based exercise group received a booklet explaining the physical exercises to be practiced at home at least 3 times per week, 40 minutes per session, at low-to-moderate intensity. All participants received dietary counseling aimed at reducing caloric intake by 100-300 calories per day, with a normal distribution of macro-nutrients (26-28% of energy as fat). Clinicaltrials.gov: NCT01206413 RESULTS: The home-based exercise group showed a significantly greater reduction in weight and body mass index at six months, but no difference between groups was observed thereafter. With regard to the inflammatory markers, a greater but non-statistically significant reduction was found for C-reactive protein in the home-based exercise group at six months; however, this difference disappeared after adjusting for weight change. No differences in adiponectin were found at the 6- or 12-month follow-up. CONCLUSION: Small-volume, home-based exercise did not promote changes in inflammatory markers independent of weight change.

Ghrelin and leptin modulate the feeding behaviour of the hawksbill turtle Eretmochelys imbricata during nesting season.

Female sea turtles have rarely been observed foraging during the nesting season. This suggests that prior to their migration to nesting beaches the females must store sufficient energy and nutrients at their foraging grounds and must be physiologically capable of undergoing months without feeding. Leptin (an appetite-suppressing protein) and ghrelin (a hunger-stimulating peptide) affect body weight by influencing energy intake in all vertebrates. We investigated the levels of these hormones and other physiological and nutritional parameters in nesting hawksbill sea turtles in Rio Grande do Norte State, Brazil, by collecting consecutive blood samples from 41 turtles during the 2010-2011 and 2011-2012 reproductive seasons. We found that levels of serum leptin decreased over the nesting season, which potentially relaxed suppression of food intake and stimulated females to begin foraging either during or after the post-nesting migration. Concurrently, we recorded an increasing trend in ghrelin, which may have stimulated food intake towards the end of the nesting season. Both findings are consistent with the prediction that post-nesting females will begin to forage, either during or immediately after their post-nesting migration. We observed no seasonal trend for other physiological parameters (values of packed cell volume and serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, low-density lipoprotein, and high-density lipoprotein). The observed downward trends in general serum biochemistry levels were probably due to the physiological challenge of vitellogenesis and nesting in addition to limited energy resources and probable fasting.

Changes in body weight, C-reactive protein, and total adiponectin in non-obese women after 12 months of a small-volume, home-based exercise program

OBJECTIVE: Our objective was to evaluate the effects of small-volume, home-based exercise combined with slight caloric restriction on the inflammatory markers C-reactive protein and adiponectin. METHODS: In total, 54 women were randomly assigned to one of two groups for exercise intervention: the control or home-based exercise groups. Weight, waist and hip circumferences, and inflammatory markers were measured at baseline and after 6 and 12 months. Women allocated to the home-based exercise group received a booklet explaining the physical exercises to be practiced at home at least 3 times per week, 40 minutes per session, at low-to-moderate intensity. All participants received dietary counseling aimed at reducing caloric intake by 100-300 calories per day, with a normal distribution of macro-nutrients (26-28% of energy as fat). Clinicaltrials.gov: NCT01206413 RESULTS: The home-based exercise group showed a significantly greater reduction in weight and body mass index at six months, but no difference between groups was observed thereafter. With regard to the inflammatory markers, a greater but non-statistically significant reduction was found for C-reactive protein in the home-based exercise group at six months; however, this difference disappeared after adjusting for weight change. No differences in adiponectin were found at the 6- or 12-month follow-up. CONCLUSION: Small-volume, home-based exercise did not promote changes in inflammatory markers independent of weight change. .

Lymphocytes mitochondrial physiology as biomarker of energy metabolism during fasted and fed conditions.

Mitochondria are central coordinators of energy metabolism, and changes of their physiology have long been associated with metabolic disorders. Thus, observations of energy dynamics in different cell types are of utmost importance. Therefore, tools with quick and easy handling are needed for consistent evaluations of such interventions. In this paper, our main hypothesis is that during different nutritional situations lymphocytes mitochondrial physiology could be associated with the metabolism of other cell types, such as cardiomyocytes, and consequently be used as metabolic biomarker. Blood lymphocytes and heart muscle fibers were obtained from both fed and 24 h-fasted mice, and mitochondrial analysis was assessed by high-resolution respirometry and western blotting. Carbohydrate-linked oxidation and fatty acid oxidation were significantly higher after fasting. Carnitine palmitoil transferase 1 and uncouple protein 2 contents were increased in the fasted group, while the glucose transporters 1 and 4 and the ratio phosphorylated AMP-activated protein kinase/AMPK did not change between groups. In summary, under a nutritional status modification, mitochondria demonstrated earlier adaptive capacity than other metabolic sensors such as glucose transporters and AMPK, suggesting the accuracy of mitochondria physiology of lymphocytes as biomarker for metabolic changes.

Ghrelin signaling in heart remodeling of adult obese mice.

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), has been suggested to be associated to obesity, insulin secretion, cardiovascular growth and homeostasis. GHS-R has been found in most of the tissues, and among the hormone action it is included the regulation of heart energy metabolism. Therefore, hypernutrition during early life leads to obesity, induces cardiac hypertrophy, compromises myocardial function, inducing heart failure in adulthood. We examined ghrelin signaling process in cardiac remodeling in these obese adult mice. The cardiomyocytes (cmy) of left ventricle were analyzed by light microscopy and stereology, content and phosphorilation of cardiac proteins: ghrelin receptor (growth hormone secretagogue receptor 1a, GHSR-1a), protein kinase B (AKT and pAKT), phosphatidil inositol 3 kinase (PI3K), AMP-activated protein kinase (AMPK and pAMPK) and actin were achieved by Western blotting. GHSR-1a gene expression was analyzed by Real Time-PCR. We observed hyperglycemia and higher liver and visceral fat weight in obese when compared to control group. Obese mice presented a marked increase in heart weight/tibia length, indicating an enlarged heart size or a remodeling process. Obese mice had increased GHSR-1a content and expression in the heart associated to PI3K content and increased AKT content and phosphorylation. In contrast, AMPK content and phosphorylation in heart was not different between experimental groups. Ghrelin plasma levels in obese group were decreased when compared to control group. Our data suggest that remodeled myocardial in adult obese mice overnourished in early life are associated with higher phosphorylation of GHSR-1a, PI3K and AKT but not with AMPK.

Vitis vinifera L. grape skin extract activates the insulin-signalling cascade and reduces hyperglycaemia in alloxan-induced diabetic mice.

OBJECTIVES: This study examined the effect of Vitis vinifera grape skin extract (ACH09) on hyperglycaemia and the insulin-signalling cascade in alloxan-treated mice. METHODS: Glycaemia, serum insulin and Western blot analysis of insulin cascade proteins were evaluated in the gastrocnemius muscles of four groups of adult mice: control, ACH09 (200 mg/kg per day, p.o.), alloxan (300 mg/kg, i.p.) and alloxan + ACH09. Insulin secretion in isolated pancreatic islets was also studied. KEY FINDINGS: Glycaemia values in the alloxan + ACH09 and ACH09 groups were significantly lower than in the alloxan-treated and control groups, respectively. Increased insulin resistance (HOMA index) was observed in the alloxan-treated group but not in the alloxan + ACH09 group. Insulin receptor content and Akt phosphorylation were significantly greater in the alloxan + ACH09 group compared with the alloxan-treated group. The glucose transporter (GLUT-4) content was reduced in alloxan-treated mice compared with the control group, while alloxan + ACH09 and ACH09-treated mice showed a significant increase in GLUT-4 content. ACH09 treatment did not change glucose-induced insulin secretion in isolated pancreatic islets. CONCLUSIONS: The results suggest that ACH09 has hypoglycaemic and antihyperglycaemic effects that are independent of an increase in insulin release but are probably dependent on an increase in insulin sensitivity resulting from an activation of the insulin-signalling cascade in skeletal muscle.

Early life overfeeding decreases acylated ghrelin circulating levels and upregulates GHSR1a signaling pathway in white adipose tissue of obese young mice.

Ghrelin is a hormone synthesized by the stomach that acts in different tissues via a specific receptor (GHS-R1a), including hypothalamus and adipose tissue. For instance, recent reports have shown that ghrelin has a direct action on hypothalamic regulation of food intake mainly inducing an orexigenic effect. On the other hand, ghrelin also modulates energy stores and expenditure in the adipocytes. This dual action has suggested that this hormone may act as a link between the central nervous system and peripheral mechanisms. Furthermore, concerning nutritional disorders, it has been suggested that obesity may be considered an impairment of the above cited link. Therefore, considering that neonatal overfeeding induces obesity in adulthood by unknown mechanisms, in this study we examined the effects of early life overnutrition on the development of obesity and in particular on adipose tissue ghrelin signaling in young mice. Our data demonstrated that overnutrition during early life induces a significant increase in body weight of young mice, starting at 10 days, and this increase in weight persisted until adulthood (90 days of age). In these animals, blood glucose, liver weight and visceral fat weight were found higher at 21 days when compared to the control group. Acylated ghrelin circulating levels were found lower in the young obese pups. In addition, in white adipose tissue ghrelin receptor (GHS-R1a) expression increased and was associated to positive modulation of content and phosphorylation of proteins involved in cell energy store and use as AKT, PI3K, AMPK, GLUT-4, and CPT1. However, PPARγ content decreased in obese group. Basically, we showed that adipose tissue metabolism is altered in early life acquired obesity and probably due to such modification a new pattern of ghrelin signaling pathway takes place.