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To verify whether the treatment with linagliptin induces the browning of the subcutaneous WAT (sWAT) and thermogenesis in murine diet-induced obesity (DIO) model. Forty animals were randomly assigned to receive a control diet (C, 10% lipids as energy) or a high-fat diet (HF, 50% lipids as energy) for 10 weeks. Each group was re-divided to begin the 5-week treatment, totalizing four experimental groups: C, C-L (C plus linagliptin, 30 mg/kg body mass; BM), HF, and HF-L (HF plus linagliptin, 30 mg/kg BM). The drug was mixed with diet. HF animals showed overweight, glucose intolerance, and a greater cross-sectional area of adipocytes. The treatment with linagliptin was able to normalize the BM, restore the glucose tolerance and the cross-sectional area of adipocytes. These observations comply with the observation of UCP1-positive multilocular adipocytes in the sWAT of treated animals. Both treated groups (C-L and HF-L) showed high expression of thermogenic and type 2 cytokines genes, which agree with the enhanced body temperature and the lower respiratory exchange ratio, implying enhanced thermogenesis with the use of lipids as fuel. The reduced BM, the enhanced body temperature, and the presence of positive UCP1 beige cells in the sWAT point to the activation of the browning cascade on the sWAT of linagliptin-treated mice, and hence, linagliptin could induce the thermogenic pathway as a pleiotropic effect that can have translational potential.

Fructose dietary intake affects the composition of the intestinal microbiota and influences the development of hepatic steatosis. Endotoxins produced by gram-negative bacteria alter intestinal permeability and cause bacterial translocation. This study evaluated the effects of gut microbiota modulation by a purified PPAR-alpha agonist (WY14643), a DPP-4 inhibitor (linagliptin), or their association on intestinal barrier integrity, endotoxemia, and hepatic energy metabolism in high-fructose-fed C57BL/6 mice. Fifty mice were divided to receive the control diet (C group) or the high-fructose diet (HFRU) for 12 weeks. Subsequently, the HFRU group was divided to initiate the treatment with PPAR-alpha agonist (3.5 mg/kg/BM) and DPP-4 inhibitor (15 mg/kg/BM). The HFRU group had glucose intolerance, endotoxemia, and dysbiosis (with increased Proteobacteria) without changes in body mass in comparison with the C group. HFRU group showed damaged intestinal ultrastructure, which led to liver inflammation and marked hepatic steatosis in the HFRU group when compared to the C group. PPAR-alpha activation and DPP-4 inhibition countered glucose intolerance, endotoxemia, and dysbiosis, ameliorating the ultrastructure of the intestinal barrier and reducing Tlr4 expression in the liver of treated animals. These beneficial effects suppressed lipogenesis and mitigated hepatic steatosis. In conclusion, the results herein propose a role for PPAR-alpha activation, DPP-4 inhibition, and their association in attenuating hepatic steatosis by gut-liver axis modulation in high-fructose mice model. These observations suggest these treatments as potential targets to treat hepatic steatosis and avoid its progression.

The study aimed to evaluate the consequences of the consumption of a high-fructose diet (HFR; fructose was responsible for 45% of the energy from carbohydrates) by the mother, the father, or both on C57BL/6 adult male offspring. Non-consanguineous parents received the diet (HFR or control, C) from 8 weeks before mating until weaning (n=10 fathers and n=10 mothers on each diet). After weaning, only the C diet was offered to offspring. The groups were formed by one male randomly taken from each litter. The offspring groups were identified according to the mother’s diet (the first letter), then the father’s diet (the second letter), that is, C/C, C/HFR, HFR/C, HFR/HFR (n=10 per group). The parents exhibited the following characteristics: compared with those of the C group, the HFR parents had higher blood pressure (BP), enlarged liver, increased hepatic triacylglycerol content, hypercholesterolemia, hypertriglyceridemia, high plasma leptin and low adiponectin. The offspring exhibited the following characteristics: compared with the C/C group, the HFR/HFR group had high BP. The C/HFR, HFR/C and HFR/HFR showed elevated uric acid and leptin levels and diminished adiponectin. The HFR/HFR group showed liver inflammation (increased NFκB, SOCS3, JNK, TNF-α, IL1-β and IL6 levels). Likewise, SREBP-1c and FAS were upregulated. In conclusion, the consumption of a HFR by the mother and/or father is associated with adverse effects on liver metabolism in adult male offspring. When both mother and father are fed a HFR, the adverse effects on the offspring are more severe.

The study was conducted to understand better the mechanisms involved in liver changes when there is a combination of diet-induced obesity (DIO) and vitamin D deficiency (VDD). After 8 wk of feeding a control diet (C group) or a high-fat diet (HF), both with vitamin D, and counterpart groups without vitamin D (VitD- groups), we found in plasma: higher alanine aminotransferase, and aspartate aminotransferase in the VitD- groups, and more elevated total cholesterol in the HF group. Compared to their counterparts, HF and HF/VitD- showed hyperinsulinemia and higher hepatic triglycerides and steatosis. The protein expressions of markers linked with the vitamin D action were altered by VDD (vitamin D receptor VDR, 25-hydroxyvitamin D-24-hydroxylase CYP24A1, CYP27B1, and CYP2R1). The hepatic lipogenesis and fatty acid synthesis were enhanced by VDD (peroxisome proliferator-activated receptor PPARγ, sterol regulatory element-binding proteins SREBP1c, carbohydrate-responsive element-binding protein ChREBP, and fatty acid synthase FAS), but markers of beta-oxidation were reduced (PPARα and phosphoenolpyruvate carboxykinase PEPCK). In conclusion, the study provides convincing new evidence that there is an additive and adverse effect on the liver caused by the combination of VDD and DIO. The essence of these changes in the liver is in an increased lipogenesis and a reduced beta-oxidation, which predisposes to the accumulation of fat in the liver, accompanied by IR. The worsening of the pathogenesis of NAFLD may tilt to more severe stages of liver disease.

The evaluation of the local Renin-Angiotensin-Aldosterone system (RAAS) gene expressions in the heart of ovariectomized (OVX) apolipoprotein E deficient mice (ApoE).Four-months old C57BL/6 female mice (wild-type, wt, n=20), and ApoE female mice (n=20), were submitted to OVX or a surgical procedure without ovary removal (SHAM) and formed four groups (n=10/group): SHAM/wt, SHAM/ApoE, OVX/wt, and OVX/ApoE.OVX led to greater body mass, plasma triglycerides (TG) and total cholesterol, and resulted in insulin resistance and altered RAAS gene expressions in the heart tissue. The gene expression of angiotensin-converting enzyme (ACE)-2 was lower in OVX/wt than in SHAM/wt (P=0.0004), Mas receptor (MASr) was lower in OVX/wt compared to SHAM/wt (P0.0001). Also, angiotensin II receptor type 1 (AT1r) was higher in OVX/wt than in SHAM/wt (P=0.0229), and AT2r was lower in OVX/wt than in SHAM/wt (P=0.0121). OVX and ApoE deficiency showed interaction potentializing the insulin resistance, increasing TG levels and altering ACE and MASr gene expressions. ACE gene expression was higher in OVX/ApoE than in OVX/wt (P0.0001), and MASr gene expression was lower in OVX/ApoE than in OVX/wt (P0.0001).The impact of OVX on local RAAS cascade in the heart of ApoE deficient animals, besides the metabolic changes culminating with insulin resistance, involves an upregulation of renin, ACE, and AT1r gene expressions. The findings may contribute to clarify the mechanisms of development of postmenopausal hypertension and the link between RAAS and apolipoprotein E.

Fructose-rich caloric sweeteners induce adverse changes in the metabolism of humans. The study evaluated the effects of high-intensity interval training (HIIT) on a fructose feeding model, focusing on the liver, white adipose tissue (WAT), skeletal muscle, and their interplay. Male C57BL/6 mice were fed for 18 wk one of the following diets: control (C; 5% of total energy from fructose) or fructose (F; 55% of total energy from fructose). In the 10th week, for an additional 8-wk period, the groups were divided into nontrained (NT) or HIIT groups, totaling four groups: C-NT, C-HIIT, F-NT, and F-HIIT. At the end of the experiment, fructose consumption in the F-NT group led to a high systolic blood pressure, high plasma triglycerides, insulin resistance with glucose intolerance, and lower insulin sensitivity. We also observed liver steatosis, adipocyte hypertrophy, and diminished gene expressions of peroxisome proliferator-activated receptor-γ coactivator 1-α and fibronectin type III domain containing 5 (FNDC5; irisin) in this F-NT group. These results were accompanied by decreased gene expressions of nuclear respiratory factor 1 and mitochondrial transcription factor A (markers of mitochondrial biogenesis), and peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase 1 (markers of β-oxidation). HIIT improved all of these data in the C-HIIT and F-HIIT groups. In conclusion, in mice fed a fructose diet, HIIT improved body mass, blood pressure, glucose metabolism, and plasma triglycerides. Liver, WAT, and skeletal muscle were positively modulated by HIIT, indicating HIIT as a coadjutant treatment for diseases affecting these tissues. NEW & NOTEWORTHY We investigated the effects of high-intensity interval training (HIIT) in mice fed a fructose-rich diet and the resulting severe negative effect on the liver, white adipose tissue (WAT), and skeletal muscle, which reduced the expression of fibronectin type III domain containing 5 (FNDC5, irisin) and PGC1α and, consequently, affected markers of mitochondrial biogenesis and β-oxidation. Because HIIT may block these adverse effects in all of these three tissues, it might be suggested that it functions as a coadjutant treatment in combatting the alterations caused by high-fructose intake.

The obesity and its comorbidities, including resistance to leptin, impacts the reproductive function. Testes express leptin receptors in the germ cells and Leydig cells. Then, leptin-deficient animals are obese and infertile. We aimed to evaluate the structure and steroidogenic pathway of the testis of deficient leptin mice. Three months old male C57BL/6 mice (wild-type, WT) and deficient leptin (ob/ob) mice had their testes dissected and prepared for analyses. Compared to the WT group, the ob/ob group showed a greater body mass with smaller testes, and alterations in the germinative epithelium: fewer spermatogonia, spermatocytes, and spermatids. The Sertoli cells and the germ cells showed condensed nuclei and nuclear fragmentation indicating cell death, in agreement with a low expression of the proliferating cell nuclear antigen and a high expression of Caspase3. In the ob/ob group, the sperm was absent in the seminiferous tubules, and the steroidogenic pathway was compromised (low 3Beta hydroxysteroid dehydrogenase and steroidogenic acute regulatory protein). Further, all hormone receptors involved in the testicular function were down expressed (androgen, estrogen, follicle-stimulating, luteinizing, aromatase, and nicotinamide adenine dinucleotide phosphate). In conclusion, the findings indicate significant morphological, hormonal and enzymatic changes in the testis of the ob/ob mice. The shifts in the enzymatic steroidogenic pathway and the enzymes related to spermatic activity support the insights about the failures in the fertility of these animals. The study provides new evidence and contributes to the understanding of how the lack of leptin and obesity might negatively modulate the testicular function leading to infertility.

Studies show that the continuous consumption of fructose can lead to nonalcoholic fatty liver disease (NAFLD) and steatohepatitis. We aimed to investigate the role of Metformin in an animal model of liver injury caused by fructose intake, focusing on the molecular markers of lipogenesis, beta-oxidation, and antioxidant defenses. Male three months old C57BL/6 mice were divided into control group (C) and fructose group (F, 47% fructose), maintained for ten weeks. After, the groups received Metformin or vehicle for a further eight weeks: control (C), control + Metformin (CM), fructose (F), and fructose + Metformin (FM). Fructose resulted in hepatic steatosis, insulin resistance and lower insulin sensitivity in association with higher mRNA levels of proteins linked with de novo lipogenesis and increased lipid peroxidation. Fructose diminished mRNA expression of antioxidant enzymes, and of proteins responsible for mitochondrial biogenesis. Metformin reduced de novo lipogenesis and increased the expression of proteins related to mitochondrial biogenesis, thereby increasing beta-oxidation and decreasing lipid peroxidation. Also, Metformin upregulated the expression and activity of antioxidant enzymes, providing a defense against increased reactive oxygen species generation. Therefore, a significant reduction in triglyceride accumulation in the liver, steatosis and lipid peroxidation was observed in the FM group. In conclusion, fructose increases de novo lipogenesis, reduces the antioxidant defenses, and diminishes mitochondrial biogenesis. After an extended period of fructose intake, Metformin treatment, even in continuing the fructose intake, can reverse, at least partially, the liver injury and prevents NAFLD progression to more severe states., Highlights • Fructose increases lipogenesis and lipid peroxidation, reduces the antioxidant defenses, and mitochondrial biogenesis. • Metformin mechanism of action remains partially understood and controversial. • Metformin can reverse the liver injury preventing the progression to more severe states.

Studies demonstrated the influence of mother’s obesity on offspring. However, the father is also related to programming the future generation. The study aimed to evaluate the effects of father’s obesity upon white adipose tissue (WAT) remodeling, resulting in activation of signaling pathways and inflammation in male and female offspring. Male C57BL/6 mice received control diet (lean father group; 17% energy from lipids) or high-fat diet (obese father group; 49% energy from lipids) for 8 weeks before mating. The mothers received control diet throughout the experiment. Mice were mated: lean mother and lean father, and lean mother and obese father. Offspring received control diet from weaning until 3 months of age when they were studied. In the offspring, father’s obesity led to decreased QUICKI with impairment of the insulin signaling pathway in both sexes. In line with these findings, in white adipose tissue, male offspring demonstrated hypertrophied adipocytes, enhanced proinflammatory cytokines, overactivation of components of the local renin–angiotensin system (RAS) and extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of peroxisome proliferator-activated receptors (alpha and gamma). We observed that father’s obesity influences the offspring in adult life, with an impairment in insulin homeostasis, adipocyte remodeling, and adipose tissue overexpression of IL-6 and TNF-alpha in male offspring. The activation of local RAS and ERK1/2, a concomitant PPAR diminishing, and impairment in phosphorylation of AKT and IRS-1 could explain at least in part the findings regardless of the increase in body mass in the offspring.

Aims Agonists of the NPY receptor might be potential in protecting pancreatic islets from injury. We aimed to characterize the role of [Leu31, Pro34]-PYY, an NPYR1 agonist, in pancreatic islets of a diet-induced obesity and insulin resistance model. Methods We studied long-term high-fat diet intake as a model and selective agonist of the Y1 receptor to explore the pancreatic islet architecture and stereology, and insulin secretion in isolated islets and a whole animal model. Gene and protein expressions were assessed in isolated islets investigating the signaling cascades involved in inflammation, insulin signaling, and secretion. Also, the insulin release potential was studied in vitro. Results Our data reveal that an infusion of NPYR1 for 14 days did not change the body mass of mice and eating behavior. NPYR1 did not modify the islet and beta-cell mass but positively impacted the inflammatory process by lowering the expressions of Tnf alpha and If gamma. Besides, NPYR1 restored the insulin signaling and the exocytose pattern by activating the PDX1/STAT3 pathway and improving the leptin signaling cascade. Conclusions The findings are compellingly indicating the potential effect of the NPYR1 as a target for improving the insulin resistance condition. As such, the infusion of the NPYR1 agonist would help to enhance insulin secretion by the beta-cell from the PDX1/STAT3 pathway and the improvement of the inflammatory process.

Langerhans published in 1869, the thesis entitled “Contributions to the microscopic anatomy of the pancreas” (translated from German). In a healthy adult man, the islet mass is usually 1–2% of the pancreas mass, and can reach 500,000–1 million islets with 50–250 μm of diameter. Nowadays, at least five types of cells were identified in the pancreatic islets, which are responsible for the secretion of hormones: alpha, beta, delta, PP, and epsilon cells. Although pancreatic progenitor cells can be differentiated from stem cells, progenitor cells treated with some combinations of signaling factors can generate different cell types. Beta-cells are hard to produce, and people should be informed on how important it is to have a healthy lifestyle, in order to avoid exposing beta cells to the toxicity of sustained hyperglycemia. In the future, beta-cell neogenesis could repopulate the injured islets of the diabetic individual.

Aims There is a pancreatic islet adaptation in obese subjects, resulting in insulin resistance and diabetes type 2. We studied the effect of intermittent fasting (IntF) on the islet structure of diet-induced obese (DIO) mice. Methods Three-month-old male mice fed a control diet (C, 10% Kcal fat) or a high-fat diet (HF, 50% Kcal fat) for two months (n = 20 each group). Then, half of each group did IntF (alternating 24 h fed/24 h fast), continuing in their diets four more weeks: C, C-IntF, HF, HF-IntF. Islets were prepared to microscopy or isolated for molecular analysis. Results HF group (vs. C group) showed hyperglycemia, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, glucose intolerance, insulin resistance, and islet hypertrophy with a consequent higher both the alpha-cell and beta-cell masses. In the HF group (vs. C), there was low PDX1 (pancreatic and duodenal homeobox 1), and IntF did not alter PDX1. There was a low p-AKT/AKT ratio (protein kinase B), and IntF enhanced it. Also, tumor suppressor p53 was increased, and IntF decreased it. IL (interleukin) -6 was higher in the HF group (vs. C), and HF-IntF (vs. C-IntF). Any significant change in NFkB was seen among groups. Conclusions IntF improves pancreatic islet structure in DIO mice, even with continued HF diet intake, primarily considering on the alpha- and beta-cell masses regulation, then improving insulin signaling and decreasing cell apoptosis. Future research should explore whether the shortening of the IntF extend could maintain the benefits observed in the long term.

Objectives The aim of this study was to observe the developmental origins of health and disease affecting offspring owing to the consumption of a diet containing high fructose by the father or mother or both, considering that progeny only received a control diet during postnatal life. Methods Male (future father) and female (future mother) C57 BL/6 mice were fed a high-fructose diet (HFru; 45% energy) or a control diet (C) for 8 wk before mating until lactation. The offspring was termed according to sex, maternal diet (first acrostic), paternal diet (second acrostic), and received a balanced control diet until 3-mo of age when they were sacrificed. Body mass (BM), plasmatic leptin, adiponectin, uric acid, and systolic blood pressure (BP) were measured in mature offspring. Results Fasting glycemia and insulin were elevated in HFru fathers and mothers. Although there was no change in BM, fasting glycemia, or insulin of the offspring, those of HFru fathers, HFru mothers, and HFru fathers and mothers presented higher genital fat pad, leptin, uric acid, and BP, and lower adiponectin. The values of leptin and BP were maximized when both parents consumed a HFru diet. Also, there was sexual dimorphism in most of the variables, with the male offspring being affected to a greater extent than the females. Conclusions Consumption of a fructose-rich diet by either the father or mother, or both negatively affected the adipokines, BP, and uric acid concentrations of mature offspring, with males being more affected than females. It is significant to consider that high BP and plasmatic uric acid correspond to markers of elevated cardiovascular risk to the progeny.

Aim To investigate the effects of Rosuvastatin in a model of diet-induced obesity and nonalcoholic fatty liver disease (NAFLD), with attention on the activation of hepatic stellate cells (HSCs). Method Male C57BL/6 mice received a control diet (C, 10 % energy as lipids) or a high-fat diet (HF, 50 % energy as lipids) for 12 weeks, followed by seven weeks of treatment. Groups: C, CR (C + Rosuvastatin), HF and HFR (HF + Rosuvastatin). Results The HF group showed higher insulin, total cholesterol, and triacylglycerol and leptin levels than the C group, all of which were significantly diminished by Rosuvastatin in the HFR group. The HF group had greater steatosis and activated hepatic stellate cells (HSCs) than the C group, whereas Rosuvastatin diminished the steatosis (less 21 %, P

Brown adipose tissue (BAT) is mainly composed of adipocytes, it is highly vascularized and innervated, and can be activated in adult humans. Brown adipocytes are responsible for performing non-shivering thermogenesis, which is exclusively mediated by uncoupling protein (UCP) -1 (a protein found in the inner mitochondrial membrane), the hallmark of BAT, responsible for the uncoupling of the proton leakage from the ATP production, therefore, generating heat (i.e. thermogenesis). Besides UCP1, other compounds are essential not only to thermogenesis, but also to the proliferation and differentiation of BAT, including peroxisome proliferator-activated receptor (PPAR) family, PPARgamma coactivator 1 (PGC1)-alpha, and PRD1-BF-1-RIZ1 homologous domain protein containing protein (PRDM) -16. The sympathetic nervous system centrally regulates thermogenesis through norepinephrine, which acts on the adrenergic receptors of BAT. This bound leads to the initialization of the many pathways that may activate thermogenesis in acute and/or chronic ways. In summary, this mini-review aims to demonstrate the latest advances in the knowledge of BAT.

Objective Mothers fed a high-fat (HF) diet can cause different adverse alterations in their offspring. The study aimed to verify the pancreatic islet structure and insulin-signaling pathway in adulthood of offspring of mothers fed a HF diet during the pregnancy. Methods Female mice (mothers) were randomly assigned to receive either standard chow (Mo-SC) or a HF diet (Mo-HF) ad libitum. After 2 mo on the experimental diets, 3-mo-old female mice were mated with male C57 BL/6 mice that were fed a SC diet. The male offspring was evaluated at 6 mo old. Results At 6 mo of age, Mo-HF offspring had an increment in body mass and adiposity, hypercholesterolemia, and hypertriacylglycerolemia, higher levels of insulin, and leptin with a concomitant decrease in adiponectin levels. In the islet, we observed an alteration in the structure characterized by the migration of some alpha cells from the edge to the core of the islet in association with an increase in the masses of the islet, beta cell, and alpha cell, featuring a pancreatic islet remodeling. Additionally, the Mo-HF offspring demonstrated a decrease in IRS1, PI3 k p-Akt, Pd-1, and Glut2 protein expressions compared to Mo-SC offspring. However, an increase was observed in FOXO1 and insulin protein expressions in Mo-HF offspring compared to Mo-SC offspring. Conclusion The present study demonstrated that a maternal HF diet is responsible for remodeling the islet structure coupled with an adverse carbohydrate metabolism and impairment of the insulin-signaling pathway in adult male mice offspring.

Made available in DSpace on 2018-11-26T16:32:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-05-01 Seasonal plasticity in the small intestine of neonatal tegu lizards was investigated using morphometry and analysis of enzymes involved in supplying energy to the intestinal tissue. In the autumn, the intestinal mass (Mi) was 1.0% of body mass and the scaling exponent b = 0.92 indicated that Mi was larger in smaller neonates. During arousal from dormancy Mi was 23% smaller; later in spring, Mi increased 60% in relation to the autumn and the exponent b = 0.14 indicated that the recovery was disproportionate in smaller tegus. During the autumn, the intestinal villi were greatly elongated; by midwinter, the Hv, SvEp, and VvEp were smaller than during the autumn (59%, 54%, 29%) and were restored to autumn levels during spring. In the active tegus, the maximum activity (Vmax) of enzymes indicated that the enterocytes can obtain energy from different sources, and possess gluconeogenic capacity. During winter, the Vmax of CS, HOAD, GDH, PEPCK was 40-50% lower in relation to the autumn and spring, while the Vmax of HK, PK, LDH, AST was unchanged. The hypoglycemia and the mucosal atrophy/ischemia during winter would prevent the enterocytes from using glucose, whereas they could slowly oxidize fatty acids released from body stores and amino acids from the tissue proteolysis to satisfy their needs of energy. Contrastingly, starvation during spring caused severe mass loss (50%); the tissue protein and the VvEp and VvLP did not change while the thickness of the muscular layer increased 51%, which suggested different effects along the length of the organ. In addition, the Vmax of the glycolytic enzymes was lower, indicating that a regulatory mechanism would spare blood glucose for vital organs during unanticipated food restriction. (C) 2016 Elsevier Inc. All rights reserved. Univ Sao Paulo, Inst Biosci, Dept Physiol, BR-05508900 Sao Paulo, SP, Brazil Univ Sao Paulo, Inst Biomed Sci, Dept Cellular & Dev Biol, BR-05508900 Sao Paulo, SP, Brazil State Univ Sao Paulo, Inst Biosci, Dept Zool, POB 199, BR-13506900 Rio Claro, SP, Brazil Univ Estado Rio De Janeiro, Inst Biol, Dept Anat, BR-20551030 Rio De Janeiro, Brazil State Univ Sao Paulo, Inst Biosci, Dept Zool, POB 199, BR-13506900 Rio Claro, SP, Brazil

Human and experimental studies have shown that chronic schistosomiasis mansoni protects against metabolic disorders through direct and indirect pathways. This study aims to investigate the co-morbidity between the acute schistosomiasis and nonalcoholic fatty liver. To address this, male C57BL/6 mice fed a high-fat chow (60% fat) or standard chow (10% fat) for 13 weeks and later infected with 80 Schistosoma mansoni cercariae. Mice were assigned into four groups: uninfected fed standard (USC), uninfected fed high-fat chow (UHFC), infected fed standard (ISC), and infected fed high-fat chow (IHFC). Blood sample and tissues were obtained at nine weeks post-infection (acute schistosomiasis) by necropsy. UHFC mice showed higher body mass, visceral adiposity, impaired glucose tolerance, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), triglyceride (TG), and liver steatosis compared to USC mice. IHFC mice showed lower blood lipid levels, blood glucose, improved glucose tolerance, body mass, and liver steatosis (macro and microvesicular) compared to UHFC mice. IHFC showed more massive histopathological changes (sinusoidal fibrosis, hepatocellular ballooning, and inflammatory infiltrates) compared to ISC. In conclusion, the co-morbidity results in both beneficial (friend) and detrimental (foe) for the host. While the acute schistosomiasis improves some metabolic features of metabolic syndrome, comorbidity worsens the liver injury.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have benefits in the metabolism of adipose tissue. However, its contribution to the adipogenesis is not entirely elucidated. The study aimed to evaluate the effects of EPA and DHA on adipogenesis, especially in the PPARγ (peroxisome proliferator-activated receptor-gamma) and Cidec (cell death-inducing DFFA-like effector c) pathway. Twenty-four hours after confluence, 3T3-L1 adipocytes were treated with EPA (100 μM), DHA (50μM) and EPA (100μM) + DHA (50μM) and at the end of differentiation (day 11) the cells were collected for analysis. Cell viability analysis indicated that the concentrations used for EPA and DHA did not cause cytotoxicity in cultured 3T3l1 adipocytes. The treatments have lessened the triacylglycerol accumulation in the adipocyte cytoplasm that, compared to the control group, were EPA-32%, DHA-38%, EPA + DHA -24%. The double-labeling immunofluorescence showed a signal attenuation of protein expressions of PPARγ, CIDEC, and SREBP-1c (sterol regulatory element-binding protein). EPA and DHA had a significant impact on the expression of cleaved CASPASE 3, which increases cell apoptosis and gene expressions of Pparγ and Cidec in the treated groups. Also, there was a reduction of C/ebpα (CCAAT/enhancer-binding protein alpha), Cd36 (cluster differentiation 36), and Foxo1 (forkhead box O). In conclusion, the study determined the ability of both EPA and DHA, alone or combined, in the adipogenesis modulation in cultured 3T3-L1 adipocytes, affecting the cell differentiation, maturation, and consequently, reducing adipogenesis via PPARγ-CIDEC suppression.

Aims We studied the effect of metformin on the brown adipose tissue (BAT) in a fructose-rich-fed model, focusing on BAT proliferation, differentiation, and thermogenic markers. Main methods C57Bl/6 mice received isoenergetic diets for ten weeks: control (C) or high-fructose (F). For additional eight weeks, animals received metformin hydrochloride (M, 250 mg/kg/day) or saline. After sacrifice, BAT and white fat pads were prepared for light microscopy and molecular analyses. Key findings Body mass gain, white fat pads, and adiposity index were not different among the groups. There was a reduction in energy intake in the F group and energy expenditure in the F and FM groups. Metformin led to a more massive BAT in both groups CM and FM, associated with a higher adipocyte proliferation (β1-adrenergic receptor, proliferating cell nuclear antigen, and vascular endothelial growth factor), and differentiation (PR domain containing 16, bone morphogenetic protein 7), in part by activating 5′ adenosine monophosphate-activated protein kinase. Metformin also enhanced thermogenic markers in the BAT (uncoupling protein type 1, peroxisome proliferator-activated receptor gamma coactivator-1 alpha) through adrenergic stimuli and fibroblast growth factor 21. Metformin might improve mitochondrial biogenesis in the BAT (nuclear respiratory factor 1, mitochondrial transcription factor A), lipolysis (perilipin, adipose triglyceride lipase, hormone-sensitive lipase), and fatty acid uptake (lipoprotein lipase, cluster of differentiation 36, adipocyte protein 2). Significance Metformin effects are not linked to body mass changes, but affect BAT thermogenesis, mitochondrial biogenesis, and fatty acid uptake. Therefore, BAT may be a metformin adjuvant target for the treatment of metabolic disorders.

We aimed to investigate the effects of medium-chain triglyceride oil on the high fructose diet-provoked hepatic abnormalities in mice. We used C57bl/6 mice of 3-months-old divided into four groups for 12 weeks: control (C), control with MCT (C-MCT), fructose (F), and fructose with MCT (F-MCT). We investigated food and water intake, body mass, blood pressure, glucose tolerance, plasma and liver biochemistry, hepatic protein and gene expression. There were no changes in body mass, food intake and glucose tolerance among the groups. The F group presented increased water intake and blood pressure associated with hepatic steatosis and elevated de novo lipogenesis, beta-oxidation, mitochondrial biogenesis and inflammation in the liver. Surprisingly, the C-MCT group also showed hepatic steatosis and inflammation in the liver, and the F-MCT group had no exacerbations of fructose-induced abnormalities, showing marked hepatic steatosis, lipogenesis de novo and hepatic inflammation. The MCT oil groups also presented increased beta-oxidation and mitochondrial biogenesis. In conclusion, MCT oil showed detrimental hepatic effects and should be used with caution, especially in the presence of hepatic alterations.

Fructose may induce an endocrine dysfunction in adipose tissue in rodents. Browning is identified by deposits of beige adipocytes in subcutaneous white adipose tissue (sWAT). We study the effects of the high-intensity interval training (HIIT) on the formation of beige adipocytes in the sWAT of mice fed a high-fructose diet. Sixty male mice (3 months old; C57BL/6) were fed two diets for 18 weeks (n=30 each): control diet (C) or high-fructose diet (F). At the 10th week, for an additional 8-week period, the groups were (n=15 each) nontrained (NT) or trained (HIIT): C-NT, C-HIIT, F-NT and F-HIIT. We evaluated body mass, energy expenditure and molecular analyses for browning and thermogenic markers in sWAT. The HIIT groups showed significantly lower body mass and increased energy expenditure. The consumption of fructose was linked with an increased sWAT mass. However, HIIT caused a reduction of sWAT mass compared to the NT groups. Energy intake was parallel in the groups, regardless of the diet type and HIIT. Fructose was related to higher glucose and insulin levels and hypertrophied sWAT adipocytes, but HIIT decreased both glucose and insulin levels and led to the appearance of brown fat-like adipocytes dispersed in sWAT with higher expression of browning markers. Also, fructose reduced the sWAT markers of mitochondrial biogenesis and beta-oxidation, which were enhanced by HIIT. In conclusion, HIIT might stimulate the sWAT browning in mice fed a high-fructose diet associated with beneficial changes in mitochondrial biogenesis and beta-oxidation markers, contributing to a whole-body metabolic improvement.

Los madres alimentadas con dieta rica en grasas (HF) pueden programar una susceptibilidad al desarrollo de enfermedades cronicas en su descendencia y de este modo afectar a las generaciones posteriores. El presente estudio evaluo la estructura del higado en la edad adulta, centrandose en las generaciones F1 y F2. Las hembras C57BL/6 (F0) fueron alimentadas con dieta estandar (CS) o dieta HF (8 semanas) antes del apareamiento y durante la gestacion y lactancia para producir la generacion F1 (CS-F1 y HF-F1). Todas las demas madres y crias fueron alimentadas con CS. A los 3 meses de edad, las hembras F1 fueron apareadas para producir la generacion F2 (CS-F2 y HF-F2). El higado se conservo en varios fragmentos y se preparo, por un lado, para el analisis histologico, y por otro, se lo congelo para realizar analisis bioquimicos y moleculares. La descendencia F1 y F2 se estudio a los 3 meses de edad. HF-F1 tuvo una mayor masa corporal (BM) en comparacion con CS-F1 (P= 0,001), pero no el grupo HF-F2 en comparacion con CS-F2. HF-F1 tenia intolerancia a la glucosa en comparacion con CS-F1, pero no el grupo HF-F2 en comparacion con CS-F2. HF-F1 (P= 0,009) y HF-F2 (P= 0,03) mostraron hiperinsulinemia en comparacion con sus homologos. Ambos grupos HF-F1 y HF-F2 mostraron mas esteatosis que las contrapartes CS (F1 y F2, P

Fish oil improves obesity and its comorbidities, but its mechanisms of action remain unknown. We evaluate the effects of a diet rich in fish oil in white adipose tissue (WAT) inflammation pathways, renin-angiotensin system (RAS) and mitogen-activated protein kinases (MAPKs). To achieve our aims, four groups of male C57BL/6 mice were fed different diets: standard chow diet (SC; 10% energy from fat), SC+fish oil diet (SC-FO; 10% energy from fat), high-fat lard diet (HF-L; 50% energy from lard) and HF fish oil diet (HF-FO; 50% energy from fish oil). We evaluated body mass, epididymal fat pad mass, food intake and glucose tolerance. In WAT, we assessed adipocyte hypertrophy, monocyte chemotactic protein-1 immunofluorescence, and gene and protein expression of insulin signaling, inflammation, MAPKs, RAS, peroxisome proliferator-activated receptors (PPARs) and AMP-activated protein kinase (AMPK). In relation to the results, the HF-L group, as expected, showed elevated body mass and adiposity, glucose intolerance and hypertrophied adipocytes. In WAT, we found a defect in insulin signaling, infiltration of macrophages and inflammatory markers with the associated activation of MAPKs and local RAS. On the contrary, the HF-FO group did not present increased body mass, adiposity or glucose intolerance. In this group, insulin signaling, macrophage infiltration and inflammation were reduced in WAT in comparison with the HF-L group. We also observed decreases of MAPKs and local RAS and elevation of PPAR and AMPK. In summary, fish oil activates PPAR (the three isoforms) and AMPK, decreases WAT insulin resistance and inflammation, and inhibits MAPK and RAS pathways activation.

Obesity is considered a public health problem worldwide. Fenofibrate, a selective peroxisome proliferator-activated receptor α (PPAR-α) agonist, elicits weight loss in animal models. This study aimed to examine the effects of fenofibrate on energy expenditure, body mass (BM) and gene expression of thermogenic factors in brown adipose tissue of diet-induced obese mice. Male C57BL/6 mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 50% lipids) diet for 10 weeks. Afterwards, groups were subdivided as SC, SC-F, HF and HF-F (n = 10, each). Treatment with fenofibrate (100 mg kg−1 BM mixed into the diet) lasted 5 weeks. Treated groups had reduced final BM compared with their counterparts (p

High activation of the angiotensin-converting enzyme (ACE)/(angiotensin-II type 1 receptor) AT1r axis is closely linked to pro-inflammatory effects and liver damage. The aim of this study was to evaluate the effects of the short-term administration of GW501516 on pro-inflammatory markers in white adipose tissue (WAT) and hepatic stellate cells (HSCs), lipogenesis and insulin resistance in the liver upon high-fructose diet (HFru)-induced ACE/AT1r axis activation. Three-month-old male C57Bl/6 mice were fed a standard chow diet or a HFru for 8 weeks. Then, the animals were separated randomly into four groups and treated with GW501516 for 3 weeks. Morphological variables, systolic blood pressure, and plasma determinations were analyzed. In the WAT, the ACE/AT1r axis and pro-inflammatory cytokines were assessed, and in the liver, the ACE/AT1r axis, HSCs, fatty acid oxidation, insulin resistance, and AMPK activation were evaluated. The HFru group displayed a high activation of the ACE/AT1r axis in both the WAT and liver; consequently, we detected inflammation and liver damage. Although GW501516 abolished the increased activation of the ACE/AT1r axis in the WAT, no differences were found in the liver. GW501516 blunted the inflammatory state in the WAT and reduced HSC activation in the liver. In addition, GW501516 alleviates damage in the liver by increasing the expression of the genes that regulate beta-oxidation and decreasing the expression of the genes and proteins that are involved in lipogenesis and gluconeogenesis. We conclude that GW501516 may serve as a therapeutic option for the treatment of a highly activated ACE/AT1r axis in WAT and liver.

Aims To assess the effects of peroxisome proliferator-activated receptor (PPAR) agonists on glucose tolerance and hepatic lipid metabolism in diet-induced obese mice. Main methods Male C57BL/6 mice received a standard chow diet (SC, 10% energy as lipids) or high-fat diet (HF, 50% energy as lipids) for 10 weeks, after which treatment was initiated, forming the groups: SC group, HF group, HF-BZ group (HF + bezafibrate, pan-PPAR agonist), HF-WY group (HF + WY-14643, PPARalpha agonist) and HF-GW group (HF + GW1929, PPARgamma agonist). Treatments lasted for four weeks. Insulin resistance and liver remodeling were evaluated by biochemical and molecular approaches. Key findings The HF and HF-GW mice were overweight. Conversely, the HF-BZ and HF-WY mice presented with body masses equal to those of the SC mice. All treatments restored insulin sensitivity and blood lipid and adiponectin levels. Hepatic steatosis was prevented in the HF-WY and HF-BZ mice as shown by the elevated mRNA levels of PPARalpha and Carnitine palmitoyl transferase-1a in both groups, which favored enhanced beta-oxidation. Marked decreases in liver triacylglycerol levels confirmed these findings. In contrast, the HF-GW mice exhibited increased PPARgamma and fatty acid translocase/CD136 mRNA levels, contributing to enhanced hepatic lipogenesis. Significance The WY14643 and bezafibrate treatments most effectively improved the adverse metabolic and hepatic effects caused by obesity and IR. The results reinforce the central role of PPARalpha, as well as its contrary relationship to PPARgamma in the regulation of metabolic homeostasis and lipolytic pathways in the liver.

Objective The aim of this study was to evaluate the effects of maternal obesity on pancreas structure and carbohydrate metabolism in early adult life, focusing on the F1 and F2 generations after F0 maternal pregestational, gestation, and lactation high-fat diet (HF). Methods C57 BL/6 female mice (F0) were fed standard chow (SC) or an HF diet for 8 wk before mating and during the gestation and lactation periods to provide the F1 generation (F1-SC and F1-HF). At 3 mo old, F1 females were mated to produce the F2 generation (F2-SC and F2-HF). The male offspring from all groups were evaluated at 3 mo old. Results F0-HF and F1-HF dams were overweight before gestation and had a higher body mass gain and energy intake during gestation, although only F0-HF dams presented pregestational hyperglycemia. The F1-HF offspring had higher body mass, energy intake, fasting glucose levels, and were glucose intolerant compared with F1-SC offspring. These parameters were not significantly altered in F2-HF offspring. Both F1-HF and F2-HF offspring showed hyperinsulinemia, hyperleptinemia, decreased adiponectin levels, increased pancreatic mass, and islet volume density with elevated α- and β-cell mass, hypertrophied islet characterized by an altered distribution of α- and β-cells and weak pancreatic-duodenal homeobox (Pdx)1 immunoreactivity. Conclusions Maternal HF diet consumed during the preconception period and throughout the gestation and lactation periods in mice promotes metabolism and pancreatic programming in F1 and F2 male offspring, implying intergenerational effects.

Changes in feeding habits are the primary environmental factors (though modifiable) commonly correlated with increase in diseases such as obesity and associated comorbidities. Diets rich in fructose and sucrose have been related to the epidemic of obesity. Three groups of mice were studied during 15 weeks of consuming standard chow (SC), a high-fructose diet (HFru) and a high-sucrose diet (HSu). The animals did not present significant differences in food intake, energy intake, or body mass evolution at the end of the experiment. Although the findings in the HFru and HSu animals were not equal in magnitude, in comparison with the SC mice, the HFru and HSu animals showed hyperglycemia, hyperinsulinemia and hyperleptinemia as well as high levels of inflammatory adipokines, low adiponectin, and high levels of total cholesterol, triacylglycerol, and liver enzymes. The liver of HFru (more) and HSu (less) groups showed fatty infiltration and areas of necroinflammation, which are characteristic of the transition from nonalcoholic fatty liver disease to nonalcoholic steatohepatitis. In addition, the HFru and HSu groups showed increased lipogenesis, gluconeogenesis, reduced beta-oxidation and antioxidant imbalance compared with the SC animals. In conclusion, current findings demonstrate comparable adverse effects on carbohydrate metabolism, inflammatory profile, antioxidant imbalance and NAFLD in the mice of the C57BL/6 strain fed a diet rich in sucrose or rich in fructose.

Non-alcoholic fatty liver disease (NAFLD) presents with growing prevalence worldwide, though its pharmacological treatment remains to be established. This study aimed to evaluate the effects of a PPAR-alpha agonist on liver tissue structure, ultrastructure, and metabolism, focusing on gene and protein expression of de novo lipogenesis and gluconeogenesis pathways, in diet-induced obese mice. Male C57BL/6 mice (three months old) received a control diet (C, 10% of lipids, n = 10) or a high-fat diet (HFD, 50% of lipids, n = 10) for ten weeks. These groups were subdivided to receive the treatment (n = 5 per group): C, C-alpha (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the control diet), HFD and HFD-alpha group (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the HFD). The effects were compared with biometrical, biochemical, molecular biology and transmission electron microscopy (TEM) analyses. HFD showed greater body mass (BM) and insulinemia than C, both of which were tackled by the treatment in the HFD-alpha group. Increased hepatic protein expression of glucose-6-phosphatase, CHREBP and gene expression of PEPCK in HFD points to increased gluconeogenesis. Treatment rescued these parameters in the HFD-alpha group, eliciting a reduced hepatic glucose output, confirmed by the smaller GLUT2 expression in HFD-alpha than in HFD. Conversely, favored de novo lipogenesis was found in the HFD group by the increased expression of PPAR-gamma, and its target gene SREBP-1, FAS and GK when compared to C. The treatment yielded a marked reduction in the expression of all lipogenic factors. TEM analyses showed a greater numerical density of mitochondria per area of tissue in treated than in untreated groups, suggesting an increase in beta-oxidation and the consequent NAFLD control. PPAR-alpha activation reduced BM and treated insulin resistance (IR) and NAFLD by increasing the number of mitochondria and reducing hepatic gluconeogenesis and de novo lipogenesis protein and gene expressions in a murine obesity model.

Background-Aims : We aimed to examine the effects of a maternal high-sodium diet in the kidney and blood pressure (BP) of the offspring. Materials and Methods : Beginning eight weeks before pregnancy, female mice received a diet containing either 0.25% sodium chloride (NaCl) - (standard chow, SC) or 4.0% NaCl (high-sodium, HS). Females were mated with male mice fed a SC diet. Their offspring were analyzed at three different ages: at birth, at day 10, and at three months. Results : Before mating, HS dams exhibited higher corticosterone levels and higher BP than the SC dams. At birth, neonatal mortality was higher in the offspring of HS dams than in those from SC dams. At three months of age, HS offspring compared to SC offspring, showed higher proteinuria and BP, greater glomerular sclerosis, and lower creatinine clearance, blood urea nitrogen clearance, and glomerular filtration rate. The fractional excretions of sodium, potassium, urea, and the protein expressions of the renin-angiotensin system (RAS) were higher in HS than in SC offspring, but AT2R, Wilms’ tumor suppressor gene (WT)1 and podocin were lower in HS than in SC offspring. Conclusion : The offspring exposed to a maternal diet with high sodium content shows glomerular sclerosis with consequent high blood pressure and a shift in the renal expression of proteins (WT1, podocin, and RAS) at maturity. Consequently, the renal function of the offspring deteriorates more quickly than offspring from mothers fed a standard sodium diet.

New Findings What is the central question of this study? Telmisartan, an antihypertensive, has beneficial side-effects through its peroxisome proliferator-activated receptor (PPAR) β/δ agonism in white adipose tissue, besides its well-known property of partial PPARγ agonism. Here, we investigated a potential pan-PPAR role of this drug in the white and brown adipose tissues. What is the main finding and its importance? Telmisartan enhanced pan-PPAR gene and protein expression in adipose tissue (white and brown) in obese mice, with downstream effects that resulted in the management of insulin resistance, anti-inflammatory adipokine profile and thermogenesis induction. These findings are relevant and should be explored as new targets for controlling obesity and comorbidities through pan-PPAR-related effects. Telmisartan has previously been used to target obesity, showing peroxisome proliferator-activated receptor (PPAR) β/δ-related effects in white adipose tissue (WAT). We sought to evaluate whether telmisartan enhances gene and protein expression of all PPAR isoforms in WAT and brown adipose tissue (BAT), as well as their downstream effects upon insulin resistance, adipokine profile and adaptive thermogenesis. Male C57BL/6 mice were fed standard chow (SC; 10% lipids) or high-fat diet (HF; 50% lipids) for 10 weeks. Animals were then randomly allocated into the following four groups: SC, SC-T, HF and HF-T. Telmisartan [10 mg (kg diet)−1] was administered for 4 weeks in the diet. Animals in the HF group were overweight and exhibited hypertension, insulin resistance, decreased energy expenditure, a pro-inflammatory adipokine profile and abnormal fat pad mass distribution. Animals in the HF group showed decreased expression of PPARα, β/δ and γ in WAT and BAT, resulting in impaired glucose uptake and insufficient thermogenesis. Due to the improvement in the adipokine profile and enhanced insulin sensitivity with adequate insulin-stimulated glucose uptake after treatment with telmisartan, the activation of all PPAR isoforms in WAT was beneficial. In BAT, telmisartan induced sustained sympathetic activation, because the β3-adrenergic receptor was induced by PPARβ/δ, while uncoupling protein 1 was induced by PPARα to promote thermogenesis. Telmisartan exerted anti-obesity effects through higher pan-PPAR gene and protein expression. Upon PPARα, β/δ and γ (pan-PPAR) agonism in adipose tissue of obese mice, telmisartan ameliorates inflammation and insulin resistance, as well as inducing non-shivering thermogenesis. Our results point to new therapeutic targets for the control of obesity and comorbidities through pan-PPAR-related effects.

The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. The current study evaluated the effects of RAS blockers in a model of diet-induced insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD).Male C57BL/6 mice were fed a standard chow (SC; 10% lipids, n=15) diet or a high-fat (HF; 50% lipids, n=60) diet for 8 weeks and then treated with aliskiren (HF-A; 50 mg/kg per day, n=15), enalapril (HF-E; 30 mg/kg per day, n=15), or losartan (HF-L; 10 mg/kg per day, n=15) for an additional 6 weeks. We assessed glucose and lipid metabolism, hepatic histopathology, the expression profile of genes and proteins affecting hepatic gluconeogenesis, RAS and insulin signaling, and lipid beta-oxidation and accumulation. The differences between the groups were tested via analysis of variance (ANOVA) and the post hoc Holm-Sidak test.All treatments restored the up-regulation of hepatic RAS. The enalapril treatment, but not aliskiren or losartan, was effective in improving leptin, glucose intolerance, IR, hepatic steatosis, and triglycerides and in preventing increased hepatic protein levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and glucose transporter-2 (GLUT-2). Furthermore, enalapril improved the response to the deleterious effects of the HF diet by upregulating signal transduction through the insulin receptor substrate (IRS) 1/protein kinase B (Akt) pathway, as well as downregulating the protein levels and mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1c (SREBP-1c), and fatty acid synthase (FAS).Enalapril was the most successful treatment in protecting against hepatic IR and NAFLD by enhancing hepatic insulin action, leptin, and gluconeogenesis and by reducing the lipogenic pathway and lipid accumulation in the liver.

It is still unclear if an isoenergetic, sucrose-rich diet leads to health consequences.To investigate the effects of excessive sucrose within an isoenergetic diet on metabolic parameters in male C57BL/6 mice.Animals were fed a control diet (10% fat, 8% sucrose - SC group), a high-sucrose diet (10% fat, 32% sucrose - HSu group), a high-fat diet (42% fat, 8% sucrose - HF group) or a high-fat/high-sucrose diet (42% fat, 32% sucrose - HF/HSu group) for 8 weeks.Mice fed HF and HF/HSu diets gained more body mass (BM) and more body adiposity than SC- or Hsu-fed mice. Despite the unchanged BM and adiposity indices, HSu mice presented adipocyte hypertrophy, which was also observed in the HF and HF/HSu groups (P.0001). The HF, HSu and HF/HSu mice were glucose intolerant and had elevated serum insulin levels (P.05). The levels of leptin, resistin and monocyte chemotactic protein-1 increased, while the serum adiponectin decreased in the HF, HSu and HF/HSu groups (P.05). In the adipose tissue, the HF, HSu and HF/HSu groups showed higher levels of leptin expression and lower levels of adiponectin expression in comparison with the SC group (P.05). Liver steatosis was higher in the HF, HSu and HF/HSu groups than in the SC group (P.0001). Hepatic cholesterol was higher in the HF and HF/HSu groups, while hepatic TG was higher in the HSu and HF/HSu groups (P.05). In hepatic tissue, the sterol receptor element-binding protein-1c expression was increased in the HF, HSu and HF/HSu groups, unlike the peroxisome proliferator-activated receptor-alpha expression that decreased in the HF, HSu and HF/HSu groups in comparison with the SC group (P.05).A sucrose-rich diet does not lead to a state of obesity but has the potential to cause changes in the adipocytes (hypertrophy) as well as glucose intolerance, hyperinsulinemia, hyperlipidemia, hepatic steatosis and increases in the number of inflammatory cytokines. The deleterious effects of a sucrose-rich diet in an animal model, even when the sucrose replaces starch isocalorically in the feed, can have far-reaching consequences for health.

The chronic intake of fructose has been linked to insulin resistance, obesity, dyslipidemia and nonalcoholic fatty liver disease (NAFLD), which in turn, may progress to nonalcoholic steatohepatitis (NASH). We aimed to evaluate the magnitude of the effects of the chronic consumption of high-fructose (HFr) and high fat (HF) alone or combined. Four groups of male mice were fed different diets for 16 weeks: standard chow (9% fat: SC), HF diet (42% fat), HFr diet (34% fructose) and HF/HFr diet (42% fat, 34% fructose). The food intake was not different among the groups, and the body mass was not greater in the HFr group than in the SC group. The homeostasis model assessment for insulin resistance (HOMA-IR), as well as plasmatic total cholesterol and triglycerides were greater in the groups HF, HFr, and HF/HFr group than in the SC group. We observed in the groups HF, HFr and HF/HFr, compared to the group SC, nonalcoholic fatty liver disease (NAFLD) with a predominance of lipogenesis mediated by SREBP-1c and PPAR-γ, and a reduction of the oxidation mediated by PPAR-α. We also observed an increase in gluconeogenesis mediated by the GLUT-2 and the PEPCK. Importantly, we identified areas of necroinflammation indicating a transition from NAFLD to nonalcoholic steatohepatitis in the HFr and HF/HFr groups. This study is relevant in demonstrating that fructose consumption, even in the absence of obesity, causes serious and deleterious changes in the liver with the presence of the dyslipidemia, insulin resistance (IR), and NAFLD with areas of necroinflammation. These conditions are associated with a poor prognosis.

Aim Weight cycling (WC) is frequent in obesity treatment. We evaluated the degree of regression of the liver damage in WC. Methods C57BL/6 male mice received standard chow (SC, 10% energy from lipids) or high-fat diet (HF, 60% energy from lipids) for 6 months (SC6 or HF6) or a diet that alternated every 2 months (SC2/HF2/SC2 or HF2/SC2/HF2). Results The body mass gain followed the HF intake and induced WC in the animals. The liver alanine aminotransferase, triglyceride and cholesterol levels were higher in the groups receiving the HF diet for any period. The plasma insulin and glucose levels were the highest in the HF6 and HF2/SC2/HF2 groups. Any HF intake increased the liver mass. All the groups had some degree of liver steatosis, with the SC6 group exhibiting the lowest level (∼23% compared with 50–70%). The activated hepatic stellate cells were sparse throughout the liver sections from the HF6 and HF2/SC2/HF2 groups. The lowest sterol regulatory element-binding protein-1c (SREBP-1c) level was detected in the SC6 group. The peroxisome proliferator-activated receptor (PPAR)-α expression was higher in the SC6 and SC2/HF2/SC2 groups than in the HF6 and HF2/SC2/HF2 groups that showed reduced expression. Conclusion WC induced by diet leads to adverse response in the liver, including biochemical and molecular alterations that are not reversed during the lean period of the WC, which must be maintained for a long period to allow the liver to recover from the damage associated with obesity.

We investigated the increasing amounts of medium-chain triacylglycerol (MCT) in the diet on hepatic lipid metabolism. Mature C57BL/6 male mice were randomly divided into five groups (n = 10/group). The animals received their diet for 12 weeks, as a control (C group, 10% of energy from lipids); high-fat lard (HF group, isoenergetic diet, 50% of energy from lipids with lard); a mixture of lard and MCT oil (with a gradual replacement of lard by MCT: HF-MCT25%, HF-MCT75%, and HF-MCT100% groups). At euthanasia, we collected blood and dissected the liver for analyses (glucose, insulin, HOMA-IR, QUICK index, and triacylglycerol, light microscopy, western blotting, and RT-qPCR). The HF diet groups showed a greater body mass gain compared to the C group, but the HF-MCT100% group showed diminished adiposity and amelioration of insulin resistance. All the HF groups also showed a clear increase in hepatic lipid accumulation, increased lipogenesis and decreased PPAR-alpha expression, although HF-MCT groups showed improved local insulin signaling. Lastly, the HF-MCT100% group had raised markers of beta-oxidation (UCP3 and MCAD) and mitochondrial biogenesis (PGC1-alpha and NRF1). In conclusion, the findings demonstrated that a high amount of MCT (HF-MCT100% group) added to an HF diet reduces the body fat accumulation and insulin resistance. However, the lipid accumulation as well as the lipid metabolism is altered in the liver of animals fed with a very high MCT diet, indicating that higher doses of MCT may be harmful in a long-term.

This study aimed to investigate the effects of maternal vitamin D restriction on carbohydrate metabolism and alterations in the pancreas and liver in the F1 and F2 generations. Therefore, we studied the first two generations of offspring (F1 and F2) of Swiss mice from mothers fed one of two diets: SC (standard chow) or VitD⁻ (vitamin D-deficient). Biometric, biochemical and molecular analyses were performed. The VitD-F1 mice had greater body mass (BM) than the SC-F1 mice. The BM changes were accompanied by increased insulin secretion. The VitD-F1 mice had a higher area under the curve in the oral glucose tolerance test and exhibited larger islet diameters than the SC-F1 mice. In addition, the VitD-F1 mice showed marked diffuse hepatic steatosis and higher expression of fatty acid synthase (FAS) protein than the SC animals in either generation or the ViD-F2 mice. Diet accounted for a greater fraction of the total variation for BM, fat pad mass and insulin secretion than generation. Both diet and generation contributed to the variation in steatosis in the liver, islet diameter and expression of FAS. However, interactions between diet and generation were observed only for insulin secretion, steatosis in the liver and FAS expression. In conclusion, these results provide compelling evidence that maternal vitamin D restriction affects the development of the offspring and leads to metabolic alterations accompanied by structural alterations in the liver and pancreas, especially in the F1 generation.

Brown adipose tissue (BAT) is specialized in heat production, but its metabolism in ob/ob mice is still a matter of debate. We aimed to verify ob/ob mice BAT using C57Bl/6 male mice (as the wild-type, WT) and leptin-deficient ob/ob mice (on the C57Bl/6 background strain), at three months of age (n=10/group). At euthanasia, animals had their interscapular BAT weighed, and prepared for analysis (Western blot, and RT-qPCR). In comparison with the WT group, the ob/ob group showed reduced thermogenic signaling markers (gene expression of beta 3-adrenergic receptor, beta3-AR; PPARgamma coactivator 1 alpha, PGC1alpha, and uncoupling protein 1, UCP1). The ob/ob group also showed impaired gene expression for lipid utilization (perilipin was increased, while other markers were diminished: carnitine palmitoyltransferase-1b, CPT-1b; cluster of differentiation 36, CD36; fatty acid binding protein 4, FABP4; fatty acid synthase, FAS, and sterol regulatory element-binding protein 1c, SREBP1c), and altered protein expression of insulin signaling (diminished pAKT, TC10, and GLUT-4). Lastly, the ob/ob group showed increased gene expression of markers of inflammation (interleukin 1 beta, IL-1beta; IL-6, tumor necrosis factor alpha, TNFalpha; and monocyte chemotactic protein-1, MCP-1). In conclusion, the ob/ob mice have decreased thermogenic markers associated with reduced gene expression related to fatty acid synthesis, mobilization, and oxidation. There were also alterations in insulin signaling and protein and gene expressions of inflammation. The findings suggest that the lack of substrate for thermogenesis and the local inflammation negatively regulated thermogenic signaling in the ob/ob mice.

Obesity leads to adverse endocrine pancreas remodelling, reduced islet lifespan and early type 2 diabetes onset. AT1R blockade shows beneficial pleiotropic effects. This study sought to compare the effects of losartan and telmisartan on pancreatic islets remodelling and glucose homeostasis in diet-induced obese mice. High-fat diet yielded overweight, insulin resistance, islet apoptosis and hypertrophy. Suitable insulin levels and preserved endocrine pancreas structure were correlated to adequate AKT-FOXO1 pathway functioning in losartan-treated animals. Conversely, telmisartan yielded enhanced PDX1 and GLP-1 islet expression along with greater GLP-1 levels, with the consequent better islet glucose sensing and uptake. Greater islet vascularisation coupled with reduced apoptosis and macrophage infiltration seems to underlie the beneficial findings in both treatments. In conclusion, these results provide compelling evidence that two antihypertensive drugs (telmisartan and losartan) ameliorate pancreatic islet structure, glucose handling, and vascularisation in obese mice. Although only telmisartan countered overweight, both drugs yielded reduced apoptosis and islet preservation, with translational potential.

We aimed to investigate the impact of different high-fat diets containing fish oil on adiposity and white adipose tissue (WAT) function in mice, comparing the effects on epididymal (eWAT) and subcutaneous (sWAT) depots. For this, we used C57BL/6 male mice fed four types of diets for eight weeks: standard chow (SC), high-fat lard (HF-L), high-fat lard plus fish oil (HF-L + FO), and high-fat fish oil (HF-FO). The HF-L group had a greater body mass (BM) gain, insulin resistance, increased gene expression related to lipogenesis (CD36, aP2, SREBP1c, and FAS), decreased gene expression of perilipin in both eWAT and sWAT, and reduced expression of genes related to beta-oxidation (CPT-1a) and to mitochondrial biogenesis (PGC1alpha, NRF1, and TFAM) in eWAT and sWAT. On the other hand, the HF-L + FO and HF-FO groups showed a smaller BM gain and adiposity, and normalization of insulin resistance and lipogenic genes in both eWAT and sWAT. These animals also showed decreased perilipin gene expression and elevated expression of beta-oxidation and mitochondrial biogenesis genes in eWAT and sWAT. 'Beige' adipocytes were identified in sWAT of the HF-FO animals. In conclusion, fish oil intake has anti-obesity effects through modulation of both eWAT and sWAT metabolism in mice and is relevant in diminishing the BM gain, adiposity, and insulin resistance even in combination with a high-fat lard diet in mice.

The aim of the present study was to evaluate the effects of ST (rosuvastatin) and GZ (rosiglitazone) on IR (insulin resistance) and on liver as well as adipose tissue in mice fed on an HF (high-fat) diet. Our data show that treatment with ST resulted in a marked improvement in insulin sensitivity characterized by enhanced glucose clearance during the insulin tolerance test and a 70% decrease in the HOMA-IR (homoeostasis model assessment of insulin resistance) index level (P=0.0008). The ST-treated mice exhibited lower gains in BM (body mass; −8%; P

A fatty diet during pregnancy in mouse dams causes metabolic abnormalities (similar to metabolic syndrome in humans) in the rodents’ offspring. We tested the hypothesis that the offspring of dams fed a high-fat diet during pregnancy and lactation develop metabolic abnormalities and leptin resistance. Pregnant C57BL/6 mice (n = 20) were fed either standard chow (SC; 19% fat) or a high-fat diet (HF; 49% fat). After weaning, male offspring were divided into four groups, according to the diet of dams and offspring: SC(dams)/SC(offspring), SC/HF, HF/SC and HF/HF (n = 30/group). For a metabolic analysis, we evaluated body mass, fat mass depots, blood plasma and adipocyte structure at 12 weeks of age. To analyse leptin sensitivity, each group was divided into two groups (vehicle or leptin) to identify the feeding response and pSTAT3 expression after acute intracerebroventricular (ICV) treatment. The offspring of mothers fed a high-fat diet presented increased body mass and visceral fat, adipocyte hypertrophy and insulin resistance. This phenotype was not associated with central leptin resistance. Thus, maternal programming by HF predisposes offspring to metabolic abnormalities despite leptin sensitivity.

Programming of fetal development is considered to be an important risk factor for noncommunicable diseases of adulthood, including coronary heart disease (CHD). Aiming to investigate the association between maternal nutrition and the development of the coronary arteries (CAs) in staged mice embryos, C57BL/6 mice embryos from Stages 16 to 23 were taken from mothers fed a normal protein (NP) or low protein (LP) diet, and the CA were studied. Although the LP embryos had lower masses, they had faster heart growth rates when compared with the NP embryos. The subepicardial plexuses were observed earlier in the NP embryos (Stage 20) than in the LP ones (Stage 22; P < 0.01). Apoptotic nuclei were seen around the aortic peritruncal ring beginning at Stage 18 in the NP and LP embryos. FLK1(+) (fetal liver kinase 1 = VEGF-r2 or vascular endothelial growth factor receptor 2) cells had a homogeneous distribution in the NP embryos as early as Stage 18, whereas a similar distribution in the LP embryos was only seen at Stages 22 and 23. Maternal protein restriction in mice leads to a delay in the growth of the heart in the embryonic period modifying the development of the subepicardial peritruncal plexus and the apoptosis in the future coronary orifice region.

We sought to evaluate the effects of telmisartan, sitagliptin, or their combination on pancreatic ultrastructural alterations in high-fat-fed C57BL/6 mice.Three-month-old C57BL/6 mice were fed with standard chow (SC, 10% lipids) or high-fat diet (HF, 60% lipids) during 10 weeks to induce obesity and its comorbidities. After this period, treatment began (lasted 6 weeks), and the HF group was divided into 4 subgroups: untreated HF, HF plus telmisartan (5 mg/kg per day), HF plus sitagliptin (1.1 g/kg per day), and HF plus telmisartan plus sitagliptin. Drugs were mixed with diet. Biochemical analyses, radioimmunoassay, immunofluorescence, stereology, and transmission electron microscopy were performed to assess pancreatic remodeling.Overweight, hyperinsulinemia, hyperglycemia, and dyslipidemia were found in the HF group, but these outcomes were controlled by the different treatments. Untreated HF animals also showed alterations concerning distribution of α/β cell followed by large and numerous lipid droplets within pancreas. Telmisartan and sitagliptin as monotherapy alleviated these findings, and a complete reversal of pancreatic steatosis was observed after treating with the combination of the 2 drugs.AT1 receptor blockade, partial peroxisome proliferator-activated receptor gamma activation, and extended incretin action emerge as feasible strategies to control pancreatic steatosis and avoid progression of pancreatic diseases due to lipotoxicity.

This work aimed to analyze the effect of low-intensity exercise training on ultrastructural and molecular aortic remodeling. Male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were allocated into four groups: sedentary WKY (SED-WKY), exercised WKY (EX-WKY, 1 h/day, 5 days/week treadmill exercise training), sedentary SHR (SED-SHR), and exercised SHR (EX-SHR). EX-SHR showed blood pressure reduction of 26% in comparison to SED-SHR after 1 month of exercise (P

To investigate changes in cardiac functional parameters and the cardiac expression of angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT1), procollagen type I (proc-I) and transforming growth factor-ß1 (TGF-ß1) in rats irradiated at heart.Male Wistar rats were irradiated with a single dose of radiation (0, 5, 10 and 15 Gray [Gy]) delivered directly to the heart and the molecular evaluations were performed at various times post-irradiation (two days, 15 days and four months). The expression of ACE, AT1, proc-I and TGF-ß1 were analysed using Real Time-Polymerase Chain Reaction (RT-PCR) and/or Western blotting. Cardiac structural and functional alterations were investigated at the four-month time point by echocardiography and by quantitative methods (stereology).Rats irradiated with 15 Gy showed a modest reduction in the ejection fraction. Cardiac proc-I, TGF-ß1, ACE and AT1 were also measurably increased.Irradiated rat hearts show simultaneous elevations in renin-angiotensin system components AT1 and ACE and cardiac remodeling markers proc-I and TGF-ß1.

The consumption of a high fat (HF) diet is considered a risk factor for the development of obesity. On the other hand, a monounsaturated HF diet has beneficial cardiometabolic effects. Since nitric oxide (NO) modulates vascular homeostasis, we investigate whether HF diets that vary in fatty acid composition have a different effect on theL-arginine-NO pathway and oxidative stress in C57BL/6 mice red blood cells (RBC). The olive oil diet induced an activation of L-arginine transport compared to other diets. NO synthase (NOS) activity was increased in all unsaturated HF diets (olive, sunflower and canola oils). Moreover, the expression of endothelial NOS (eNOS) and inducible NOS (iNOS) was increased in the olive oil group. In contrast, NOS activity from the lard group was decreased associated with diminished l-arginine transport. Olive oil also induced superoxide dismutase activation. Inhibition of the L-arginine-NO pathway in the lard group could contribute to cardiovascular diseases, while unsaturated HF diets may have a protector effect via enhanced NO bioavailability.

The aim of the present study was to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, and pancreatic and hepatic remodelling in C57BL/6 mice fed on a very HF (high-fat) diet. Male C57BL/6 mice were fed on an HF (60% lipids) diet or SC (standard chow; 10% lipids) diet for 10 weeks, after which time the following drug treatments began: HF-T (HF diet treated with telmisartan; 5.2 mg x kg-1 of body weight x day-1), HF-S (HF diet treated with sitagliptin; 1.08 g x kg-1 of body weight.day-1), HF-M (HF diet treated with metformin; 310.0 mg x kg-1 of body weight x day-1), HF-TM (HF diet treated with telmisartan+metformin), HF-TS (HF diet treated with telmisartan+sitagliptin) and HF-SM (HF diet treated with sitagliptin+metformin). Treated groups also had free access to the HF diet, and treatments lasted for 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blot analysis and electron microscopy were used. The HF diet yielded an overweight phenotype, an increase in oral glucose intolerance, hyperinsulinaemia, hypertrophied islets and adipocytes, stage 2 steatosis (>33%), and reduced liver PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) and GLUT-2 (glucose transporter-2) levels, concomitant with enhanced SREBP-1 (sterol-regulatory-element-binding protein-1) expression (P

Diet-induced obesity in C57BL/6 mice triggers common features of human metabolic syndrome (MetS). The purpose is to assess the suitability of a diet-induced obesity model for investigating non-alcoholic fatty pancreatic disease (NAFPD), fatty liver and insulin resistance. Adult C57BL/6 mice were fed either high-fat chow (HFC, 60% fat) or standard chow (SC, 10% fat) during a 16-week period. We evaluated in both groups: hepatopancreatic injuries, pancreatic islets size, alpha and beta-cell immunodensities, intraperitoneal insulin tolerance test (IPITT) and oral glucose tolerance test (OGTT). The HFC mice displayed greater mass gain (p