Cotadutide improves brown adipose tissue thermogenesis in obese mice.

We studied the effect of cotadutide, a dual agonist glucagon-like peptide 1 (GLP1)/Glucagon, on interscapular brown adipose tissue (iBAT) remodeling and thermogenesis of obese mice. Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Then, animals were redivided, adding cotadutide treatment: C, CC, HF, and HFC for four additional weeks. The multilocular brown adipocyte structure showed fat conversion (whitening), hypertrophy, and structural disarray in the HF group, which was reverted in cotadutide-treated animals. Cotadutide enhances the body temperature, thermogenesis, and sympathetic innervation (peroxisome proliferator-activated receptor-α, ß3 adrenergic receptor, interleukin 6, and uncoupled protein 1), reduces pro-inflammatory markers (disintegrin and metallopeptidase domain, morphogenetic protein 8a, and neuregulin 4), and improves angiogenesis (vascular endothelial growth factor A, and perlecan). In addition, cotadutide enhances lipolysis (perilipin and cell death-inducing DNA fragmentation factor α), mitochondrial biogenesis (nuclear respiratory factor 1, transcription factor A mitochondrial, mitochondrial dynamin-like GTPase, and peroxisome proliferator-activated receptor gamma coactivator 1α), and mitochondrial fusion/fission (dynamin-related protein 1, mitochondrial fission protein 1, and parkin RBR E3 ubiquitin protein ligase). Cotadutide reduces endoplasmic reticulum stress (activating transcription factor 4, C/EBP homologous protein, and growth arrest and DNA-damage inducible), and extracellular matrix markers (lysyl oxidase, collagen type I α1, collagen type VI α3, matrix metallopeptidases 2 and 9, and hyaluronan synthases 1 and 2). In conclusion, the experimental evidence is compelling in demonstrating cotadutide's thermogenic effect on obese mice's iBAT, contributing to unraveling its action mechanisms and the possible translational benefits.

Semaglutide (GLP-1 receptor agonist) stimulates browning on subcutaneous fat adipocytes and mitigates inflammation and endoplasmic reticulum stress in visceral fat adipocytes of obese mice.

Semaglutide (GLP-1 agonist) was approved for treating obesity. Although the effects on weight loss and metabolism are known, the responses of adipocytes to semaglutide are yet limited. C57BL/6 male mice (n = 20/group) were fed a control diet (C) or a high-fat (HF) diet for 16 weeks and then separated into four groups (n = 10/group) for an additional four weeks: C, C diet and semaglutide, HF, and HF diet and semaglutide. Epididymal white adipose tissue (eWAT) and subcutaneous white adipose tissue (sWAT) fat pads were studied with biochemistry, immunohistochemistry/fluorescence, stereology, and reverse transcription-quantitative polymerase chain reaction. In obese mice, semaglutide reduced the fat pad masses (eWAT, -55%; sWAT, -40%), plasmatic cytokines, and proinflammatory gene expressions: tumor necrosis factor-alpha (-60%); interleukin (IL)-6 (-55%); IL-1 beta (-40%); monocyte chemoattractant protein-1 (-90%); and leptin (-80%). Semaglutide also lessened endoplasmic reticulum (ER) stress genes of activating transcription factor-4 (-85%), CCAAT enhancer-binding protein homologous protein (-55%), and growth arrest and DNA damage-inducible gene 45 (-45%). The obese mice's adipocyte hypertrophy and macrophage infiltration were equally reduced by semaglutide. Semaglutide enhanced multiloculation and uncoupled protein 1 (UCP1) labeling in obese mice: peroxisome proliferator-activated receptor-alpha (+560%) and gamma (+150%), fibronectin type III domain-containing protein 5 (+215%), peroxisome proliferator-activated receptor-alpha coactivator (+110%), nuclear respiratory factor 1 (+260%), and mitochondrial transcription factor A (+120%). Semaglutide also increased thermogenetic gene expressions for the browning phenotype maintenance: beta-3 adrenergic receptor (+520%), PR domain containing 16 (+90%), and Ucp1 (+110%). In conclusion, semaglutide showed significant beneficial effects beyond weight loss, directly on fat pads and adipocytes of obese mice, remarkably anti-inflammatory, and reduced adipocyte size and ER stress. Besides, semaglutide activated adipocyte browning, improving UCP1, mitochondrial biogenesis, and thermogenic marker expressions help weight loss.

The deficiency and the supplementation of vitamin D and liver: Lessons of chronic fructose-rich diet in mice.

The fructose added to soft drinks and processed food, as well as frequent detection of vitamin D deficiency in the body, are two insults increasingly considered to cause lesions in target organs. We studied the liver after a chronic high-fructose diet deficient and supplemented with vitamin D. Sixty C57BL/6 mature male mice were allocated into six groups (n = 10) for ten weeks: control (C), control deficient in vitamin D (CDD), control supplemented with vitamin D (CDS), fructose (F), fructose deficient in vitamin D (FDD), and fructose supplemented with vitamin D (FDS). The gene expressions of vitamin D receptor and CYP27B1 and 25 hydroxyvitamin D plasma level ensured that the diets caused vitamin D deficiency or supplementation. Body mass did not change, but blood pressure (BP) increased in CDD, F, and FDD, whereas BP was controlled in FDS. Insulinemia, insulin tolerance and resistance were seen in both vitamin D deficiency and fructose groups but improved with vitamin D supplementation. The steatosis and fibrosis were observed in the CDD, F and FDD groups. Also, F and FDD showed activation of stellate cells (HSC). Lipogenesis and inflammation gene expressions were enhanced in the CDD, F and FDD groups, but diminished with vitamin D supplementation. In conclusion, we demonstrated the adverse effects of vitamin D deficiency on metabolism, liver steatosis and, combined with fructose intake, liver interstitial fibrosis with hepatic stellate cell activation, and alteration of the lipogenesis, beta-oxidation, and liver inflammation. All these data improved when vitamin D was supplemented in the animals.

Browning is activated in the subcutaneous white adipose tissue of mice metabolically challenged with a high-fructose diet submitted to high-intensity interval training.

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.

Vitamin D deficiency aggravates the liver metabolism and inflammation in ovariectomized mice.

AIMS: A prevalence of vitamin D deficiency has been reported in association with the postmenopause. Thus, we aimed to experimentally study the effect of the vitamin D deficiency and ovariectomy, alone or combined, in the liver damage. MAIN METHODS: Three-months-old female mice C57BL/6 with bilateral ovariectomy (Ovx group, n = 30) or a sham procedure (n = 30) were separated feeding control diet (C, n = 15) or a diet restricted in vitamin D (D-, n = 15) during additional 12 weeks. KEY FINDINGS: Body mass (BM) and blood pressure (BP) were higher in Ovx than in C animals, but highest in Ovx (D-) that also showed glucose intolerance/ insulin resistance. Plasmatic lipids, alanine aspartase transferase, and hepatic steatosis were increased because of the combination of Ovx and D-. However, D- had little implication in the changes of the BM and BP, but affected hepatic steatosis. Gene and protein expressions demonstrated an impaired glucose uptake in the liver because of Ovx and D-, and an increase in lipogenesis and decrease in beta-oxidation in the liver associated more to the Ovx, but also evident in D-. Also, interleukin 6 and tumor necrosis factor alpha showed an enhancement due to dietary restriction of vitamin D. SIGNIFICANCE: The findings demonstrated that ovariectomy and dietary restriction of vitamin D are inducers of harmful effects on the liver of mice, enhancing lipogenesis and inflammation and compromising beta-oxidation. The treatment of vitamin D deficiency is simple and not costly and can reduce the impact of menopause on metabolism and especially the liver.

Obese fathers lead to an altered metabolism and obesity in their children in adulthood: review of experimental and human studies / Pais obesos levam a metabolismo alterado e obesidade em seus filhos na idade adulta: revisão de estudos experimentais e humanos

Abstract Objective: To discuss the recent literature on paternal obesity, focusing on the possible mechanisms of transmission of the phenotypes from the father to the children. Sources: A non-systematic review in the PubMed database found few publications in which paternal obesity was implicated in the adverse transmission of characteristics to offspring. Specific articles on epigenetics were also evaluated. As the subject is recent and still controversial, all articles were considered regardless of year of publication. Summary of findings: Studies in humans and animals have established that paternal obesity impairs their hormones, metabolism, and sperm function, which can be transmitted to their offspring. In humans, paternal obesity results in insulin resistance/type 2 diabetes and increased levels of cortisol in umbilical cord blood, which increases the risk factors for cardiovascular disease. Notably, there is an association between body fat in parents and the prevalence of obesity in their daughters. In animals, paternal obesity led to offspring alterations on glucose-insulin homeostasis, hepatic lipogenesis, hypothalamus/feeding behavior, kidney of the offspring; it also impairs the reproductive potential of male offspring with sperm oxidative stress and mitochondrial dysfunction. An explanation for these observations (human and animal) is epigenetics, considered the primary tool for the transmission of phenotypes from the father to offspring, such as DNA methylation, histone modifications, and non-coding RNA. Conclusions: Paternal obesity can induce programmed phenotypes in offspring through epigenetics. Therefore, it can be considered a public health problem, affecting the children's future life.

Resumo Objetivo: Discutir a literatura recente sobre obesidade paterna, focalizando os possíveis mecanismos de transmissão dos fenótipos do pai para os filhos. Fontes: Uma revisão não-sistemática no banco de dados PubMed encontrou poucas publicações com obesidade paterna implicada com a transmissão adversa das características à prole. Artigos específicos sobre epigenética também foram avaliados. Como o assunto é recente e ainda controverso, todos os trabalhos foram considerados independentemente do ano de publicação. Resumo dos achados: Estudos em seres humanos e animais estabeleceram que a obesidade do pai prejudica seus hormônios, metabolismo e função espermática, que pode ser transmitida à prole. Em humanos, a obesidade paterna resulta em resistência à insulina / diabetes tipo 2 e aumento do nível de cortisol no sangue do cordão umbilical, que aumenta os fatores de risco para doença cardiovascular. Notavelmente, existe associação entre a gordura corporal nos pais e a prevalência de obesidade em suas filhas. Em animais, pais obesos condicionam, na prole, a homeostase glicose-insulina, lipogênese hepática, hipotálamo / comportamento alimentar, rim, prejudicam o potencial reprodutivo da prole masculina com estresse oxidativo espermático e disfunção mitocondrial. Uma explicação para estas observações (humanos e animais) é a epigenética, considerada a ferramenta básica para a transmissão de fenótipos do pai à prole, como a metilação do DNA, modificações nas histonas, e RNA não codificante. Conclusões: A obesidade paterna pode induzir fenótipos programados na prole através da epigenética. Portanto, a obesidade paterna pode ser considerada um problema de saúde pública, afetando a vida futura das crianças.

Obese fathers lead to an altered metabolism and obesity in their children in adulthood: review of experimental and human studies.

OBJECTIVE: To discuss the recent literature on paternal obesity, focusing on the possible mechanisms of transmission of the phenotypes from the father to the children. SOURCES: A non-systematic review in the PubMed database found few publications in which paternal obesity was implicated in the adverse transmission of characteristics to offspring. Specific articles on epigenetics were also evaluated. As the subject is recent and still controversial, all articles were considered regardless of year of publication. SUMMARY OF FINDINGS: Studies in humans and animals have established that paternal obesity impairs their hormones, metabolism, and sperm function, which can be transmitted to their offspring. In humans, paternal obesity results in insulin resistance/type 2 diabetes and increased levels of cortisol in umbilical cord blood, which increases the risk factors for cardiovascular disease. Notably, there is an association between body fat in parents and the prevalence of obesity in their daughters. In animals, paternal obesity led to offspring alterations on glucose-insulin homeostasis, hepatic lipogenesis, hypothalamus/feeding behavior, kidney of the offspring; it also impairs the reproductive potential of male offspring with sperm oxidative stress and mitochondrial dysfunction. An explanation for these observations (human and animal) is epigenetics, considered the primary tool for the transmission of phenotypes from the father to offspring, such as DNA methylation, histone modifications, and non-coding RNA. CONCLUSIONS: Paternal obesity can induce programmed phenotypes in offspring through epigenetics. Therefore, it can be considered a public health problem, affecting the children's future life.

Beneficial effects of liraglutide (GLP1 analog) in the hippocampal inflammation.

The brain is very sensitive to metabolic dysfunctions induced by diets high in saturated fatty acids, leading to neuroinflammation. The liraglutide has been found to have neuroprotective effects. However, its neuroprotective action in a model of palmitate-induced neuroinflammation had not yet been evaluated. Mice were intracerebroventricular (ICV) infused with palmitate and received subcutaneous liraglutide. The hippocampal dentate gyrus and CA1 regions were analyzed (morphology and inflammation-related proteins in microglia and astrocyte by confocal microscopy). Also, a real-time PCR was performed to measure the levels of tumor necrosis factor (TNF) alpha and interleukin (IL) 6. Palmitate ICV infusion resulted in pronounced inflammation response in the hippocampus, reactive microgliosis, and astrogliosis, with hypertrophied IBA1 immunoreactive microglia, increased microglial density with ameboid shape, decreased in the number of branches and junctions and increased the major histocompatibility complex (MHC) II expression. Also, we observed in the hippocampus of ICV palmitate infused mice an elevation in the pro-inflammatory cytokine levels TNFalpha and IL6. Liraglutide induced the neuroprotective microglial phenotype, characterized by an increased microglia complexity (enlarged Feret's diameter), an improved number of both cell junctions and processes, and lower circularity, accompanied by a significant reduction in TNFalpha and IL6 expressions. The study provides evidence that liraglutide may be a suitable treatment against the palmitate-induced neuroinflammation, which it is characterized by the reactive microgliosis and astrogliosis, as well as increased pro-inflammatory cytokines, which has been described as one of the primary causes of several pathologies of the central nervous system.

Treating fructose-induced metabolic changes in mice with high-intensity interval training: insights in the liver, white adipose tissue, and skeletal muscle.

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 ß-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 ß-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.

Rosuvastatin limits the activation of hepatic stellate cells in diet-induced obese mice.

AIM: The aim of this study was to investigate the effects of rosuvastatin in a model of diet-induced obesity and non-alcoholic fatty liver disease, with attention to 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 7 weeks of treatment. Group CR received control diet + rosuvastatin; group HFR received high-fat diet + rosuvastatin. RESULTS: The HF group showed higher insulin, total cholesterol, 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 HSCs than the C group, whereas rosuvastatin diminished the steatosis (less 21%, P < 0.001) and significantly inhibited the activation of the HSCs in the HFR group compared to the HF group. The sterol regulatory element-binding protein-1 and the peroxisome proliferator-activated receptor (PPAR)-γ protein expressions were increased in HF animals and reduced after treatment in the HFR group. By contrast, low PPAR-α and carnitine palmitoyltransferase-1 expressions were found in the HF group, and were restored by rosuvastatin treatment in the HFR group. CONCLUSION: Rosuvastatin mitigated hepatic steatosis by modulating PPAR balance, favoring PPAR-α over PPAR-γ downstream effects. The effects were accompanied by a diminishing of insulin resistance, the anti-inflammatory adipokine profile, and HSC activation, avoiding non-alcoholic fatty liver disease progression and non-alcoholic steatohepatitis onset in this model.

High-intensity interval training (swimming) significantly improves the adverse metabolism and comorbidities in diet-induced obese mice.

BACKGROUND: Controlling obesity and other comorbidities in the population is a challenge in modern society. High-intensity interval training (HIIT) combines short periods of high-intensity exercise with long recovery periods or a low-intensity exercise. The aim was to assess the impact of HIIT in the context of diet-induced obesity in the animal model. METHODS: C57BL/6 mice were fed one of the two diets: standard chow (lean group [LE]) or a high-fat diet (obese group [OB]). After twelve weeks, the animals were divided into non-trained groups (LE-NT and OB-NT) and trained groups (LE-T and OB-T), and began an exercise protocol. For biochemical analysis of inflammatory and lipid profile, we used a colorimetric enzymatic method and an automatic spectrophotometer. One-way ANOVA was used for statistical analysis of the experimental groups with Holm-Sidak post-hoc Test. Two-way ANOVA analyzed the interactions between diet and HIIT protocol. RESULTS: HIIT leads to significant reductions in body mass, blood glucose, glucose tolerance and hepatic lipid profile in T-groups compared to NT-groups. HIIT was able to reduce plasma levels of inflammatory cytokines. Additionally, HIIT improves the insulin immunodensity in the islets, reduces the adiposity and the hepatic steatosis in the T-groups. HIIT improves beta-oxidation and peroxisome proliferator-activated receptor (PPAR)-alpha and reduces lipogenesis and PPAR-gamma levels in the liver. In skeletal muscle, HIIT improves PPAR-alpha and glucose transporter-4 and reduces PPAR-gamma levels. CONCLUSIONS: HIIT leads to attenuate the adverse effects caused by a chronic ingestion of a high-fat diet.

High-intensity interval training beneficial effects in diet-induced obesity in mice: adipose tissue, liver structure, and pancreatic islets / Efectos beneficiosos del entrenamiento con intervalos de alta intensidad en la obesidad inducida por dieta en ratones: tejido adiposo: estructura del hígado e islotes pancreáticos

The study aimed to evaluate the impact of high-intensity interval training (HIIT) on adipose tissue, pancreatic islets and liver in mice fed high-fat diet. C57BL/6 male mice were fed one of two diets: standard chow (Lean group - LE) or a high-fat diet (Obese group ­ OB). After the first 12-weeks, the animals were divided into non-trained (LE-NT and OB-NT), trained groups (LE-T and OB-T), and started the exercise protocol. The HIIT protocol in the trained animals (LE-T and OB-T) compared to their counterparts (LE-NT and OB-NT) led to a reduction in size of the pancreatic islets (LE-T vs. LE-NT -40 %, OB-T vs. OB-NT -22 %) and to an increase in insulin immunodensity in pancreatic islet (LE-T vs. LE-NT +35 %, OB-T vs. OB-NT +31 %). Apart from the above results, in adipose tissue, a decrease of the diameter of adipocytes (LE-T vs. LE-NT -23 %, OB-T vs. OB-NT -12 %), a reduction in adiposity index (LE-T vs. LE-NT -49 %, OB-T vs. OB-NT -24 %) and in the liver, a decrease in the context of hepatic steatosis (LE-T vs. LE-NT -57 %, OB-T vs. OB-NT -77 %). These metabolic changes characterize a benefits performance of the HIIT protocol in swimming. HIIT is able to mitigate the bad effects caused by high-fat diet, even with continued intake of this diet in an animal model. HIIT has the advantage of requiring only a few weekly sessions with short duration in each session. These benefits are important to motivate people who nowadays live with a lack of time condition for these activities.

El objetivo fue evaluar el impacto del entrenamiento con intervalos de alta intensidad (EIAI) sobre el tejido adiposo, el hígado y los islotes pancreáticos en ratones alimentados con dieta alta en grasas. Ratones C57BL/6, machos fueron alimentados con una de dos dietas: dieta estándar (grupo magro - MA) o una dieta alta en grasas (grupo obeso - OB). Después de las primeras 12 semanas, los animales fueron divididos en dos grupos, no entrenados (MA-NE y OB-NE) y grupos entrenados (MA-E y OB-E), y comenzaron el protocolo de ejercicio. El protocolo de IEAI en los animales entrenados (MA-E y OB-E) en comparación con sus contrapartes (MA-NE y OB-NE) condujo a una reducción en el tamaño de los islotes pancreáticos (MA-E vs. MA-NE -40 %, OB-E vs. OB-NE -22 %) y al aumento de la inmunodensidad de insulina en los islotes pancreáticos (MA-E vs. MA-NE +35 %, OB-E vs. OB-NE +31 %). Además, en el tejido adiposo se detectó una disminución del diámetro de los adipocitos (MA-E vs. MA-NE -23 %, OB-E vs. OB-NE -12 %), una reducción en el índice de adiposidad (MA-E vs. MA-NE -49 %, OB-E vs. OB-NE -24 %) y en el hígado una disminución de la esteatosis (MA-E vs. MA-NE -57 %, OB-E vs. OB-NE -77 %). Estos cambios metabólicos caracterizan una actuación beneficiosa del protocolo de EIAI en la natación. El EIAI es capaz de mitigar los efectos negativos causados por la dieta alta en grasas, incluso con la ingesta continuada de esta dieta en el modelo animal. La EIAI tiene la ventaja de requir sólo unas pocas sesiones semanales con corta duración de cada sesión. Estos beneficios son importantes para motivar a la personas en las condiciones de falta de tiempo que tienen en la actualidad.

Maternal vitamin D-restricted diet has consequences in the formation of pancreatic islet/insulin-signaling in the adult offspring of mice.

The maternal deficiency of vitamin D can act on organogenesis in mice offspring, being a risk factor for chronic diseases in adulthood. This study investigates the effects of maternal deficiency of vitamin D on structural islet remodeling and insulin-signaling pathway in the offspring. We studied male C57Bl/6 offspring at 3-month old (n = 10/group) from mother fed one of the two diets: control diet (C) or vitamin D-restricted diet (VitD-). After weaning, offspring only fed the control diet ad libitum. In the offspring, we studied insulin production, islet remodeling, and islet protein expression of the insulin-signaling pathway (Western blotting, isolated islet, n = 5/group). VitD- offspring showed greater glycemia (P = 0.012), smaller beta-cell mass (P = 0.014), and hypoinsulinemia (P = 0.024) than C offspring. Comparing VitD- offspring with C offspring, we observed lower protein levels in islet of insulin (P = 0.003), insulin receptor substrate-1 (P = 0.025), phosphatidylinositol-3-kinases (P = 0.045), 3-phosphoinositide-dependent protein kinase 1 (P = 0.017), protein kinase B (P = 0.028), with reduced expression of pancreas/duodenum homeobox-1 (PDX-1) (P = 0.016), glucose transporter-2 (P = 0.003), and glucokinase (P = 0.045). The maternal vitamin D-restricted diet modifies the development of the pancreas of the offspring, leading to islet remodeling and altered insulin-signaling pathway. The decrease of PDX-1 is probably significant to the changes in the beta-cell mass and insulin secretion in adulthood.

Effects of liraglutide in hypothalamic arcuate nucleus of obese mice.

OBJECTIVE: The neuroprotective effects of liraglutide (200 µg/kg, twice daily, subcutaneous administration) in the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice were investigated. METHODS: C57BL/6 mice were separated into groups: standard chow treated with vehicle or liraglutide and the respective liraglutide pair-fed group; high-fat diet treated with vehicle or liraglutide and the respective pair-fed group. Body mass (BM) evolution, carbohydrate metabolism, leptin resistance, proteins involved in energetic balance, apoptosis, and microglia in the ARC were studied. RESULTS: Obese animals showed glucose intolerance, resistance to insulin and to anorexigenic effect of leptin, and microgliosis accompanied by elevated Bax/Bcl2 ratio in the ARC. Liraglutide improved the carbohydrate metabolism, BM loss, and the activation of pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) in the ARC. The liraglutide enhanced leptin sensitivity and diminished the microgliosis with decrease in Bax/Bcl2 ratio. CONCLUSIONS: Liraglutide activates central anorexigenic pathways, thereby diminishing the energy intake of obese mice and improving the metabolic parameters related to obesity. Liraglutide is a relevant neuroprotective agent, which can decrease the microgliosis and stimulate the anti-apoptotic pathway, a significant effect in the treatment of obesity and its comorbidities. Some benefits of liraglutide are independent of the BM loss, which usually accompanies the drug administration.

High-intensity interval training beneficial effects on body mass, blood pressure, and oxidative stress in diet-induced obesity in ovariectomized mice.

AIMS: To investigate the possible beneficial effect of high-intensity interval training (HIIT) on skeletal muscle oxidative stress, body mass (BM) and systolic blood pressure (SBP) in ovariectomized mice fed or not fed a high-fat diet. MAIN METHODS: Three-month-old female C57BL/6 mice were bilaterally ovariectomized (OVX group) or submitted to surgical stress without ovariectomy (SHAM group) and separated into standard chow (SHAM-SC; OVX-SC) and high-fat diet (SHAM-HF; OVX-HF) groups. After 13 weeks, an HIIT program (swimming) was carried out for 8 weeks in non-trained (NT) and trained (T) groups. KEY FINDINGS: The significant reduction of uterine mass and the cytological examination of vaginal smears in the OVX group confirmed that ovariectomy was successful. Before the HIIT protocol, the ovariectomized groups showed a greater BM than the SHAM group, irrespective of the diet they received. The HIIT minimized BM gain in animals fed an HF diet and/or ovariectomized. SBP and total cholesterol were increased in the OVX and HF animals compared to their counterparts, and the HIIT efficiently reduced these factors. In the HF and OVX mice, the muscular superoxide dismutase and catalase levels were low while their glutathione peroxidase and glutathione reductase levels were high and the HIIT normalized these parameters. SIGNIFICANCE: Diet-induced obesity maximizes the deleterious effects of an ovariectomy. The HIIT protocol significantly reduced BM, SBP and oxidative stress in the skeletal muscle indicating that HIIT diminishes the cardiovascular and metabolic risk that is inherent to obesity and menopause.

Short-term administration of GW501516 improves inflammatory state in white adipose tissue and liver damage in high-fructose-fed mice through modulation of the renin-angiotensin system.

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.

Differences and similarities in hepatic lipogenesis, gluconeogenesis and oxidative imbalance in mice fed diets rich in fructose or sucrose.

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.

Fenofibrate (PPARalpha agonist) induces beige cell formation in subcutaneous white adipose tissue from diet-induced male obese mice.

Browning is characterized by the formation of beige/brite fat depots in subcutaneous white adipose tissue (sWAT). This study aimed to examine whether the chronic activation of PPARalpha by fenofibrate could induce beige cell depots in the sWAT of diet-induced obese mice. High-fat fed animals presented overweight, insulin resistance and displayed adverse sWAT remodeling. Fenofibrate significantly attenuated these parameters. Treated groups demonstrated active UCP-1 beige cell clusters within sWAT, confirmed through higher gene expression of PPARalpha, PPARbeta, PGC1alpha, BMP8B, UCP-1, PRDM16 and irisin in treated groups. PPARalpha activation seems to be pivotal to trigger browning through irisin induction and UCP-1 transcription, indicating that fenofibrate increased the expression of genes typical of brown adipose tissue (BAT) in the sWAT, characterizing the formation of beige cells. These findings put forward a possible role of PPARalpha as a promising therapeutic for metabolic diseases via beige cell induction.

Role of dietary fish oil on nitric oxide synthase activity and oxidative status in mice red blood cells.

The consumption of n-3 polyunsaturated fatty acids (PUFAs) derived from fish oil concomitant with a reduced intake of saturated fats is associated with cardiovascular benefits, which may result from the participation of nitric oxide (NO). In contrast, PUFAs are vulnerable to peroxidation, which could affect the oxidative stability of the cell and reduce NO bioavailability. Therefore, we investigated the effects of high fat diets with increasing amounts of fish oil (0-40% of energy) in place of lard on the l-arginine-NO pathway, the arginase pathway and oxidative status in mice red blood cells (RBC). We found that l-arginine transport, as well as NO synthase (NOS) expression and activity, was enhanced by the highest doses of fish oil (30 and 40%). In contrast, diets rich in lard led to NOS expression and activity impairment. Arginase expression was not significantly affected by any of the dietary regimens. No significant difference in protein and lipid oxidative markers was observed among any of the fish-oil fed mice; only lard feeding induced protein damage in addition to a decreased superoxide dismutase activity. These data suggest that a substantial dose of fish oil, but not low doses, activates the RBC l-arginine-NO pathway without resulting in oxidative damage.

The inflammatory profile and liver damage of a sucrose-rich diet in mice.

UNLABELLED: It is still unclear if an isoenergetic, sucrose-rich diet leads to health consequences. AIMS: To investigate the effects of excessive sucrose within an isoenergetic diet on metabolic parameters in male C57BL/6 mice. METHODS: 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. RESULTS: 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). CONCLUSION: 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.