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AIM: Tirzepatide (Tzp), a novel dual agonist glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1, is approved for treating insulin resistance and obesity, and menopausal women consuming a high-calorie diet are a target to study the Tzp effect. Therefore, we aimed to allometrically scale body weight (BW) in Tzp-treated obese diabetic menopausal mice. MATERIALS AND METHODS: Three-month-old C57BL/6 female mice had bilateral ovariectomy (Ovx) or a sham procedure and for 12 weeks were fed a control diet or a high-fat and high sucrose diet (n = 120/each group [control (C), obese diabetic (Od), Ovx (O), sham (S), Tzp (T)]). Tzp was subcutaneously administered (10 nmol/kg) or vehicle once a day for an additional 4 weeks. The analysis considered log-transformed data and the allometric equation log y = log a + b log x. RESULTS: Od and OdO showed more upward slopes than C and CO. In C, BW was non-allometric by T administration. Od and OdO showed slightly positive slopes (more prominent in OdO than Od). OdT and OdOT showed negative slopes, significant intercepts, and more robust Pearson coefficients than untreated ones. A potent drug effect was seen with BW allometric decline. Interactions between diet versus Ovx and diet versus Tzp affected weight gain. Diet versus Ovx versus Tzp affected food intake. CONCLUSIONS: A model was developed to show three usual factors observed in mature women. Notably, Tzp improved the metabolism and weight loss of OdO mice. Tzp-treated mice showed negative allometric BW across treatment time, which is a quantitative assessment that allows better comparison between results.
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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.
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Receptor do Peptídeo Semelhante ao Glucagon 1 , Gordura Intra-Abdominal , Animais , Masculino , Camundongos , Dieta Hiperlipídica , Estresse do Retículo Endoplasmático , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Inflamação/tratamento farmacológico , Gordura Intra-Abdominal/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Receptores Ativados por Proliferador de Peroxissomo , Gordura Subcutânea , Redução de Peso , Tecido Adiposo MarromRESUMO
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.
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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.
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Hipocampo/patologia , Inflamação/tratamento farmacológico , Liraglutida/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Região CA1 Hipocampal/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Giro Denteado/patologia , Genes MHC da Classe II/genética , Gliose/patologia , Inflamação/prevenção & controle , Injeções Intraventriculares , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/ultraestrutura , Palmitatos , Reação em Cadeia da Polimerase , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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 (â¼23% 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.
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BACKGROUND: Monotherapy to treat obesity-associated liver insult is limited. OBJECTIVES: In diet-induced obese mice showing metabolic dysfunction-associated steatotic liver disease (MASLD), we aimed to compare the combinations of sodium-glucose cotransporter-2 inhibitor (SGLT2i, empagliflozin, E), dipeptidyl peptidase-4 inhibitor (DPP4i, linagliptin, L), and glucagon-like peptide type 1 receptor agonist (GLP1RA, dulaglutide, D). METHODS: Male 3-month-old C57BL/6J mice were fed for 12 weeks in a control (C, n = 10) or high-fat (HF, n = 30) diet. Then, mice were followed for three additional weeks: C, HF, HF E + L, and HF E + D (n = 10/group). RESULTS: HF versus C showed higher hepatic triacylglycerol (TAG, +82%), steatosis (+850%), glucose intolerance (+71%), insulin (+98%), and insulin resistance (+68%). Compared to the HF group, HF E + L showed lower glucose intolerance (-60%), insulin (-61%), insulin resistance (-46%), TAG (-61%), and steatosis (-58%), and HF E + D showed lower glucose intolerance (-71%), insulin (-58%), insulin resistance (-62%), TAG (-61%), and steatosis (-82%). The principal component analysis (PCA) placed the HF group and the HF E + D group on opposite sides, while the HF E + L group was placed between C and HF E + D. CONCLUSION: PCA separated the groups considering the metabolism-related genes (glucose and lipid), mitochondrial biogenesis, and steatosis. The two pharmacological combinations showed beneficial effects in treating obesity and MASLD. However, the combination of SGLT2i and GLP1RA showed more potent beneficial effects on MASLD than SGLT2i and DPP4i and, therefore, should be the recommended combination.
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The increasing global prevalence and associated comorbidities need innovative approaches for type 2 diabetes mellitus (T2DM) prevention and treatment. Genetics contributes significantly to T2DM susceptibility, and genetic counseling is significant in detecting and informing people about the diabetic risk. T2DM is also intricately linked to overnutrition and obesity, and nutritional advising is beneficial to mitigate diabetic evolution. However, manipulating pancreatic cell plasticity and transdifferentiation could help beta cell regeneration and glucose homeostasis, effectively contributing to the antidiabetic fight. Targeted modulation of transcription factors is highlighted for their roles in various aspects of pancreatic cell differentiation and function, inducing non-beta cells' conversion into functional beta cells (responsive to glucose). In addition, pharmacological interventions targeting specific receptors and pathways might facilitate cell transdifferentiation aiming to maintain or increase beta cell mass and function. However, the mechanisms underlying cellular reprogramming are not yet well understood. The present review highlights the primary transcriptional factors in the endocrine pancreas, focusing on transdifferentiation as a primary mechanism. Therefore, islet cell reprogramming, converting one cell type to another and transforming non-beta cells into insulin-producing cells, depends, among others, on transcription factors. It is a promising fact that new transcription factors are discovered every day, and their actions on pancreatic islet cells are revealed. Exploring these pathways associated with pancreatic development and islet endocrine cell differentiation could unravel the molecular intricacies underlying transdifferentiation processes, exploring novel therapeutic strategies to treat diabetes. The medical use of this biotechnology is expected to be achievable within a short time.
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Transdiferenciação Celular , Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/citologia , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/metabolismo , Animais , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Diferenciação Celular , Pâncreas/metabolismo , Pâncreas/patologiaRESUMO
Maternal obesity might induce obesity and metabolic alterations in the progeny. The study aimed to determine the effect of supplementing obese mothers with Mel (Mel) on thermogenesis and inflammation. C57BL/6 female mice (mothers) were fed from weaning to 12 weeks control diet (C, 17% kJ as fat) or a high-fat diet (HF, 49% kJ as fat) and then matted with male mice fed the control diet. Melatonin (10 mg/kg daily) was supplemented to mothers during gestation and lactation, forming the groups C, CMel, HF, and HFMel (n = 10/group). Twelve-week male offspring were studied (plasma biochemistry, immunohistochemistry, protein, and gene expressions at the hypothalamus - Hyp, subcutaneous white adipose tissue - sWAT, and interscapular brown adipose tissue - iBAT). Comparing HFMel vs. HF offspring, fat deposits and plasmatic proinflammatory markers decreased. Also, HFMel showed decreased Hyp proinflammatory markers and neuropeptide Y (anabolic) expression but improved proopiomelanocortin (catabolic) expression. Besides, HFMel sWAT adipocytes changed to a beige phenotype with-beta-3 adrenergic receptor and uncoupling protein-1 activation, concomitant with browning genes activation, triggering the iBAT thermogenic activity. In conclusion, compelling evidence indicated the beneficial effects of supplementing obese mothers with Mel on the health of their mature male offspring. Mel led to sWAT browning-related gene enhancement, increased iBAT thermogenis, and mitigated hypothalamic inflammation. Also, principal component analysis of the data significantly separated the untreated obese mother progeny from the progeny of treated obese mothers. If confirmed in humans, the findings encourage a future guideline recommending Mel supplementation during pregnancy and breastfeeding.
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Dieta Hiperlipídica , Suplementos Nutricionais , Hipotálamo , Inflamação , Melatonina , Camundongos Endogâmicos C57BL , Obesidade Materna , Termogênese , Animais , Termogênese/efeitos dos fármacos , Feminino , Melatonina/farmacologia , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Masculino , Gravidez , Obesidade Materna/metabolismo , Inflamação/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Fenômenos Fisiológicos da Nutrição Materna , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genéticaRESUMO
The hypothalamic neuropeptides linked to appetite and satiety were investigated in obese mice treated with cotadutide (a dual receptor agonist of glucagon-like peptide 1 (GLP-1R)/Glucagon (GCGR)). 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. Each group was further divided, adding cotadutide treatment and forming groups C, CC, HF, and HFC for four additional weeks. The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART). Cotadutide enhanced POMC and CART neuropeptides and depressed NPY and AGRP neuropeptides. In addition, gene expressions (RT-qPCR) determined that Lepr (leptin receptor) and Calcr (calcitonin receptor) were diminished in HF compared to C but enhanced in CC compared to C and HFC compared to HF. Besides, Socs3 (suppressor of cytokine signaling 3) was decreased in HFC compared to HF, while Sst (somatostatin) was higher in HFC compared to HF; Tac1 (tachykinin 1) and Mc4r (melanocortin-4-receptor) were lower in HF compared to C but increased in HFC compared to HF. Also, Glp1r and Gcgr were higher in HFC compared to HF. In conclusion, the findings are compelling, demonstrating the effects of cotadutide on hypothalamic neuropeptides and hormone receptors of obese mice. Cotadutide modulates energy balance through the gut-brain axis and its associated signaling pathways. The study provides insights into the mechanisms underlying cotadutide's anti-obesity effects and its possible implications for obesity treatment.
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Glucagon , Neuropeptídeos , Peptídeos , Camundongos , Animais , Masculino , Proteína Relacionada com Agouti , Glucagon/metabolismo , Camundongos Obesos , Pró-Opiomelanocortina/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Camundongos Endogâmicos C57BL , Neuropeptídeos/genética , Hipotálamo/metabolismo , Neuropeptídeo Y/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismoRESUMO
PURPOSE: This study aimed to evaluate the role of caffeine chronic administration during gestation of C57BL/6 mice on cardiac remodeling and the expression of components of the renin-angiotensin system (RAS) in male offspring as adults. METHODS: Pregnant C57BL/6 female mice were divided into two groups (n = 10): Control group (C), dams were injected with the vehicle only (saline 0.9% NaCl); Caffeine group (CF), dams received daily a subcutaneous injection of 20 mg/kg of caffeine/day (1 mg/mL saline). Pups had free access to standard chow since weaning to 3 months of age, when they were killed. RESULTS: CF group showed increased energy expenditure (+7%) with consequent reduction in body mass (BM) gain (-18%), increased blood pressure (+48%), and higher heart rate (+10%) than C group. The ratio between LV mass/BM was greater (+10%), with bigger cardiomyocytes (+40%), and reduced vascularization (-25%) in CF group than in C group. In the LV, the expression of angiotensin-converting enzyme (+30%), Angiotensin II (AngII) (+60%), AngII receptor (ATR)-1 (+77%) were higher, and the expression of ATR-2 was lower (-46%; P < 0.05) in CF group than in C group. In the kidney, the expressions of renin (+128%) and ATR-1 (+88%) were higher in CF group than in C group. CONCLUSIONS: Chronic administration of caffeine to pregnant dams led to persistent activation of local RAS in the kidney and heart of the offspring, which, in turn, leads to high BP and adverse cardiac remodeling. These findings highlight the urge to encourage pregnant women to avoid food or medicines containing caffeine.
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Cafeína/administração & dosagem , Cafeína/efeitos adversos , Coração/efeitos dos fármacos , Coração/embriologia , Exposição Materna/efeitos adversos , Angiotensina II/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Hipertensão/etiologia , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Rim/embriologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Renina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
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.
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Fígado Gorduroso/metabolismo , Frutose/metabolismo , Resistência à Insulina , Fígado/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Fígado Gorduroso/patologia , Frutose/administração & dosagem , Humanos , Fígado/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica , Obesidade/metabolismo , Obesidade/patologia , Sobrepeso/metabolismo , Sobrepeso/patologiaRESUMO
Melatonin supplementation to obese mothers during gestation and lactation might benefit the pancreatic islet cellular composition and beta-cell function in male offspring adulthood. C57BL/6 females (mothers) were assigned to two groups (n = 20/each) based on their consumption in control (C 17% kJ as fat) or high-fat diet (HF 49% kJ as fat). Mothers were supplemented with melatonin (Mel) (10 mg/kg daily) during gestation and lactation, or vehicle, forming the groups (n = 10/each): C, CMel, HF, and HFMel. The male offspring were studied, considering they only received the C diet after weaning until three months old. The HF mothers and their offspring showed higher body weight, glucose intolerance, insulin resistance, and low insulin sensitivity than the C ones. However, HFMel mothers and their offspring showed improved glucose metabolism and weight loss than the HF ones. Also, the offspring's higher expressions of pro-inflammatory markers and endoplasmic reticulum (ER) stress were observed in HF but reduced in HFMel. Contrarily, antioxidant enzymes were less expressed in HF but improved in HFMel. In addition, HF showed increased beta-cell mass and hyperinsulinemia but diminished in HFMel. Besides, the beta-cell maturity and identity gene expressions diminished in HF but enhanced in HFMel. In conclusion, obese mothers supplemented with melatonin benefit their offspring's islet cell remodeling and function. In addition, improving pro-inflammatory markers, oxidative stress, and ER stress resulted in better glucose and insulin levels control. Consequently, pancreatic islets and functioning beta cells were preserved in the offspring of obese mothers supplemented with melatonin.
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Resistência à Insulina , Ilhotas Pancreáticas , Melatonina , Efeitos Tardios da Exposição Pré-Natal , Feminino , Masculino , Gravidez , Humanos , Melatonina/farmacologia , Melatonina/metabolismo , Obesidade/metabolismo , Ilhotas Pancreáticas/metabolismo , Lactação/metabolismo , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
AIMS: To investigate, in the liver of adult offspring, the possible effects of melatonin supplementation in the obese mother during pregnancy and lactation. MAIN METHODS: C57BL/6 females were fed with a control (C) or a high-fat (HF) diet and supplemented with melatonin (Mel) during the pregnancy and lactation, forming the groups: C, CMel, HF, and HFMel. After weaning until three months old, the offspring only received the C diet. KEY FINDINGS: The HF mothers and their offspring showed higher body weight (BW) than the C mothers and offspring. However, at 3-mo-old, BW was reduced in HFMel vs. HF offspring. Also, plasmatic and liver lipid markers increased in HF vs. C offspring but were reduced in HFMel vs. HF offspring. Liver lipid content was lessened in HFMel vs. HF offspring by 50 %. Also, lipid metabolism, pro-inflammatory and endoplasmic reticulum (ER) stress genes were higher expressed in HF vs. C offspring but reduced in HFMel vs. HF offspring. Contrarily, beta-oxidation and antioxidant enzyme genes were less expressed in HF vs. C offspring but improved in HFMel vs. HF offspring. Finally, AMPK/mTOR pathway genes, initially dysregulated in the HF, were restored in the HFMel offspring. SIGNIFICANCE: The obese mother leads to liver alterations in the offspring. Current findings demonstrated the maternal melatonin supplementation during pregnancy and lactation in adult offspring's liver. Consequently, the effects were seen in mitigating the liver's AMPK/mTOR pathway genes, lipogenesis, beta-oxidation, inflammation, oxidative stress, and ER stress, preventing liver disease progression in the offspring.
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Fígado Gorduroso , Melatonina , Obesidade , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Camundongos , Gravidez , Proteínas Quinases Ativadas por AMP , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Estresse do Retículo Endoplasmático , Inflamação , Lipídeos , Fenômenos Fisiológicos da Nutrição Materna , Melatonina/farmacologia , Camundongos Endogâmicos C57BL , Mães , Estresse Oxidativo , Serina-Treonina Quinases TORRESUMO
AIMS: The extracellular matrix (ECM) is fundamental for the normal endocrine functions of pancreatic islet cells and plays key roles in the pathophysiology of type 2 diabetes. Here we investigated the turnover of islet ECM components, including islet amyloid polypeptide (IAPP), in an obese mouse model treated with semaglutide, a glucagon-like peptide type 1 receptor agonist. MAIN METHODS: Male one-month-old C57BL/6 mice were fed a control diet (C) or a high-fat diet (HF) for 16 weeks, then treated with semaglutide (subcutaneous 40 µg/kg every three days) for an additional four weeks (HFS). The islets were immunostained and gene expressions were assessed. KEY FINDINGS: Comparisons refer to HFS vs HF. Thus, IAPP immunolabeling and beta-cell-enriched beta-amyloid precursor protein cleaving enzyme (Bace2, -40 %) and heparanase immunolabeling and gene (Hpse, -40 %) were mitigated by semaglutide. In contrast, perlecan (Hspg2, +900 %) and vascular endothelial growth factor A (Vegfa, +420 %) were enhanced by semaglutide. Also, semaglutide lessened syndecan 4 (Sdc4, -65 %) and hyaluronan synthases (Has1, -45 %; Has2, -65 %) as well as chondroitin sulfate immunolabeling, and collagen type 1 (Col1a1, -60 %) and type 6 (Col6a3, -15 %), lysyl oxidase (Lox, -30 %) and metalloproteinases (Mmp2, -45 %; Mmp9, -60 %). SIGNIFICANCE: Semaglutide improved the turnover of islet heparan sulfate proteoglycans, hyaluronan, chondroitin sulfate proteoglycans, and collagens in the islet ECM. Such changes should contribute to restoring a healthy islet functional milieu and should reduce the formation of cell-damaging amyloid deposits. Our findings also provide additional evidence for the involvement of islet proteoglycans in the pathophysiology of type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Camundongos , Animais , Masculino , Camundongos Obesos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Camundongos Endogâmicos C57BL , Ilhotas Pancreáticas/metabolismo , Peptídeos Semelhantes ao Glucagon/farmacologia , Matriz Extracelular/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , DietaRESUMO
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.
Assuntos
Tecido Adiposo Marrom , Fator A de Crescimento do Endotélio Vascular , Camundongos , Animais , Masculino , Tecido Adiposo Marrom/metabolismo , Camundongos Obesos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Adipócitos Marrons , Dieta Hiperlipídica/efeitos adversos , Termogênese , Dinaminas/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismoRESUMO
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<0.0001). Conversely, all drug treatments resulted in significant weight loss, a reversal of insulin resistance, islet and adipocyte hypertrophy, and alleviated hepatic steatosis. Only the HF-T and HF-TS groups had body weights similar to the SC group at the end of the experiment, and the latter treatment reversed hepatic steatosis. Increased PPAR-alpha immunostaining in parallel with higher GLUT-2 and reduced SREBP-1 expression may explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-alpha (tumour necrosis factor-alpha) levels (P<0.0001) in the drug-treated groups. In conclusion, all of the drug treatments were effective in controlling the metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-gamma agonism and PPAR-alpha activation in the liver with extended incretin action.
Assuntos
Benzimidazóis/uso terapêutico , Benzoatos/uso terapêutico , Gorduras na Dieta/administração & dosagem , Síndrome Metabólica/tratamento farmacológico , Metformina/uso terapêutico , Obesidade/tratamento farmacológico , Pirazinas/uso terapêutico , Triazóis/uso terapêutico , Adipócitos/patologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Ingestão de Energia/efeitos dos fármacos , Teste de Tolerância a Glucose , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Fígado/fisiopatologia , Fígado/ultraestrutura , Masculino , Síndrome Metabólica/patologia , Síndrome Metabólica/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/patologia , Obesidade/fisiopatologia , Pâncreas/fisiopatologia , Fosfato de Sitagliptina , TelmisartanRESUMO
OBJECTIVE: This work aimed to verify the hypothesis that maternal intake of high-fat diet in critical periods of pregnancy and/or suckling period predisposes nonalcoholic fatty liver disease in adult C57BL/6 mice offspring. STUDY DESIGN: Male pups were divided into 5 groups: (1) SC, from standard chow-fed dams; (2) G, from high-fat chow (HF)-fed dams during the gestation (G) period; (3) L, from HF-fed dams during the lactation (L) period; (4) GL, from HF-fed dams during the gestation and lactation (GL) periods; and (5) GL/HF, from HF-fed dams during GL, maintaining an HF diet from postweaning to adulthood. We analyzed body mass, plasma blood, and liver structure. RESULTS: The G offspring showed insulin resistance and lower glucose transporter-2 expression. Hepatic steatosis was present in the G, L, GL, and mainly in GL/HF offspring. Sterol regulatory element-binding protein-1c expression was higher in G, GL, and GL/HF offspring. CONCLUSION: Programming by HF chow predisposes hepatic adverse remodeling in the liver of adult offspring.
Assuntos
Gorduras na Dieta/metabolismo , Fígado Gorduroso/etiologia , Fígado/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Análise de Variância , Animais , Glicemia , Western Blotting , Peso Corporal , Suscetibilidade a Doenças/metabolismo , Ensaio de Imunoadsorção Enzimática , Fígado Gorduroso/metabolismo , Feminino , Teste de Tolerância a Glucose , Insulina/sangue , Resistência à Insulina , Masculino , Camundongos , Gravidez , Radioimunoensaio , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Photodynamic therapy (PDT) is an option for skin rejuvenation. Although many studies report clinical improvement with PDT in photodamaged skin, histologic and morphometric evidence is not documented in most cases. OBJECTIVE: To evaluate clinical and histopathologic changes induced by methyl aminolevulinate (MAL)-PDT and to morphometrically quantify collagen and elastic fibers in skin remodeling induced by MAL-PDT in photodamaged skin. METHODS AND MATERIALS: Fourteen patients were treated with two sessions of MAL-PDT. The light source was a light-emitting diode: 635 nm, 37 J/cm(2). Skin biopsies were performed before and 3 and 4 months after treatment. All fragments were stained using the hematoxylin-eosin, orcein, and picrosirius techniques. Morphometric studies were done of three samples from each patient. RESULTS: Global clinical improvement was observed in 10 of 14 patients. The histopathologic study showed increased collagen fibers 3 and 6 months after treatment. The decrease in the amount of elastic fiber was statistically significant 3 (p=.016) and 6 (p=.008) months after treatment. The increase in the amount of collagen fiber was statistically significant 6 months after treatment (p=.048). CONCLUSION: Clinical improvement with regard to texture, firmness, wrinkle depth, skin coloration, and clearance of actinic keratoses was observed. Histopathologic and morphometric studies were consistent with the clinical findings.
Assuntos
Ácido Aminolevulínico/análogos & derivados , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Envelhecimento da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Ácido Aminolevulínico/uso terapêutico , Colágeno , Tecido Elástico , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , RejuvenescimentoRESUMO
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), and 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 the father, the 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 in the progeny.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Açúcares da Dieta/efeitos adversos , Frutose/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fatores Sexuais , Adiponectina/sangue , Tecido Adiposo/fisiopatologia , Animais , Glicemia/análise , Pressão Sanguínea , Pai , Comportamento Alimentar , Feminino , Fatores de Risco de Doenças Cardíacas , Insulina/sangue , Leptina/sangue , Masculino , Exposição Materna , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Camundongos Endogâmicos C57BL , Mães , Exposição Paterna , Gravidez , Ácido Úrico/sangueRESUMO
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 14â¯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.