RESUMO
Antipsychotic medications are used in the management of schizophrenia and a growing number of off-label conditions. While effective at reducing psychoses, these drugs possess noted metabolic side effects including weight gain, liver lipid accumulation and disturbances in glucose and lipid metabolism. To counter the side effects of antipsychotics standard of care has typically included metformin. Unfortunately, metformin does not protect against antipsychotic induced metabolic disturbances in all patients and thus additional treatment approaches are needed. One potential candidate could be salsalate, the prodrug of salicylate, which acts synergistically with metformin to improve indices of glucose and lipid metabolism in obese mice. The purpose of the current investigation was to compare the effects of salsalate, metformin and a combination of both drugs, on weight gain and indices of metabolic health in female mice treated with the antipsychotic, olanzapine. Herein we demonstrate that salsalate was equally as effective as metformin in protecting against olanzapine induced weight gain and liver lipid accumulation with no additional benefit of combining both drugs. Conversely, metformin treatment, either alone or in combination with salsalate, improved indices of glucose metabolism and increased energy expenditure in olanzapine treated mice. Collectively, our findings provide evidence that dual therapy with both metformin and salsalate could be an efficacious approach with which to dampen the metabolic consequences of antipsychotic medications.
Assuntos
Antipsicóticos , Metformina , Humanos , Feminino , Camundongos , Animais , Olanzapina , Antipsicóticos/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Salicilatos/farmacologia , Aumento de Peso , Lipídeos , Glucose , BenzodiazepinasRESUMO
Increases in postprandial lipids are linked to the development of cardiometabolic and fatty liver disease. Prior work has suggested that dairy possesses beneficial cardiometabolic effects and thus the aim of the current investigation was to test the hypotheses that the habitual consumption of dairy, in the form of skim milk powder (SMP), would protect against increases in circulating lipids and liver lipid accumulation following an oral fat challenge in rats. Male rats were fed either a semipurified low-fat control diet with casein or a diet with an equivalent amount of protein (â¼13% kcal) provided through skim milk powder (SMP) for 6 weeks (n = 40/group). Rats were then given an oral gavage of palm oil (5 mL/kg body weight) or an equivalent volume of water, and serum and liver were harvested 90 minutes or 4 hours after. Rats fed the SMP diet gained less weight than controls but there were no differences in glucose tolerance between groups. The fat gavage increased serum lipids in both diet groups, whereas there was a main effect of the fat challenge to increase, and the SMP diet, to decrease liver triacylglycerol accumulation. The percentage of saturated and monounsaturated fatty acids and the protein content/activity of lipogenic enzymes were reduced in livers from SMP-fed rats, whereas the percentage of polyunsaturated fatty acids was increased. In summary, we provide evidence that SMP consumption, although not protecting against postprandial lipemia, markedly attenuates triacylglycerol accumulation and the relative amount of saturated and monounsaturated fatty acids in the liver.
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Doenças Cardiovasculares , Hiperlipidemias , Ratos , Masculino , Animais , Triglicerídeos , Leite , Lipídeos , Pós , Dieta , Fígado/metabolismo , Hiperlipidemias/etiologia , Ácidos Graxos Monoinsaturados , Doenças Cardiovasculares/metabolismo , Ácidos Graxos/metabolismo , Gorduras na Dieta/metabolismoRESUMO
Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and several on- and off-label conditions. While effective in reducing psychoses, acute olanzapine treatment causes rapid hyperglycemia, insulin resistance, and dyslipidemia and these perturbations are linked to an increased risk of developing cardiometabolic disease. Pharmacological agonists of the glucagon-like peptide-1 (GLP1) receptor have been shown to offset weight-gain associated with chronic SGA administration and mitigate the acute metabolic side effects of SGAs. The purpose of this study was to determine if increasing endogenous GLP1 is sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine, in the absence or presence of an oral glucose tolerance test (OGTT), and a combination of compounds to increase endogenous GLP1. These include the non-nutritive sweetener allulose which acts to induce GLP1 secretion but not other incretins, the DPPiv inhibitor sitagliptin which prevents degradation of active GLP1, and an SSTR5 antagonist which relieves inhibition on GLP1 secretion. We hypothesized that this cocktail of agents would increase circulating GLP1 to supraphysiological concentrations and would protect against olanzapine-induced perturbations in glucose and lipid homeostasis. We found that 'triple treatment' increased both active and total GLP1 and protected against olanzapine-induced perturbations in lipid and glucose metabolism under glucose stimulated conditions and this was paralleled by an attenuation in the olanzapine induced increase in the glucagon:insulin ratio. Our findings provide evidence that pharmacological approaches to increase endogenous GLP1 could be a useful adjunct approach to reduce acute olanzapine-induced perturbations in lipid and glucose metabolism.
RESUMO
OBJECTIVE: In contrast to what is seen clinically, male mice are resistant to antipsychotic-induced obesity. This is problematic as preclinical studies examining mechanisms of antipsychotic-induced metabolic dysfunction might be relevant to only half the population. This study sought to determine whether housing mice at thermoneutrality and under conditions of preexisting obesity, steps that have not been previously considered, would uncover a greater obesogenic effect of the antipsychotic olanzapine (OLZ). METHODS: C57BL6/J mice were fed a low- or high-fat diet (HFD) for 4 weeks and then switched to a control HFD or an HFD supplemented with OLZ for 6 weeks. RESULTS: Irrespective of obesity, OLZ treatment attenuated weight gain and increased energy expenditure in male mice. In females, OLZ increased food intake and potentiated weight gain in mice with preexisting obesity. CONCLUSIONS: Despite taking steps to increase clinical translatability, this study did not unmask an obesogenic effect of OLZ in male mice. Interestingly, prior studies in female mice could have been underestimating the metabolic consequences of OLZ by not considering the importance of preexisting obesity. Uncovering the mechanisms conferring resistance to weight gain in males may provide clues for approaches to counter the metabolic side effects of antipsychotics clinically.
Assuntos
Antipsicóticos , Masculino , Feminino , Camundongos , Animais , Olanzapina , Antipsicóticos/efeitos adversos , Habitação , Benzodiazepinas/efeitos adversos , Obesidade/metabolismo , Aumento de PesoRESUMO
Antipsychotic (AP) medications, such as olanzapine (OLZ), are used in the treatment of schizophrenia and a growing number of 'off-label' conditions. A single dose of OLZ causes robust increases in blood glucose within minutes of treatment. The purpose of the current study was to investigate whether interventions that increase circulating ketone bodies (fasting, ß-hydroxybutyrate (ßHB), ketone esters or a ketogenic diet (KD)) would be sufficient to protect against the acute metabolic side effects of OLZ. We demonstrate that fasting or the short-term consumption of a KD protects against OLZ-induced hyperglycaemia, independent of alterations in whole-body insulin action, and in parallel with a blunted rise in serum glucagon. Interestingly, the effects of fasting and KDs were not recapitulated by acutely increasing circulating concentrations of ketone bodies through treatment with ßHB or oral ketone esters, approaches which increase ketone bodies to physiological or supra-physiological levels, respectively. Collectively, our findings demonstrate that fasting and the short-term consumption of a KD can protect against acute AP-induced perturbations in glucose homeostasis, whereas manipulations which acutely increase circulating ketone bodies do not elicit the same beneficial effects. KEY POINTS: Antipsychotic medications cause rapid and robust increases in blood glucose. Co-treatment approaches to offset these harmful metabolic side effects have not been identified. We demonstrate that fasting or the consumption of a short-term ketogenic diet, but not treatment with ß-hydroxybutyrate or oral ketone esters, protects against acute antipsychotic-induced hyperglycaemia. The protective effects of fasting and ketogenic diets were paralleled by reductions in serum glucagon, but not improvements in whole-body insulin action.
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Antipsicóticos , Dieta Cetogênica , Hiperglicemia , Ácido 3-Hidroxibutírico/efeitos adversos , Ácido 3-Hidroxibutírico/metabolismo , Animais , Antipsicóticos/efeitos adversos , Glicemia , Ésteres , Jejum , Glucagon , Hiperglicemia/induzido quimicamente , Hiperglicemia/prevenção & controle , Insulina , Corpos Cetônicos/metabolismo , Cetonas , Camundongos , Olanzapina/efeitos adversosRESUMO
Increasing whole-body energy expenditure via the pharmacological activation of uncoupling protein 1 (UCP1)-dependent brown adipose tissue (BAT) thermogenesis is a promising weight management strategy, yet most therapeutics studied in rodents to date either induce compensatory increases in energy intake, have thermogenic effects that are confounded by sub-thermoneutral housing temperatures or are not well tolerated in humans. Here, we sought to determine whether the non-invasive topical application of the pharmacological cold mimetic and transient receptor potential (TRP) cation channel subfamily M member 8 (TRPM8) agonist L-menthol (MNTH), could be used to stimulate BAT thermogenesis and attenuate weight gain in mice housed at thermoneutrality. Using three different strains of mice and multiple complimentary approaches to quantify thermogenesis in vivo, coupled with ex vivo models to quantify direct thermogenic effects, we were able to convincingly demonstrate the following: (1) acute topical MNTH application induces BAT thermogenesis in a TRPM8- and UCP1-dependent manner; (2) MNTH-induced BAT thermogenesis is sufficient to attenuate weight gain over time without affecting energy intake in lean and obese mice; (3) the ability of topical MNTH application to stimulate BAT thermogenesis is mediated, in part, by a central mechanism involving the release of norepinephrine. These data collectively suggest that topical application of MNTH may be a promising weight management strategy.
Assuntos
Tecido Adiposo Marrom/metabolismo , Mentol/farmacologia , Canais de Cátion TRPM/metabolismo , Termogênese , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Temperatura Baixa , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Canais de Cátion TRPM/agonistasRESUMO
Repeated activation of the beta 3 adrenergic receptor (ß3AR) with the agonist CL 316,243 (CL) results in remodeling of white adipose tissue (WAT) characterized by increased mitochondrial enzymes and expression of uncoupling protein 1 (UCP1). ß3AR activation also has profound acute metabolic effects including rapidly decreasing blood glucose, secondary to fatty acid-induced increases in insulin, and increasing energy expenditure. The acute (single dose) effects of ß3AR activation have largely been examined in treatment naive animals and under room temperature housing conditions. The current study examined if repeated CL treatment would lead to an attenuation of acute metabolic effects of CL treatment under thermoneutral housing conditions and if this could be rescued with cilostamide, a phosphodiesterase inhibitor. We provide evidence demonstrating that the acute effects of CL to increase serum fatty acids and insulin and reduce blood glucose, but not increases in energy expenditure, are attenuated in mice following repeated treatment with CL. This occurs in parallel with reductions in indices of protein kinase A signaling in WAT including the phosphorylation of hormone sensitive lipase. The findings of attenuated serum fatty acid, insulin, and blood glucose responses were confirmed in both high-fat fed and UCP1-/- mice repeatedly treated with CL. Desensitization to CL in mice was rescued by cilostamide. Herein, we provide evidence that the glucose lowering, but not thermogenesis inducing, effects of CL are attenuated with repeated treatment and can be rescued by cilostamide. The findings of this study point toward novel adjunct treatment approaches that could be used to maximize therapeutic, glucose lowering effects of ß3AR agonists.
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Glicemia/metabolismo , Dioxóis/farmacologia , Hipoglicemiantes/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Quinolonas/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Ácidos Graxos/metabolismo , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Termogênese , Proteína Desacopladora 1/metabolismoRESUMO
Growth differentiating factor-15 (GDF15) is expressed, and secreted, from a wide range of tissues and serves as a marker of cellular stress. A key transcriptional regulator of this hormone is the endoplasmic reticulum stress protein, CHOP (C/EBP homologous protein). Exercise increases GDF15 levels but the underlying mechanisms of this are not known. To test whether CHOP regulates GDF15 during exercise, we used various models of altered ER stress. We examined the effects of acute exercise on circulating GDF15 and Gdf15 mRNA expression in liver, triceps skeletal muscle, and epididymal white adipose tissue and examined the GDF15 response to acute exercise in lean and high-fat diet-induced obese mice, sedentary and exercise trained mice, and CHOP-deficient mice. We found that obesity augments exercise-induced circulating GDF15 although ER stress markers were similar in lean and obese mice. Exercise-induced GDF15 was increased in trained and sedentary mice that ran at the same relative exercise intensity, despite trained mice being protected against increased markers of ER stress. Finally, exercise-induced increases in GDF15 at the tissue and whole body level were intact in CHOP-deficient mice. Together, these results provide evidence that exercise-induced GDF15 expression and secretion occurs independent of ER stress/CHOP.NEW & NOTEWORTHY GDF15 is expressed in a wide range of tissues, is a marker of cellular stress, and has been shown to be regulated by the ER stress protein CHOP. Although exercise increases GDF15, the mechanisms mediating this effect have not been elucidated. Using various models of altered ER stress, we demonstrate that exercise-induced increases in GDF15 occur independent of ER stress/CHOP.
Assuntos
Estresse do Retículo Endoplasmático , Fígado , Animais , Dieta Hiperlipídica , Camundongos , Camundongos Obesos , ObesidadeRESUMO
KEY POINTS: Ambient cold exposure is often regarded as a promising anti-obesity treatment in mice. However, most preclinical studies aimed at treating obesity via cold-induced thermogenesis have been confounded by subthermoneutral housing temperatures. Therefore, the ability of ambient cold to combat diet-induced obesity in mice housed under humanized thermoneutral conditions is currently unknown. Moreover, mammals such as mice are rarely exposed to chronic ambient cold without reprieve, yet mice are often subjected to experimental conditions of chronic rather than intermittent cold exposure (ICE), despite ICE being more physiologically relevant. In the present study, we provide novel evidence that thermoneutral housing uncouples the effects of ICE on glucose and energy homeostasis suggesting that ICE, despite improving glucose tolerance, is not an effective obesity treatment when mice are housed under humanized thermoneutral conditions. ABSTRACT: The present study examines whether a physiologically relevant model of ambient cold exposure, intermittent cold exposure (ICE), could ameliorate the metabolic impairments of diet-induced obesity in male and female mice housed under humanized thermoneutral conditions. Male and female C57BL/6J mice housed at thermoneutrality (29°C) were fed a low-fat diet or high-fat diet for 6 weeks before being weight matched into groups that remained unperturbed or underwent ICE for 4 weeks (4°C for 60 min day-1 ; 5 days week-1 ) when being maintained on their respective diets. ICE induced rapid and persistent hyperphagia exacerbating rather than attenuating high-fat diet-induced obesity over time. These ICE-induced increases in adiposity were found to be energy intake-dependent via pair-feeding. Despite exacerbating high-fat diet-induced obesity, ICE improved glucose tolerance, independent of diet, in a sex-specific manner. The effects of ICE on glucose tolerance were not attributed to improvements in whole-body insulin tolerance, tissue specific insulin action, nor differences in markers of hepatic insulin clearance or pancreatic beta cell proliferation. Instead, ICE increased serum concentrations of insulin and C-peptide in response to glucose, suggesting that ICE may improve glucose tolerance by potentiating pancreatic glucose-stimulated insulin secretion. These data suggest that ICE, despite improving glucose tolerance, is not an effective obesity treatment in mice housed under humanized conditions.
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Tecido Adiposo Marrom , Habitação , Tecido Adiposo Marrom/fisiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético , Feminino , Glucose/metabolismo , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismoRESUMO
Impaired action of insulin in skeletal muscle, termed insulin resistance, leads to increased blood glucose levels resulting in compensatory increase in insulin levels. The elevated blood glucose and insulin levels exacerbate insulin resistance and contribute to the pathogenesis of type 2 diabetes mellitus. In previous studies we found attenuation of free fatty acid-induced muscle cell insulin resistance by rosemary extract (RE). In the present study we investigated the effects of RE on high glucose (HG) and high insulin (HI)-induced muscle cell insulin resistance. Exposure of L6 myotubes to 25 mmol/L glucose and 100 nmol/L insulin for 24 h, to mimic hyperglycemia and hyperinsulinemia, abolished the acute insulin-stimulated glucose uptake, increased the serine phosphorylation of IRS-1 and the phosphorylation/activation of mTOR and p70S6K. Treatment with RE significantly improved the insulin-stimulated glucose uptake and increased the acute insulin-stimulated tyrosine phosphorylation while reducing the HG+HI-induced serine phosphorylation of IRS-1 and phosphorylation of mTOR and p70S6K. Additionally, treatment with RE significantly increased the phosphorylation of AMPK, its downstream effector ACC and the plasma membrane GLUT4 levels. Our data indicate a potential of RE to counteract muscle cell insulin resistance and more studies are required to investigate its effectiveness in vivo. Novelty: RE phosphorylated muscle cell AMPK and ACC under both normal and HG+HI conditions. The HG+HI-induced serine phosphorylation of IRS-1 and activation of mTOR and p70S6K were attenuated by RE. RE restored the insulin-stimulated glucose uptake by enhancing GLUT4 glucose transporter translocation to plasma membrane.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ativação Enzimática/efeitos dos fármacos , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Resistência à Insulina/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Extratos Vegetais/farmacologia , Rosmarinus , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Glicemia/metabolismo , Células Cultivadas , Desoxiglucose/metabolismo , Modelos Animais de Doenças , Transportador de Glucose Tipo 4/metabolismo , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/metabolismo , Fosforilação , Ratos , Serina/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Tirosina/metabolismoRESUMO
Growth differentiating factor-15 (GDF15) is an emerging target for the treatment of obesity and metabolic disease partly due to its ability to suppress food intake. GDF15 expression and secretion are thought to be regulated by a cellular integrated stress response, which involves endoplasmic reticulum (ER) stress. AMPK is another cellular stress sensor, but the relationship between AMPK, ER stress, and GDF15 has not been assessed in vivo. Wildtype (WT), AMPK ß1 deficient (AMPKß1-/- ), and CHOP-/- mice were treated with three distinct AMPK activators; AICAR, which is converted to ZMP mimicking the effects of AMP on the AMPKγ isoform, R419, which indirectly activates AMPK through inhibition of mitochondrial respiration, or A769662, a direct AMPK activator which binds the AMPKß1 isoform ADaM site causing allosteric activation. Following treatments, liver Gdf15, markers of ER-stress, AMPK activity, adenine nucleotides, circulating GDF15, and food intake were assessed. AICAR and R419 caused ER and energetic stress, increased GDF15 expression and secretion, and suppressed food intake. Direct activation of AMPK ß1 containing complexes by A769662 increased hepatic Gdf15 expression, circulating GDF15, and suppressed food intake, independent of ER stress. The effects of AICAR, R419, and A769662 on GDF15 were attenuated in AMPKß1-/- mice. AICAR and A769662 increased GDF15 to a similar extent in WT and CHOP-/- mice. Herein, we provide evidence that AMPK plays a role in mediating the induction of GDF15 under conditions of energetic stress in mouse liver in vivo.
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Proteínas Quinases Ativadas por AMP/metabolismo , Estresse do Retículo Endoplasmático , Fator 15 de Diferenciação de Crescimento/metabolismo , Fígado/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Fator 15 de Diferenciação de Crescimento/genética , Camundongos , Camundongos Knockout , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismoRESUMO
Antipsychotic (AP) medications are associated with an increased risk for developing metabolic side effects including weight gain, dyslipidemia, hypertension, type 2 diabetes (T2D), and cardiovascular disease. Previous reviews have focused on the chronic metabolic side effects associated with AP use. However, an underappreciated aspect of APs are the rapid perturbations in glucose and lipid metabolism that occur with each dose of drug. The purpose of this narrative review is to summarize work examining the peripheral mechanisms of acute olanzapine-induced related metabolic disturbances. We also discuss recent studies that have attempted to elucidate treatment approaches to mitigate AP-induced impairments in fuel metabolism.
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Antipsicóticos/efeitos adversos , Modelos Animais de Doenças , Doenças Metabólicas/induzido quimicamente , Olanzapina/efeitos adversos , Animais , Antipsicóticos/administração & dosagem , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Doenças Metabólicas/prevenção & controle , Olanzapina/administração & dosagemRESUMO
Olanzapine (OLZ) is used in the treatment of schizophrenia and a growing number of "off-label" conditions. Although effective in reducing psychoses, OLZ causes rapid impairments in glucose and lipid homeostasis. The purpose of this study was to investigate if voluntary physical activity via wheel running (VWR) would protect against the acute metabolic side effects of OLZ. Male C57BL/6J mice remained sedentary or were provided with running wheels overnight, before treatment with OLZ either at the beginning of the light cycle, or 7 or 24 h following the cessation of VWR. Prior VWR protected against OLZ-induced hyperglycemia immediately and 7 h following a bout of overnight wheel running. Protection against, hyperglycemia immediately following VWR was associated with increased insulin tolerance and an attenuated OLZ-induced increase in the serum glucagon:insulin ratio. The protective effect of VWR against OLZ-induced increases in hyperglycemia and glucagon:insulin ratio was maintained in high-fat fed, and AMPK ß1-deficient mice, models which display a potentiated OLZ-induced increase in blood glucose. Repeated OLZ treatment did not impair VWR performance and protection against the acute effects of OLZ on blood glucose was present after 1 wk of daily OLZ treatment in mice given access to running wheels. In contrast to the effects on glucose metabolism, VWR, for the most part, did not impact OLZ-induced perturbations in lipolysis, liver triglyceride accumulation, or whole body substrate oxidation. Collectively, our findings demonstrate the efficacy of voluntary physical activity as an approach to protect against OLZ-induced impairments in glucose metabolism.NEW & NOTEWORTHY The antipsychotic medication olanzapine causes rapid and large increases in blood glucose. We demonstrate that a prior bout of voluntary overnight wheel running can protect against this harmful side effect and is likely mediated by reductions in olanzapine-induced increases in the circulating glucagon to insulin ratio. This study highlights the powerful effects of voluntary activity in conditions of treatment with antipsychotic medications.
Assuntos
Hiperglicemia , Atividade Motora , Animais , Glicemia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , OlanzapinaRESUMO
Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and a number of off-label conditions. Although effective in reducing psychoses, acute olanzapine treatment causes hyperglycemia. Pharmacological agonists of the glucagon-like peptide 1 (GLP1) receptor have been shown to offset weight gain associated with chronic SGA administration. It is not known whether GLP1 receptor agonism would mitigate the acute metabolic side effects of SGAs. Within this context, we sought to determine whether pharmacological targeting of the GLP1 receptor would be sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine and/or the GLP1 receptor agonists liraglutide and exendin 4, and the blood glucose response was measured. We found that liraglutide or exendin 4 completely protected male mice against olanzapine-induced hyperglycemia in parallel with increases in circulating insulin (liraglutide, exendin 4) and reductions in glucagon (liraglutide only). In additional experiments, female mice, which are protected from acute olanzapine-induced hyperglycemia, displayed hyperglycemia, increases in glucagon, and reductions in insulin when treated with olanzapine and the GLP1 receptor antagonist exendin 9-39 compared with olanzapine treatment alone. Although in some instances the pharmacological targeting of the GLP1 receptor attenuated indexes of olanzapine-induced lipolysis, increases in liver triglyceride accumulation were not impacted. Our findings provide evidence that signaling through the GLP1 receptor can remarkably influence acute olanzapine-induced hyperglycemia, and from the standpoint of protecting against acute excursions in blood glucose, GLP1 receptor agonists should be considered as an adjunct treatment approach.NEW & NOTEWORTHY Antipsychotic drugs cause rapid perturbations in glucose and lipid metabolism. In the present study we have demonstrated that cotreatment with glucagon-like peptide 1 (GLP1) receptor agonists, such as liraglutide, protects against metabolic dysregulation caused by the antipsychotic drug olanzapine. These findings suggest that pharmacological targeting of the GLP1 receptor could be an effective adjunct approach to mitigate the harmful acute metabolic side effects of antipsychotic drugs.
Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hiperglicemia/induzido quimicamente , Hiperglicemia/prevenção & controle , Olanzapina , Inibidores Seletivos de Recaptação de Serotonina , Animais , Exenatida/uso terapêutico , Feminino , Teste de Tolerância a Glucose , Hipoglicemiantes/uso terapêutico , Lipólise/efeitos dos fármacos , Liraglutida/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Triglicerídeos/metabolismoRESUMO
OBJECTIVE: This study aimed to explore the individual and combined effects of skim milk powder (SMP) and exercise on indices of systemic and liver lipid metabolism in male obese rats. METHODS: Rats were fed a high-fat (~ 40% kcal from fat), high-sugar diet for 8 weeks. At 12 weeks of age, rats were assigned to one of four weight-matched, isocaloric, high-fat, high-sugar groups for 6 weeks: (1) casein-sedentary, (2) casein-exercise, (3) SMP-sedentary, and (4) SMP-exercise. Nonfat SMP or casein was the sole protein source in the dairy and control casein diets, respectively. Exercise training occurred 5 d/wk for 60 minutes on a motorized treadmill. Whole-body metabolism was assessed by a Comprehensive Lab Animal Monitoring System. Lipidomics, Western blot, and polymerase chain reaction were used to assess markers of hepatic lipid metabolism. RESULTS: Exercise, but not SMP, altered the fatty acid composition of liver triglycerides, reduced indices of lipogenesis, and increased expression of genes linked to oxidative metabolism, in conjunction with increases in whole-body fat oxidation. SMP and exercise reduced plasma triglycerides in an additive manner. CONCLUSIONS: These findings provide evidence that SMP and exercise exert distinct effects on whole-body and hepatic carbohydrate and lipid metabolism and that they could work in a synergistic manner to reduce serum triglyceride concentrations.
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Laticínios/normas , Lipogênese/fisiologia , Fígado/fisiopatologia , Leite/química , Obesidade/etiologia , Condicionamento Físico Animal/métodos , Animais , Metabolismo dos Lipídeos , Lipídeos/sangue , Masculino , RatosRESUMO
Olanzapine (OLZ) is a second-generation antipsychotic that is used to treat schizophrenia but also causes acute hyperglycemia. This study aimed to determine if the ablation of AMPK ß1-containing complexes potentiates acute OLZ-induced metabolic dysfunction and if the activation of AMPK ß1 suppresses these effects. Female AMPK ß1-/- or wild-type (WT) control mice were treated with OLZ, and changes in blood glucose, serum and liver metabolites, whole-body fuel oxidation, and pyruvate-induced increases in blood glucose were measured. Additionally, WT mice were cotreated with OLZ and A769662, a specific AMPK ß1 activator, and we determined if cotreatment protected against acute, OLZ-induced metabolic dysfunction. OLZ-induced increases in blood glucose were exacerbated in AMPK ß1-/- mice compared with WT mice, and this was paralleled by greater OLZ-induced increases in markers of liver glucose production, such as pyruvate tolerance, serum glucagon, and glucagon responsiveness. Cotreatment with A769662 attenuated OLZ-induced increases in blood glucose, serum nonesterified fatty acid, and glycerol. Furthermore, this effect was absent in AMPK ß1-/- mice, consistent with A769662's specificity for the AMPK ß1 subunit. Reductions in AMPK activity potentiate the effects of acute OLZ treatment on blood glucose, whereas specifically targeting AMPK ß1-containing complexes is sufficient to protect against OLZ-induced hyperglycemia.-Shamshoum, H., Medak, K. D., Townsend, L. K., Ashworth, K. E., Bush, N. D., Hahn, M. K., Kemp, B. E., Wright, D. C. AMPK ß1 activation suppresses antipsychotic-induced hyperglycemia in mice.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antipsicóticos/efeitos adversos , Hiperglicemia/induzido quimicamente , Olanzapina/efeitos adversos , Proteínas Quinases Ativadas por AMP/genética , Animais , Compostos de Bifenilo , Glicemia/efeitos dos fármacos , Feminino , Deleção de Genes , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Teste de Tolerância a Glucose , Camundongos , Pironas/farmacologia , Ácido Pirúvico/efeitos adversos , Tiofenos/farmacologiaRESUMO
KEY POINTS: Mice are commonly housed at room temperatures below their thermoneutral zone meaning they are exposed to chronic thermal stress. Endurance exercise induces browning and mitochondrial biogenesis in white adipose tissue of rodents, but there are conflicting reports of this phenomenon in humans. We hypothesized that the ambient room temperature at which mice are housed could partially explain these discrepant reports between humans and rodents. We housed mice at room temperature or thermoneutrality and studied their physiological responses to acute and chronic exercise. We found that thermoneutral housing altered running behaviour and glucose homeostasis, and further, that exercise-induced markers of mitochondrial biogenesis and the browning of white adipose tissue were reduced in mice housed at thermoneutrality. ABSTRACT: Mice are often housed at temperatures below their thermoneutral zone resulting in compensatory increases in thermogenesis. Despite this, many studies report housing mice at room temperature (RT), likely for the convenience of the researchers studying them. As such, the conflicting reports between humans and rodents regarding the ability of exercise to increase mitochondrial and thermogenic markers in white adipose tissue may be explained by the often-overlooked variable, housing temperature. To test this hypothesis, we housed male C57BL/6 mice at RT (22°C) or thermoneutrality (TN) (29°C) with or without access to a voluntary running wheel for 6 weeks or subjected them to an acute exhaustive bout of treadmill running. We examined the gene expression and protein content of select mitochondrial and thermogenic markers in skeletal muscle, epididymal white adipose tissue (eWAT), inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT). We also assessed adipocyte morphology and indices of glucose homeostasis. Housing temperature influenced glucose tolerance and insulin action in vivo, yet the beneficial effects of exercise, both acute and chronic, remained intact in eWAT, BAT and skeletal muscle irrespective of housing temperature. Housing mice at TN led to an attenuation of some of the effects of exercise on iWAT. Collectively, we present data characterizing the acute and chronic metabolic adaptations to exercise at different housing temperatures and demonstrate, for the first time, that temperature influences the ability of exercise to increase markers of mitochondrial biogenesis and the browning of white adipose tissue.
Assuntos
Adaptação Fisiológica/fisiologia , Metabolismo Energético/fisiologia , Condicionamento Físico Animal/fisiologia , Aclimatação/fisiologia , Adipócitos/metabolismo , Adipócitos/fisiologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/fisiologia , Expressão Gênica/fisiologia , Habitação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Temperatura , Termogênese/fisiologiaRESUMO
Type 2 diabetes mellitus (T2DM), a disease on the rise and with huge economic burden to health care systems around the globe, results from defects in insulin action (termed insulin resistance) combined with impaired insulin secretion. Current methods of prevention and treatments for insulin resistance and T2DM are lacking in number and efficacy and, therefore, there is a need for new preventative measures and targeted therapies. In recent years, chemicals found in plants/herbs have attracted attention for their use as functional foods or nutraceuticals for preventing and treating insulin resistance and T2DM. Rosemary is an evergreen shrub indigenous to the Mediterranean region and South America, which contains various polyphenols. Rosemary extract and its polyphenolic constituents have been reported to have antioxidant, anti-inflammatory, anticancer, and anti-hyperglycemic properties. The current review summarizes the existing in vitro and in vivo studies examining the anti-diabetic effects of rosemary extract and its polyphenolic components and highlights the known mechanism of action.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Rosmarinus/química , Humanos , Resistência à Insulina , Extratos Vegetais/químicaRESUMO
Cancer cells exhibit enhanced proliferation rate and a resistance to apoptosis. Epidemiological studies suggest that olive oil intake is associated with a reduced risk of cancer. Olive oil, olives, and olive leaves contain many polyphenols, including oleuropein. Recently, several studies have demonstrated that oleuropein inhibits proliferation and induces apoptosis in different cancer cell lines. In addition, anticancer effects of oleuropein have been seen in animal studies. These effects are associated with oleuropein's ability to modulate gene expression and activity of a variety of different signaling proteins that play a role in proliferation and apoptosis. This article summarizes the existing in vitro and in vivo studies focusing on the anticancer effects of oleuropein and its effects on key signaling molecules. © 2017 BioFactors, 43(4):517-528, 2017.