RESUMO
GPR120 and GPR40 were recently reported as omega-3 (ω3) receptors with anti-inflammatory properties. Physical exercise could increase the expression of these receptors in the liver, improving hepatic metabolism in obesity and type 2 diabetes. Our aim was to investigate GPR120/40 in the liver of lean and obese mice after acute or chronic physical exercise, with or without the supplementation of ω3 rich flaxseed oil (FS), as well as assess the impact of exercise and FS on insulin signaling and inflammation. Mice were fed a high-fat diet (HF) for 4 weeks to induce obesity and subsequently subjected to exercise with or without FS, or FS alone. Insulin signaling, inflammatory markers and GPR120/40 and related cascades were measured. Chronic, but not acute, exercise and FS increased GPR120, but not GPR40, activating ß-arrestin-2 and decreasing the inflammatory response, as well as reducing fat depots in liver and adipose tissue. Exercise or a source of ω3 led to a higher tolerance to fatigue and an increased running distance and speed. The combination of physical exercise and ω3 food sources could provide a new strategy against obesity through the modulation of hepatic GPR120 and an increase in exercise performance.
Assuntos
Ácidos Graxos Insaturados/farmacologia , Óleo de Semente do Linho/química , Fígado/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Tecido Adiposo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Dieta Hiperlipídica/efeitos adversos , Teste de Tolerância a Glucose , Insulina/metabolismo , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Obesidade/dietoterapia , Obesidade/metabolismo , Condicionamento Físico AnimalRESUMO
The "first hit" to atherogenesis is driven by toll-like receptor 4, endoplasmic reticulum stress and ultimately metabolic dysfunction. In this study, we hypothesized that a flaxseed oil-enriched diet (FS) abolishes these inflammatory signaling pathway and restore metabolic homeostasis by activating the fatty acid receptor GPR120 in aorta of obese mice. Glucose homeostasis was assessed by GTT and ITT; lipidomics was performed using a Hybrid Ion Trap-Orbitrap Mass Spectrometer; serum lipids were measured using colorimetric assays; GPR120 and infiltrating macrophages were analyzed by immunofluorescence; protein immunoprecipitation and gene expression were evaluated by Western blot and RT-PCR, respectively. There were no differences in body weight and food intake between the groups from both strains (Swiss and LDLr-KO mice). GTT and cholesterol levels were improved by FS in both mice models. Lipidomics showed an increase in ω3 (C18:3) content, meanwhile stearic acid (C18:0) was not detected in endothelial tissue in response to FS. Moreover, FS markedly decreased pro-inflammatory (IL-1ß, TNF-α, pIκBα, pIKKß) and unfolded protein response markers (ATF6 and GRP78) in aorta. In Swiss mice, GPR120 was partially involved in the ω3-mediated anti-inflammatory actions, disrupting TLR4 pathway, but not in LDLr-KO mice. Partial replacement of dietary saturated by unsaturated ω3 fatty acids contributes to inhibition of cardiovascular risk markers, pro-inflammatory cytokines and ER stress sensors and effectors in the aorta. However, downregulation of inflammation is not mediated by arterial GPR120 activation.
Assuntos
Aortite/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Óleo de Semente do Linho/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Aortite/metabolismo , Modelos Animais de Doenças , Dislipidemias/dietoterapia , Dislipidemias/fisiopatologia , Chaperona BiP do Retículo Endoplasmático , Ácidos Graxos Ômega-3/farmacologia , Óleo de Semente do Linho/química , Lipídeos/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Obesidade/dietoterapia , Obesidade/fisiopatologia , Substâncias Protetoras/farmacologia , Receptores de LDL/genéticaRESUMO
Nonalcoholic steatohepatitis (NASH) is a fatty liver disorder that could be improved with extra virgin olive oil (EVOO) supplementation in diet. We propose the monitoring, in whole mouse liver extracts and in isolated mitochondria, of the absorption of compounds from three different diets: standard (CT), high-fat (HFD) and high-fat supplemented with EVOO (HFSO). Male mice were submitted to one of the following three diets: CT or HFD for 16 weeks or HFD for 8 weeks followed by additional 8 weeks with HFSO. Following this period, liver was extracted for histological evaluation, mitochondria isolation and mass spectrometry analyses. Diets, liver extracts and Percoll-purified mitochondria were analyzed using ESI-MS and the lipidomics approach. Morphological, histological and spectrometric results indicated a decrease in NASH severity with EVOO supplementation in comparison with animals maintained with HFD. Spectrometric data also demonstrated that some compounds presented on the diets are absorbed by the mitochondria. EVOO was shown to be a potential therapeutic alternative in food for NASH. Our results are in accordance with the proposition that the major factor that influences different responses to diets is their composition - and not only calories - especially when it comes to studies on obesity.