RESUMO
High-fat diet (HFD) promotes obesity-related metabolic complications by activating cellular senescence in white adipose tissue (WAT). Growing evidence supports the importance of microRNA-22 (miR-22) in metabolic disorders and cellular senescence. Recently, we showed that miR-22 deletion attenuates obesity-related metabolic abnormalities. However, whether miR-22 mediates HFD-induced cellular senescence of WAT remains unknown. Here, we uncovered that obese mice displayed increased pri-miR-22 levels and cellular senescence in WAT. However, miR-22 ablation protected mice against HFD-induced WAT senescence. In addition, in vitro studies showed that miR-22 deletion prevented preadipocyte senescence in response to Doxorubicin (Doxo). Loss-of-function studies in vitro and in vivo revealed that miR-22 increases H2ax mRNA and γH2ax levels in preadipocytes and WAT without inducing DNA damage. Intriguingly, miR-22 ablation prevented HFD-induced increase in γH2ax levels and DNA damage in WAT. Similarly, miR-22 deletion prevented Doxo-induced increase in γH2ax levels in preadipocytes. Adipose miR-22 levels were enhanced in middle-aged mice fed a HFD than those found in young mice. Furthermore, miR-22 deletion attenuated fat mass gain and glucose imbalance induced by HFD in middle-aged mice. Overall, our findings indicate that miR-22 is a key regulator of obesity-induced WAT senescence and metabolic disorders in middle-aged mice.
Assuntos
Doenças Metabólicas , MicroRNAs , Camundongos , Animais , Obesidade/genética , Obesidade/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Doenças Metabólicas/genética , Doenças Metabólicas/prevenção & controle , MicroRNAs/genética , MicroRNAs/metabolismo , Camundongos Endogâmicos C57BLRESUMO
AIMS: Blood vessels are surrounded by perivascular adipose tissue (PVAT), which plays an important role in vascular tonus regulation due to its anticontractile effect; however, this effect is impaired in obesity. We previously demonstrated that miRNA-22 is involved in obesity-related metabolic disorders. However, the impact of miRNA-22 on vascular reactivity and PVAT function is unknown. AIM: To investigate the role of miRNA-22 on vascular reactivity and its impact on obesity-induced PVAT dysfunction. MAIN METHODS: Wild-type and miRNA-22 knockout (KO) mice were fed a control or a high-fat (HF) diet. To characterize the vascular response, concentration-responses curves to noradrenaline were performed in PVAT- or PVAT+ thoracic aortic rings in absence and presence of L-NAME. Expression of adipogenic and thermogenic markers and NOS isoforms were evaluated by western blotting or qPCR. KEY FINDINGS: HF diet and miRNA-22 deletion reduced noradrenaline-induced contraction in PVAT- aortic rings. Additionally, miRNA-22 deletion increased noradrenaline-induced contraction in PVAT+ aortic rings without affecting its sensitivity; however, this effect was not observed in miRNA-22 KO mice fed a HF diet. Interestingly, miRNA-22 deletion reduced the contraction of aortic rings to noradrenaline via a NOS-dependent mechanism. Moreover, HF diet abolished the NOS-mediated anticontractile effect of PVAT, which was attenuated by miRNA-22 deletion. Mechanistically, we found that PVAT from miRNA-22 KO mice fed a HF diet presented increased protein expression of nNOS. SIGNIFICANCE: These results suggest that miRNA-22 is important for aorta reactivity under physiological circumstances and its deletion attenuates the loss of the NOS-mediated anticontractile effect of PVAT in obesity.
Assuntos
Tecido Adiposo , Aorta , MicroRNAs , Obesidade , Animais , Camundongos , Tecido Adiposo/metabolismo , Aorta/metabolismo , MicroRNAs/metabolismo , Norepinefrina/metabolismo , Obesidade/metabolismo , Obesidade/patologia , VasoconstriçãoRESUMO
BACKGROUND: Obesity, characterized by excessive expansion of white adipose tissue (WAT), is associated with numerous metabolic complications. Conversely, brown adipose tissue (BAT) and beige fat are thermogenic tissues that protect mice against obesity and related metabolic disorders. We recently reported that deletion of miR-22 enhances energy expenditure and attenuates WAT expansion in response to a high-fat diet (HFD). However, the molecular mechanisms involved in these effects mediated by miR-22 loss are unclear. METHODS AND RESULTS: Here, we show that miR-22 expression is induced during white, beige, and brown adipocyte differentiation in vitro. Deletion of miR-22 reduced white adipocyte differentiation in vitro. Loss of miR-22 prevented HFD-induced expression of adipogenic/lipogenic markers and adipocyte hypertrophy in murine WAT. In addition, deletion of miR-22 protected mice against HFD-induced mitochondrial dysfunction in WAT and BAT. Loss of miR-22 induced WAT browning. Gain- and loss-of-function studies revealed that miR-22 did not affect brown adipogenesis in vitro. Interestingly, miR-22 KO mice fed a HFD displayed increased expression of genes involved in thermogenesis and adrenergic signaling in BAT when compared to WT mice fed the same diet. CONCLUSIONS: Collectively, our findings suggest that loss of miR-22 attenuates fat accumulation in response to a HFD by reducing white adipocyte differentiation and increasing BAT activity, reinforcing miR-22 as a potential therapeutic target for obesity-related disorders.
Assuntos
Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Dieta Hiperlipídica/efeitos adversos , MicroRNAs/genética , Adipogenia/genética , Animais , Diferenciação Celular/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Obesidade/genética , Obesidade/metabolismoRESUMO
BACKGROUND/AIMS: Obesity is a risk factor associated with cardiometabolic complications. Recently, we reported that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia without affecting cardiac hypertrophy in male mice. In this study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females. METHODS: Wild type (WT) and miRNA-22 knockout (miRNA-22 KO) females were fed a control or an obesogenic diet. Body weight gain, adiposity, glucose tolerance, insulin tolerance, and plasma levels of total cholesterol and triglycerides were measured. Cardiac and white adipose tissue remodeling was assessed by histological analyses. Echocardiography was used to evaluate cardiac function and morphology. RNA-sequencing analysis was employed to characterize mRNA expression profiles in female hearts. RESULTS: Loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. WT obese females developed cardiac hypertrophy. Interestingly, miRNA-22 KO females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. Both miRNA-22 deletion and obesogenic diet changed mRNA expression profiles in female hearts. Enrichment analysis revealed that genes associated with regulation of the force of heart contraction, protein folding and fatty acid oxidation were enriched in hearts of WT obese females. In addition, genes related to thyroid hormone responses, heart growth and PI3K signaling were enriched in hearts of miRNA-22 KO females. Interestingly, miRNA-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls. CONCLUSION: This study reveals that miRNA-22 deletion induces cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic target to treat obesity-related metabolic disorders in females.