RESUMO
A dynamically regulated microenvironment, which is mediated by crosstalk between adipocytes and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on key molecules and/or signaling pathways regulating the crosstalk remains limited. In this study, we identify adipocyte miRNA-182-5p (miR-182-5p) as a crucial antiobesity molecule that stimulated beige fat thermogenesis by promoting the crosstalk between adipocytes and macrophages. miR-182-5p was highly enriched in thermogenic adipocytes, and its expression was markedly stimulated by cold exposure in mice. In contrast, miR-182-5p expression was significantly reduced in adipose tissues of obese humans and mice. Knockout of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promoted FGF21 expression and secretion in adipocytes by suppressing nuclear receptor subfamily 1 group D member 1 (Nr1d1) at 5'-UTR, which in turn stimulates acetylcholine synthesis and release in macrophages. Increased acetylcholine expression activated the nicotine acetylcholine receptor in adipocytes, which stimulated PKA signaling and consequent thermogenic gene expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis. Activation of the miR-182-5p-induced signaling pathway in adipose tissue may be an effective approach to ameliorate obesity and associated metabolic diseases.
Assuntos
Acetilcolina/genética , Adipócitos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Macrófagos/metabolismo , MicroRNAs/genética , Obesidade/genética , Termogênese/genética , Acetilcolina/biossíntese , Adipócitos/patologia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/biossíntese , Macrófagos/patologia , Camundongos , Camundongos Knockout , MicroRNAs/biossíntese , Obesidade/metabolismo , Obesidade/patologia , Transdução de SinaisRESUMO
Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are associated with hepatic steatosis and insulin resistance. Molecular mechanisms underlying ER stress and/or mitochondrial dysfunction that cause metabolic disorders and hepatic steatosis remain to be fully understood. Here, we found that a high fat diet (HFD) or chemically induced ER stress can stimulate mitochondrial stress protein HSP60 expression, impair mitochondrial respiration, and decrease mitochondrial membrane potential in mouse hepatocytes. HSP60 overexpression promotes ER stress and hepatic lipogenic protein expression and impairs insulin signaling in mouse hepatocytes. Mechanistically, HSP60 regulates ER stress-induced hepatic lipogenesis via the mTORC1-SREBP1 signaling pathway. These results suggest that HSP60 is an important ER and mitochondrial stress cross-talking protein and may control ER stress-induced hepatic lipogenesis and insulin resistance.
Assuntos
Chaperonina 60/metabolismo , Fígado/metabolismo , Proteínas Mitocondriais/metabolismo , Animais , Western Blotting , Chaperonina 60/genética , Estresse do Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/fisiologia , Lipogênese/genética , Lipogênese/fisiologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Potencial da Membrana Mitocondrial/genética , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/genética , Consumo de Oxigênio/genética , Consumo de Oxigênio/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Increasing brown and beige fat thermogenesis have an anti-obesity effect and thus great metabolic benefits. However, the molecular mechanisms regulating brown and beige fat thermogenesis remain to be further elucidated. We recently found that fat-specific knockout of Rheb promoted beige fat thermogenesis. In the current study, we show that Rheb has distinct effects on thermogenic gene expression in brown and beige fat. Fat-specific knockout of Rheb decreased protein kinase A (PKA) activity and thermogenic gene expression in brown adipose tissue of high-fat diet-fed mice. On the other hand, overexpression of Rheb activated PKA and increased uncoupling protein 1 expression in brown adipocytes. Mechanistically, Rheb overexpression in brown adipocytes increased Notch expression, leading to disassociation of the regulatory subunit from the catalytic subunit of PKA and subsequent PKA activation. Our study demonstrates that Rheb, by selectively modulating thermogenic gene expression in brown and beige adipose tissues, plays an important role in regulating energy homeostasis.
Assuntos
Tecido Adiposo Marrom/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Termogênese , Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Metabolismo Energético , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Modelos Biológicos , Obesidade/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
Beiging of white adipose tissue has potential antiobesity and antidiabetes effects, yet the underlying signaling mechanisms remain to be fully elucidated. Here we show that adipose-specific knockout of Rheb, an upstream activator of mechanistic target of rapamycin complex 1 (mTORC1), protects mice from high-fat diet-induced obesity and insulin resistance. On the one hand, Rheb deficiency in adipose tissue reduced mTORC1 signaling, increased lipolysis, and promoted beiging and energy expenditure. On the other hand, overexpression of Rheb in primary adipocytes significantly inhibited CREB phosphorylation and uncoupling protein 1 (UCP1) expression. Mechanistically, fat-specific knockout of Rheb increased cAMP levels, cAMP-dependent protein kinase (PKA) activity, and UCP1 expression in subcutaneous white adipose tissue. Interestingly, treating primary adipocytes with rapamycin only partially alleviated the suppressing effect of Rheb on UCP1 expression, suggesting the presence of a novel mechanism underlying the inhibitory effect of Rheb on thermogenic gene expression. Consistent with this notion, overexpression of Rheb stabilizes the expression of cAMP-specific phosphodiesterase 4D5 (PDE4D5) in adipocytes, whereas knockout of Rheb greatly reduced cellular levels of PDE4D5 concurrently with increased cAMP levels, PKA activation, and UCP1 expression. Taken together, our findings reveal Rheb as an important negative regulator of beige fat development and thermogenesis. In addition, Rheb is able to suppress the beiging effect through an mTORC1-independent mechanism.
Assuntos
Adipócitos/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Metabolismo Energético/genética , Resistência à Insulina/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Neuropeptídeos/genética , Obesidade/genética , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dieta Hiperlipídica , Regulação para Baixo , Regulação da Expressão Gênica , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Knockout , Complexos Multiproteicos/metabolismo , Fosforilação , Proteína Enriquecida em Homólogo de Ras do Encéfalo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteína Desacopladora 1/genéticaRESUMO
BACKGROUND: Chlorogenic acids (CGAs) are widely distributed in plant material, including foods and beverages. 5-Caffeoylquinic acid (5-CQA) is the most studied CGA, but the mechanism of its hypolipidaemic effect remains unclear. This study aimed to determine the effect of 5-CQA on lipid metabolism in the liver of Sprague-Dawley rats fed a high-fat diet (HFD). RESULTS: 5-CQA suppressed HFD-induced increases in body weight and visceral fat-pad weight, serum lipid levels, and serum and hepatic free fatty acids in a dose-dependent manner. Real-time polymerase chain reaction revealed that 5-CQA altered the mRNA expression of the transcription factors peroxisome proliferator-activated receptor α (PPARα) and liver X receptor α (LXRα) and target genes involved in hepatic fatty acid uptake, ß-oxidation, fatty acid synthesis, and cholesterol synthesis. Moreover, hepatic tissue sections from HFD-fed rats showed many empty vacuoles, suggesting that liver cells were filled with more fat droplets. However, 5-CQA significantly ameliorated this effect. CONCLUSION: 5-CQA may improve lipid metabolism disorders by altering the expression of PPARα and LXRα, which are involved in multiple intracellular signalling pathways.
