RESUMO
Thiazolidinediones (TZDs) are insulin-sensitizing drugs currently used to treat type 2 diabetes. They are activators of peroxisome proliferator-activated receptor (PPAR)-gamma, and adipose tissue constitutes a major site for their biological effects. PPAR coactivator (PGC)-1alpha is a transcriptional coactivator of PPARgamma and other transcription factors. It is involved in the control of mitochondrial biogenesis, and its activity has been linked to insulin sensitization. Here we report that PGC-1alpha gene expression in brown and white adipocytes is a direct target of TZDs via PPARgamma activation. Activators of the retinoid X receptor also induce PGC-1alpha gene expression. This is due to the presence of a PPARgamma-responsive element in the distal region of the PGC-1alpha gene promoter that binds PPARgamma/retinoid X receptor heterodimers. Moreover, there is a positive autoregulatory loop of control of the PGC-1alpha gene through coactivation of PPARgamma responsiveness to TZDs by PGC-1alpha itself. These data indicate that some of the effects of TZDs, especially promotion of mitochondrial biogenesis and oxidative pathways in adipose depots, entail PGC-1alpha up-regulation via enhanced transcription of the PGC-1alpha gene.
Assuntos
Adipócitos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , PPAR gama/fisiologia , Tiazolidinedionas/farmacologia , Transativadores/genética , Tretinoína/farmacologia , Células 3T3-L1 , Alitretinoína , Animais , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Homeostase , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Elementos de Resposta , Rosiglitazona , Fatores de Transcrição , Ativação TranscricionalRESUMO
Lithium impairs the appearance of the characteristic morphology of brown adipocytes and downregulates the expression of marker genes of brown adipocyte differentiation. These effects are dose-dependent and are more pronounced when exposure of preadipocytes to lithium is initiated at early stages of differentiation. Although lithium reduces the expression of genes common to both white and brown adipocytes [fatty acid binding protein aP2 (aP2/FABP) or peroxisome proliferating activated receptor gamma], genes expressed differentially in brown adipocytes, i.e., uncoupling protein 1, PPAR gamma coactivator-1alpha, and peroxisome proliferating activated receptor alpha, are particularly sensitive to lithium treatment-dependent downregulation. Brown adipocytes appear as preferential targets of the inhibitory action of lithium on adipocyte differentiation.
Assuntos
Adipócitos/efeitos dos fármacos , Tecido Adiposo Marrom/citologia , Lítio/farmacologia , Adipócitos/citologia , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Proteínas de Transporte/genética , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Regulação para Baixo , Expressão Gênica/efeitos dos fármacos , Canais Iônicos , Proteínas de Membrana/genética , Camundongos , Proteínas Mitocondriais , Norepinefrina/farmacologia , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Tretinoína/farmacologia , Proteína Desacopladora 1RESUMO
OBJECTIVE: Human adipose depots contain remnant brown adipocytes interspersed among white adipocytes, and disturbances of brown with respect to white adipocyte biology have been implicated in highly active antiretroviral therapy (HAART)-induced lipomatosis. Brown adipocytes express the uncoupling protein-1 (UCP1) and contain a large number of mitochondria, potential targets of HAART toxicity. The aim of this study was to evaluate the effects of reverse transcriptase inhibitors (RTIs) on primary brown adipocytes differentiated in culture. DESIGN AND METHODS: We analysed the effects of RTIs, nucleoside analogues (NRTIs: stavudine, zidovudine, didanosine and lamivudine) and non-nucleoside analogues (NNRTIs: nevirapine and efavirenz), on differentiation, mitochondrial biogenesis and gene expression in brown adipocytes. RESULTS: None of the NRTIs altered brown adipocyte differentiation whereas NNTRIs had differing effects. Efavirenz blocked lipid deposition and expression of adipose marker genes but nevirapine induced lipid accumulation and adipose gene expression, promoted mitochondrial biogenesis and increased UCP1. Stavudine, zidovudine and didanosine reduced mitochondrial DNA (mtDNA) content. However, mitochondrial genome expression was only impaired in didanosine-treated adipocytes. Stavudine, but not zidovudine, induced expression of the mitochondrial transcription factors and this may explain compensatory mechanisms for the depletion of mtDNA by up-regulating mtDNA transcription. Stavudine caused a specific induction of UCP1 gene expression through direct interaction with a retinoic acid-dependent pathway. CONCLUSIONS: Specific disturbances in brown adipocytes in adipose depots may contribute to HAART-induced lipomatosis. Mitochondrial depletion does not appear to be the only mechanism explaining adverse effects in brown adipocytes because there is evidence of compensatory mechanisms that maintain mtDNA expression, and the expression of the UCP1 gene is specifically altered.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Proteínas de Transporte/biossíntese , Proteínas de Membrana/biossíntese , Mitocôndrias/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , DNA Mitocondrial/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Canais Iônicos , Mitocôndrias/metabolismo , Proteínas Mitocondriais , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1RESUMO
The developmental regulation of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) gene expression was studied in mice and compared with that of marker genes of liver energy metabolism. The PGC-1alpha gene was highly expressed in fetal liver compared with that in adults and remained high in neonatal liver. The regulation of PGC-1alpha gene expression during the fetal and early neonatal periods was dissociated from that of gluconeogenic genes, i.e. the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. Only under the effects of starvation was PGC-1alpha gene expression induced in parallel to phosphoenolpyruvate carboxykinase and G6Pase mRNAs during the perinatal period. Furthermore, the PGC-1alpha gene was not regulated as part of the developmental program of gene expression associated with the maturation of hepatic gluconeogenesis, as revealed by the impaired PEPCK and G6Pase gene expression but unaltered PGC-1alpha mRNA levels in CCAAT/enhancer-binding protein-alpha-null fetus and neonates. Regulation of the PGC-1alpha gene and that of mitochondrial 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase, acyl-coenzyme A oxidase, and long-chain acyl-coenzyme dehydrogenase, marker genes of lipid catabolism, were dissociated in fetuses and neonates. The expression of lipid catabolism genes was down-regulated in fasted neonates, whereas PGC-1alpha was oppositely regulated. The independent regulation of PGC-1alpha and lipid catabolism genes was also found in peroxisome proliferator-activated receptor-alpha-null neonates, in which PGC-1alpha mRNA levels were unaffected whereas gene expression for 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase and acyl-coenzyme A oxidase was impaired. Thus, regulation of the PGC-1alpha gene is partially dissociated from the patterns of regulation of hepatic genes encoding enzymes involved in gluconeogenesis and lipid catabolism during fetal ontogeny and in response to the initiation of lactation.