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首页> 外文期刊>American Journal of Physiology >Intracellular fatty acids suppress β-adrenergic induction of PKA-targeted gene expression in white adipocytes
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Intracellular fatty acids suppress β-adrenergic induction of PKA-targeted gene expression in white adipocytes

机译：细胞内脂肪酸抑制白脂肪细胞中PKA靶向基因表达的β-肾上腺素能诱导

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摘要

β-Adrenergic receptor (P-AR) activation elevates cAMP levels in fat cells and triggers both metabolic and transcriptional responses; however, the potential interactions between these pathways are poorly understood. This study investigated whether lipolysis affects p-AR-mediated gene expression in adipocytes. Acute β_3-adrenergic receptor (β_3-AR) stimulation with CL 316,243 (CL) increased expression of PKA-targeted genes PCG-1α, UCP1, and NOR-1 in mouse white fat. Limiting lipolysis via inhibition of hormone-sensitive lipase (HSL), a direct target of PKA, sharply potentiated CL induction of PCG-lα, UCP1, and NOR-1. CL also induced greater expression of PKA-targeted genes in white fat of HSL-null mice compared with wild-type littermates, further indicating that HSL activity limits PKA-mediated gene expression. Inhibiting HSL in 3T3-L1 adipocytes also potentiated the induction of PGC-1α, UCP1, and NOR-1 by P-AR activation, as did siRNA knockdown of adipose triglyceride lipase, the rate-Limiting enzyme for lipolysis. Conversely, treatments that promote intracellular fatty acid accumulation suppressed induction of PGC-1α and UCP1 through β-AR stimulation. Analysis of β-adrenergic signaling indicated that excessive intracellular fatty acid production inhibits adenylyl cyclase activity and thereby reduces PKA signaling to the nucleus. Lastly, partially limiting lipolysis by inhibition of HSL increased the induction of oxidative gene expression and mitochondrial electron transport chain activity in white adipose tissue and facilitated fat loss in mice treated for 5 days with CL. Overall, our results demonstrate that fatty acids limit the upregulation of β-AR-responsive genes in white adipocytes and suggest that limiting lipolysis may be a novel means of enhancing β-AR signaling.
机译：β-肾上腺素能受体（p-ar）活化升高脂肪细胞中的CAMP水平，并触发代谢和转录反应;然而，这些途径之间的潜在相互作用较差地理解。该研究研究了脂肪解是否影响脂肪细胞中的P-Ar介导的基因表达。急性β_3-肾上腺素能受体（β_3-AR）用Cl 316,243（CL）刺激（CL）增加了小鼠白色脂肪中PKA靶向基因PCG-1α，UCP1和NOR-1的表达。通过抑制激素敏感性脂肪酶（HSL），PKA的直接靶标，PCG-Lα，UCP1和NOR-1的直接靶向抑制激素敏感脂肪酶（HSL），其直接靶向脂肪解。 CL还与野生型凋落物相比诱导了HSL-XULL小鼠白脂的PKA靶向基因的更大表达，进一步表明HSL活性限制了PKA介导的基因表达。抑制3T3-L1 adipocytes的HSL还通过P-AR活化激活了PGC-1α，UCP1和NOR-1的诱导，如脂肪甘油三酯脂肪酶的siRNA敲低，脂解的速率限制酶。相反，促进促进细胞内脂肪酸累积的治疗抑制PGC-1α和UCP1至β-AR刺激的诱导。 β-肾上腺素能信号传导的分析表明，过量的细胞内脂肪酸产生抑制腺苷酸环酶活性，从而减少了对细胞核的PKA信号传导。最后，通过抑制HSL部分限制脂解增加了白色脂肪组织中的氧化基因表达和线粒体电子传输链活性，并用Cl处理了5天的小鼠中的脂肪损失。总体而言，我们的结果表明，脂肪酸限制了白色脂肪细胞中β-ar响应基因的上调，并表明限制脂解可以是增强β-AR信号传导的新方法。

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