Intracellular fatty acids suppress β-adrenergic induction of PKA-targeted gene expression in white adipocytes
Intracellular fatty acids suppress β-adrenergic induction of PKA-targeted gene expression in white adipocytes
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DOI：
10.1152/ajpendo.00039.2011
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发表时间：
2011-07-01
影响因子：
5.1
通讯作者：
Granneman, James G.
中科院分区：
文献类型：
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作者：
Mottillo, Emilio P.;Granneman, James G.
Mottillo EP，Granneman JG。细胞内脂肪酸抑制β-肾上腺素能诱导白色脂肪细胞中PKA靶向基因的表达。Am J Physiol Endocrinol Metab 301：E122-E131,2011。--β-肾上腺素能受体(beta-AR)激活可提高脂肪细胞中的cAMP水平，并触发代谢和转录反应；然而，这些通路之间的潜在相互作用尚不清楚。这项研究调查了脂肪细胞中脂肪分解是否影响β-AR介导的基因表达。用CL 316,243(CL)刺激急性β(3)-肾上腺素能受体(beta(3)-AR)可增加小鼠白色脂肪中PKA靶向基因PCG-1α、UCP1和NOR-1的表达。通过抑制PKA的直接靶点激素敏感脂酶(HSL)来限制脂解，可显著增强CL对PCG-1α、UCP1和NOR-1的诱导。CL还诱导HSL缺失小鼠白色脂肪中PKA靶向基因的表达高于野生型小鼠，进一步表明HSL活性限制了PKA介导的基因表达。抑制3T3-L1脂肪细胞中的HSL也加强了β-AR激活对PGC-1α、UCP1和NOR-1的诱导，以及抑制脂肪甘油三酯脂肪酶的siRNA抑制，脂肪甘油三酯脂肪酶是脂肪分解的限速酶。相反，促进细胞内脂肪酸积累的治疗抑制了通过刺激β-AR诱导PGC-1α和UCP1的诱导。对β-肾上腺素能信号的分析表明，细胞内过多的脂肪酸产生抑制了腺苷环化酶的活性，从而减少了通往细胞核的PKA信号。最后，通过抑制HSL来部分限制脂肪分解增加了白色脂肪组织中氧化基因的表达和线粒体电子传输链的活性，并促进了CL处理5天的小鼠的脂肪丢失。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反应基因的上调，并表明限制脂解可能是增强β-AR信号的一种新方法。
Mottillo EP, Granneman JG. Intracellular fatty acids suppress beta-adrenergic induction of PKA-targeted gene expression in white adipocytes. Am J Physiol Endocrinol Metab 301: E122-E131, 2011. First published April 19, 2011; doi: 10.1152/ajpendo.00039.2011 doi: 10.1152/ajpendo.00039.2011.-beta-Adrenergic receptor (beta-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 beta-AR-mediated gene expression in adipocytes. Acute beta(3)-adrenergic receptor (beta(3)-AR) stimulation with CL 316,243 (CL) increased expression of PKA-targeted genes PCG-1 alpha, 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-1 alpha, 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-1 alpha, UCP1, and NOR-1 by beta-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-1 alpha and UCP1 through beta-AR stimulation. Analysis of beta-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 beta-AR-responsive genes in white adipocytes and suggest that limiting lipolysis may be a novel means of enhancing beta-AR signaling.