Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Mol Cell Biol. 2018 Oct 29;38(22). doi: 10.1128/MCB.00242-18. Print 2018 Nov 15.
Adipose-derived vascular endothelial growth factor A (VEGF-A) stimulates functional blood vessel formation in obese fat pads, which in turn facilitates healthy expansion of the adipose tissue. However, the detailed mechanism(s) governing the process remains largely unknown. Here, we investigated the role of sympathetic nervous system activation in the process. To this end, we induced overexpression of VEGF-A in an adipose tissue-specific doxycycline (Dox)-inducible transgenic mouse model for a short period of time during high-fat diet (HFD) feeding. We found that local overexpression of VEGF-A in adipose tissue stimulated lipolysis and browning rapidly after Dox induction. Immunofluorescence staining against tyrosine hydroxylase (TH) indicated higher levels of sympathetic innervation in adipose tissue of transgenic mice. In response to an increased norepinephrine (NE) level, expression of β3-adrenoceptor was significantly upregulated, and the downstream protein kinase A (PKA) pathway was activated, as indicated by enhanced phosphorylation of whole PKA substrates, in particular, the hormone-sensitive lipase (HSL) in adipocytes. As a result, the adipose tissue exhibited increased lipolysis, browning, and energy expenditure. Importantly, all of these effects were abolished upon treatment with the β3-adrenoceptor antagonist SR59230A. Collectively, these results demonstrate that transient overexpressed VEGF-A activates the sympathetic nervous system, which hence promotes lipolysis and browning in adipose tissue.
脂肪组织来源的血管内皮生长因子 A（VEGF-A）可刺激肥胖脂肪垫中功能性血管的形成，进而促进脂肪组织的健康扩张。然而，调控这一过程的详细机制在很大程度上仍不清楚。在这里，我们研究了交感神经系统激活在此过程中的作用。为此，我们在高脂肪饮食（HFD）喂养期间，通过短暂诱导 VEGF-A 在脂肪组织中特异性过表达，在一种脂肪组织特异性的强力霉素（Dox）诱导型转基因小鼠模型中实现了这一点。我们发现，Dox 诱导后，脂肪组织中 VEGF-A 的局部过表达迅速刺激脂肪分解和棕色化。酪氨酸羟化酶（TH）的免疫荧光染色表明，转基因小鼠的脂肪组织中交感神经支配水平更高。对去甲肾上腺素（NE）水平升高的反应是，β3-肾上腺素能受体的表达显著上调，下游蛋白激酶 A（PKA）途径被激活，表现为脂肪细胞中全 PKA 底物，特别是激素敏感脂肪酶（HSL）的磷酸化增强。结果，脂肪组织表现出增强的脂肪分解、棕色化和能量消耗。重要的是，用β3-肾上腺素能受体拮抗剂 SR59230A 处理后，所有这些作用均被消除。总之，这些结果表明，短暂过表达的 VEGF-A 可激活交感神经系统，从而促进脂肪组织中的脂肪分解和棕色化。
