Transient Overexpression of Vascular Endothelial Growth Factor A in Adipose Tissue Promotes Energy Expenditure via Activation of the Sympathetic Nervous System

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.