co-staining-blood-vessels-and-nerve-fibers-in-adipose-tissue

Co-staining Blood Vessels and Nerve Fibers in Adipose Tissue

Recent studies have highlighted the critical role of angiogenesis and sympathetic innervation in adipose tissue remodeling during the development of ...

University of Texas Health Science Center at Houston

Endotrophin is a cleavage product of collagen 6 (Col6) in adipose tissue (AT). Previously, we demonstrated that endotrophin serves as a costimulator to trigger fibrosis and inflammation within the unhealthy AT milieu. However, how endotrophin affects lipid storage and breakdown in AT and how different cell types in AT respond to endotrophin stimulation remain unknown. In the current study, by using a doxycycline-inducible mouse model, we observed significant upregulation of adipogenic genes in the white AT (WAT) of endotrophin transgenic mice. We further showed that the mice exhibited inhibited lipolysis and accelerated hypertrophy and hyperplasia in WAT. To investigate the effects of endotrophin in vitro, we incubated different cell types from AT with conditioned medium from endotrophin-overexpressing 293T cells. We found that endotrophin activated multiple pathological pathways in different cell types. Particularly in 3T3-L1 adipocytes, endotrophin triggered a fibrotic program by upregulating collagen genes and promoted abnormal lipid accumulation by downregulating hormone-sensitive lipolysis gene and decreasing HSL phosphorylation levels. In macrophages isolated from WAT, endotrophin stimulated higher expression of the collagen-linking enzyme lysyl oxidase and M1 proinflammatory marker genes. In the stromal vascular fraction isolated from WAT, endotrophin induced upregulation of both profibrotic and proinflammatory genes. In conclusion, our study provides a new perspective on the effect of endotrophin in abnormal lipid accumulation and a mechanistic insight into the roles played by adipocytes and a variety of other cell types in AT in shaping the unhealthy microenvironment upon endotrophin treatment.

Divergent functions of endotrophin on different cell populations in adipose tissue.

Adipose-derived 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 the increased norepinephrine (NE) level, expression of β3-andrenoceptor was significantly upregulated and the downstream protein kinase A (PKA) pathway was activated, as indicated by the enhanced phosphorylation of the 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 these effects were abolished upon the treatment with β3-adrenoceptor antagonist SR59230A. Collectively, these results demonstrate that transient overexpressed VEGF-A activates sympathetic nervous system which hence promotes lipolysis and browning in adipose tissue.

Transient Overexpression of VEGF-A in Adipose Tissue Promotes Energy Expenditure via Activation of the Sympathetic Nervous System.

Lipolysis is a critical process to hydrolyze triglyceride in adipose tissue, thereby breaking down the stored lipid and maintaining energy homeostasis. Recent studies have made significant progress in understanding the steps of lipolysis. This chapter discusses the major pathways that regulate lipolysis in adipose tissue. Specifically we focus on the mechanisms by which the activities of critical lipolytic enzymes are regulated. We further discuss how the lipolysis is regulated by other factors, including insulin and neurotransmitters, in particular catecholamines and the role of sympathetic nervous system in the whole process. Finally we provide clinical perspectives about the novel therapeutic strategies to target or promote adipose tissue lipolysis for treatment/prevention of obesity and type 2 diabetes.

Article	Year
Divergent functions of endotrophin on different cell populations in adipose tissue. American journal of physiology. Endocrinology and metabolism\| PubMed ID: 27729337	2016
Transient Overexpression of VEGF-A in Adipose Tissue Promotes Energy Expenditure via Activation of the Sympathetic Nervous System. Molecular and cellular biology\| PubMed ID: 30126894	2018
Regulation of Lipolysis in Adipose Tissue and Clinical Significance. Advances in experimental medicine and biology\| PubMed ID: 30390292	2018

Kai Sun

Biography

JoVE Journal Publications

Other Publications