Inhibition of adipose tissue angiogenesis prevents rebound weight gain after caloric restriction in mice fed a high-fat diet.

AIMS: We investigated whether modulation of white adipose tissue (WAT) vasculature regulates rebound weight gain (RWG) after caloric restriction (CR) in mice fed a high-fat diet (HFD). MAIN METHODS: We compared changes in energy balance, hypothalamic neuropeptide gene expression, and characteristics of WAT by RT-qPCR, ELISA, immunohistochemistry, and adipose-derived stromal vascular fraction spheroid sprouting assay in obese mice fed a HFD ad libitum (HFD-AL), mice under 40 % CR for 3 or 4 weeks, mice fed HFD-AL for 3 days after CR (CRAL), and CRAL mice treated with TNP-470, an angiogenic inhibitor. KEY FINDINGS: WAT angiogenic genes were expressed at low levels, but WAT vascular density was maintained in the CR group compared to that in the HFD-AL group. The CRAL group showed RWG, fat regain, and hyperphagia with higher expression of angiogenic genes and reduced pericyte coverage of the endothelium in WAT on day 3 after CR compared to the CR group, indicating rapidly increased angiogenic activity after CR. Administration of TNP-470 suppressed RWG, fat regain, and hyperphagia only after CR compared to the CRAL group. Changes in circulating leptin levels and hypothalamic neuropeptide gene expression were correlated with changes in weight and fat mass, suggesting that TNP-470 suppressed hyperphagia independently of the hypothalamic melanocortin system. Additionally, TNP-470 increased gene expression related to thermogenesis, fuel utilization, and browning in brown adipose tissue (BAT) and WAT, indicating TNP-470-induced increase in thermogenesis. SIGNIFICANCE: Modulation of the WAT vasculature attenuates RWG after CR by suppressing hyperphagia and increasing BAT thermogenesis and WAT browning.

Depot- and diabetes-specific differences in norepinephrine-mediated adipose tissue angiogenesis, vascular tone, collagen deposition and morphology in obesity.

AIMS: Norepinephrine (NE) is a known regulator of adipose tissue (AT) metabolism, angiogenesis, vasoconstriction and fibrosis. This may be through autocrine/paracrine effects on local resistance vessel function and morphology. The aims of this study were to investigate, in human subcutaneous and omental adipose tissue (SAT and OAT): NE synthesis, angiogenesis, NE-mediated arteriolar vasoconstriction, the induction of collagen gene expression and its deposition in non-diabetic versus diabetic obese subjects. MATERIALS AND METHODS: SAT and OAT from obese patients were used to investigate tissue NE content, tyrosine hydroxylase (TH) density, angiogenesis including capillary density, angiogenic capacity and angiogenic gene expression, NE-mediated arteriolar vasoconstriction and collagen deposition. KEY FINDINGS: In the non-diabetic group, NE concentration, TH immunoreactivity, angiogenesis and maximal vasoconstriction were significantly higher in OAT compared to SAT (p < 0.05). However, arterioles from OAT showed lower NE sensitivity compared to SAT (10-8 M to 10-7.5 M, p < 0.05). A depot-specific difference in collagen deposition was also observed, being greater in OAT than SAT. In the diabetic group, no significant depot-specific differences were seen in NE synthesis, angiogenesis, vasoconstriction or collagen deposition. SAT arterioles showed significantly lower sensitivity to NE (10-8 M to 10-7.5 M, p < 0.05) compared to the non-diabetic group. SIGNIFICANCE: SAT depot in non-diabetic obese patients exhibited relatively low NE synthesis, angiogenesis, tissue fibrosis and high vasoreactivity, due to preserved NE sensitivity. The local NE synthesis in OAT and diabetes desensitizes NE-induced vasoconstriction, and may also explain the greater tissue angiogenesis and fibrosis in these depots.

Systems Biology Will Direct Vascular-Targeted Therapy for Obesity.

Healthy adipose tissue expansion and metabolism during weight gain require coordinated angiogenesis and lymphangiogenesis. These vascular growth processes rely on the vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFRs). Several studies have shown that controlling vascular growth by regulating VEGF:VEGFR signaling can be beneficial for treating obesity; however, dysregulated angiogenesis and lymphangiogenesis are associated with several chronic tissue inflammation symptoms, including hypoxia, immune cell accumulation, and fibrosis, leading to obesity-related metabolic disorders. An ideal obesity treatment should minimize adipose tissue expansion and the advent of adverse metabolic consequences, which could be achieved by normalizing VEGF:VEGFR signaling. Toward this goal, a systematic investigation of the interdependency of vascular and metabolic systems in obesity and tools to predict personalized treatment ranges are necessary to improve patient outcomes through vascular-targeted therapies. Systems biology can identify the critical VEGF:VEGFR signaling mechanisms that can be targeted to regress adipose tissue expansion and can predict the metabolic consequences of different vascular-targeted approaches. Establishing a predictive, biologically faithful platform requires appropriate computational models and quantitative tissue-specific data. Here, we discuss the involvement of VEGF:VEGFR signaling in angiogenesis, lymphangiogenesis, adipogenesis, and macrophage specification - key mechanisms that regulate adipose tissue expansion and metabolism. We then provide useful computational approaches for simulating these mechanisms, and detail quantitative techniques for acquiring tissue-specific parameters. Systems biology, through computational models and quantitative data, will enable an accurate representation of obese adipose tissue that can be used to direct the development of vascular-targeted therapies for obesity and associated metabolic disorders.