Angiogenesis modulates obesity and insulin sensitivity

• Both white and brown fat are highly vascularized tissues and vascular functions in adipose tissues remain largely unknown. In this thesis work, we aimed to study blood vessels in modulation of adipose tissue functions under physiological conditions. To achieve these goals, we have used genetic mouse models in combination with pharmacological approaches as powerful tools to investigate adipose vascularization in modulation of adipose tissue functions and metabolism. We have developed unique in vitro and in vivo methods and techniques to functionally and mechanistically address the interactions between endothelial cells (ECs) and adipocytes (ACs). These novel methods and findings may potentially pave new avenues for development of therapeutics for treatment of obesity and metabolic diseases by targeting the adipose vasculature. In paper I, we describe novel methods to induce browning and angiogenic phenotypes in white adipose tissues (WAT) by exposing mice to cold ambient temperature (4°C). We have also defined methodologies to measure basal and non-shivering thermogenesis-related metabolism in mice. Several immunohistological methods that are coupled to confocal microscopy analysis were established to accurately quantify expression of gene products that are associated with thermogenesis and angiogenesis. These model systems and methodologies have provided a fundamental basis for subsequent projects within and outside our laboratory to study adipogenesis and metabolism. With the available methods developed in paper I, in paper II we have studied the age-related vascular effects in modulation of fat mass, AC functions, blood lipid profiles and insulin sensitivity. Notably, Vegf expression levels in various WATs underwent continuous changes in different age populations. Anti-VEGF and anti-VEGFR2 treatment showed marked variations of vascular regression, with middle-aged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT AC sizes in different age populations and affected vascular density and AC sizes in brown adipose tissue (BAT). Consistent with changes of vasculatures and AC sizes, anti-VEGF treatment significantly increased insulin sensitivity in all groups, except for a rather modest improvement of insulin sensitivity in the middle-aged group. Similar to healthy mice, anti-VEGF treatment substantially improved insulin sensitivity in obese mice on a high fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based drugs. In paper III, we studied the paracrine regulation of AC functions by angiogenic ECs following cold- or pharmacologically induced adrenergic activation. We have found that ECs play an essential role in modulating AC functions during WAT browning. This paracrine effect is mediated by EC-derived PDGF-CC, which acts on progenitor cells to induce differentiation into ACs. Deletion of the Pdgfc gene in mice or blocking of PDGFRα largely impairs the paracrine regulation of AC functions during WAT browning. In paper IV, we have developed an effective and reliable lymphangiogenesis assay that allows us to study the lymphangiogenic capacity of various factors in the absence of pre-existing lymphatics and other angiogenic stimuli. We took advantage of the avascular nature of the cornea to study the lymphangiogenic effect of any given factor or combination of factors. To this end, we have tested several angiogenic factors that are commonly present in adipose tissues and quantitatively studied corneal lymphangiogenesis.

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