The impact of overweight/obesity on Veterans' health and VA healthcare costs is staggering and a better understanding of the mechanisms by which overweight/obesity lead to metabolic dysfunction, as well as the mechanisms by which exercise improves this dysfunction, is required to effectively treat these comorbidities. In addition to the storage of energy, adipose tissue contributes to metabolic homeostasis by buffering plasma free fatty acids, limiting ectopic lipid accumulation and secreting adipokines. Appropriate adipose tissue blood flow is required for normal adipose function and is influenced by its resistance artery vasoreactivity and vascular density. Thus, arterial dysfunction characterized by a loss of nitric oxide (NO) may contribute to metabolic dysfunction by impairing adipose artery endothelium dependent dilation (EDD) and angiogenesis, limiting both blood flow and the entopic storage of lipids in white adipose depots. Recently, the pro-angiogenic effects of vascular endothelial growth factor (VEGF) were shown to be inhibited by the actions of roundabout4 (Robo4) and the downstream GTPase, ARF6. Here, we will determine if altered endothelial Robo4/ARF6 activity underlies adipose artery dysfunction and subsequent metabolic dysfunction with high fat feeding. In contrast to obesity, chronic exercise has beneficial effects on metabolism that may be mediated by adenosine monophosphate-activated protein kinase (AMPK). With exercise, increased AMPK activity leads to activation of energy conserving pathways in metabolically active tissues; whereas, in endothelial cells, AMPK activity leads to NO production that occurs downstream of VEGF. However, it is not known what role AMPK activation may play in improving adipose tissue function, if endothelial Robo4/ARF6 signaling modulates the activity of AMPK or if pharmacological activation of AMPK can serve as an exercise mimetic and improve adipose tissue function in the face of obesity.
The impact of overweight/obesity on Veterans' health and VA healthcare costs is staggering and a better understanding of the mechanisms by which overweight/obesity lead to metabolic dysfunction as well as the mechanisms by which exercise improves this dysfunction is required to effectively treat these comorbidities. The goal of this research is to directly assess the role f endothelial Robo4/ARF6 signaling in modulating the detrimental effects of overweight/obesity and the beneficial effects of exercise on adipose artery function, adipose tissue function and subsequent systemic metabolic homeostasis, as well as to determine if pharmacological activation of AMPK acts as an exercise mimetic, improving these adipose artery, adipose tissue and metabolic outcomes through a modulation of Robo4/ARF6 signaling.
