The incidence of obesity is increasing globally. Once regarded as a disease of energy imbalance caused by the diet and lifestyle of developed nations, obesity is now regarded as a complex pathology involving dysfunction in the body’s regulatory systems: the nervous, immune, and endocrine systems. Societal interest in the study of obesity has progressed the burgeoning field of immunometabolism which studies how local immune environments may regulate metabolic and cellular processes. Of great interest to our group is how the sympathetic nervous system (SNS) serves as the effector arm of the neuroendocrine loop of leptin action, modulating immunity and metabolism in adipose tissue. Our group’s recent finding of a population of immunomodulatory leptin receptor (LepR)-expressing barrier cells, which ensheath sympathetic axon bundles in adipose tissues, suggests the unified field of (neuro)immunometabolism warrants further study. Over the course of this chapter, we will detail how modern developments in imaging, tissue clearing, and tracing techniques have furthered our understanding of the projections and physiology of the SNS beyond historical models. We will detail our understanding of the complex immunometabolomic interplay within adipose tissue. Finally, we will contextualize our groups’ recent findings within classical studies of the metabolic vulnerabilities of catecholaminergic neurons, theorizing that metabolic stress could lead to the loss of the (LepR)-expressing barrier cells in obesity. Loss of this barrier may unveil an immunogenic niche or possibly immune-privileged site to surveying immunocytes, thereby driving sympathetic neuropathy in obesity.