The sympathetic nervous system in the 21st century: Neuroimmune interactions in metabolic homeostasis and obesity

The sympathetic nervous system maintains metabolic homeostasis by orchestrating the activity of organs such as the pancreas, liver, and white and brown adipose tissues. From the first renderings by Thomas Willis to contemporary techniques for visualization, tracing, and functional probing of axonal arborizations within organs, our understanding of the sympathetic nervous system has started to grow beyond classical models. In the present review, we outline the evolution of these findings and provide updated neuroanatomical maps of sympathetic innervation. We offer an autonomic framework for the neuroendocrine loop of leptin action, and we discuss the role of immune cells in regulating sympathetic terminals and metabolism. We highlight potential anti-obesity therapeutic approaches that emerge from the modern appreciation of SNS as a neural network vis a vis the historical fear of sympathomimetic pharmacology, while shifting focus from post- to pre-synaptic targeting. Finally, we critically appraise the field and where it needs to go. In this review, we update the neuroanatomical maps of sympathetic innervation of the pancreas, liver, and adipose tissues. We discuss the role of the immune cells in regulating sympathetic terminals and metabolism. We conjecture on novel anti-obesity therapies that could emerge from the modern appreciation of SNS as a neural network modulated by immune cells.