Transynaptic Hypothalamic Regulation of Endocrine Pancreas Physiology

For over 150 years it has been known that certain brain injuries perturb metabolism. Within the last 30 years it has been known that there is a degree of neuronal control of insulin and glucagon secretion in response to nutrients, hormones and incretins. However, the precise neuronal pathway involved in regulating these pancreatic secretions remains largely unknown. In this study, we unveil a map of the brain that traces this pathway and indicates which parts of the brain connect to pancreatic islets, likely involved in regulating their function. We infected the pancreas of mice with a retrograde neuronal tracer, an attenuated pseudorabies virus expressing the LacZ gene reporter (PRV-BaBlu) and then probed brain beta-galactosidase detection at 24, 48, 72, and 96 hours. This enabled us to detect specific areas reached by the virus via autonomic nervous system from the pancreas. Viral tracing ends in the hypothalamus at the longest time point, indicating a major link of the hypothalamus to the endocrine pancreas. Very little PRV-BaBlu could be traced to other areas of the CNS. A characterization of this viral map co-localizes hypothalamic glucokinase to PRV-BaBlu positive neurons, indicating this tracing map overlaps with metabolic homeostasis control centers. In summary, we have generated the first map of the CNS link to the endocrine pancreas, directed to the hypothalamus, a central regulator of metabolic homeostasis and, now, also likely of endocrine pancreas physiology. Having this map will enable ongoing studies to establish the functional significance of hypothalamic control of pancreatic islet function.