While training in 1989 with Richard Have1 in San Francisco, I became interested in his studies of the role of the sympathetic nervous system in the regulation of free fatty acid (FFA) mobilization from adipose tissue.’ Therefore, when I arrived at the laboratory of Robert H. Williams as a postdoctoral endocrine fellow in 1963, I chose to study the effects of catecholamines on carbohydrate and lipid metabolism. To evaluate these effects, Alan Graber and I gave prolonged infusion of epinephrine to a male subject. We found that FAA levels rose and then returned to basal values despite continued administration of the amine. Since hyperglycemia and tachycardia persisted, we concluded that reesterification of FFA in adipose tissue or inhibition of lipolysis by insulin might be involved. To determine which mechanism was most likely, we asked Takashi Kuzuya (now at Jichi Medical School, Japan), another postdoctoral fellow, to assay the plasma samples from our catecholamine infusions for insulin using the newly developed radioimmunoassay. To our surprise, insulin levels did not change during the epinephrine infusions but rose dramatically upon their termination. Since the concept of the autonomic nervous system regulating the peripheral endocrine system was not considered likely at that time, we performed a number of control studies to stimulate the p-cell with glucose and other insulin secretagogues; all were inhibited by epinephrine. This finding had important implications for metabolic regulation and suggested that many older studies in which insulin secretion had been assumed to parallel glucose levels would need to be reexamined. Before submission of the work, I had the opportunity to present it at the meeting of the American Society of Clinical Investigation. Afterward, I received a letter and reprint’ from Arthur Colwell pointing out that he had suggested such a possibility 30 years earlier when he observed inhibition of glucose oxidation during an epinephrine infusion. So much for the originality of my scientific finding! Nevertheless, the concept was new to most scientists and opened up enough new questions that I spent the next 20 years studying its implications. What developed is the idea that the peripheral nervous system regulates many hormones, not just those of the endocrine pancreas. Eventually, a critical role for the neural control of islet function in the development of stress hyperglycemia was delineated.3 Later, I began studies of the possibility that the central nervous system, in turn, is regulated by peptide hormones secreted by peripheral endocrine cells. The central neural connections to the pancreas were eventually shown to originate in the ventral hypothalamus, an area of the brain important to glucose regulation and body energy balance. Because of this finding, Steve Woods and I developed the concept of feedback from the /?-cell to the hypothalamus via insulin for the regulation of food intake and energy expenditure.4*5 This idea of a peripheral metabolic signal for the brain has been given a big boost recently with the discovery of the ob gene and its circulating adipose tissue hormonal gene product, leptin.6 Interestingly, leptin and insulin both appear to regulate the same neural circuit, the synthesis and release of neuronal NPY in the arcuate nucleus?,* The newness of the original finding with epinephrine, and later norepinephrine, and its applicability to many other endocrine glands, plus the large number of diabetes-related investigators, led to ‘frequent citations, and in 1984 this article was recognized as a citation “classic” in Current