Model for central nervous system regulation of insulin secretion and insulin sensitivity via the SNS during cold exposure. Model for central nervous system regulation of insulin secretion and insulin sensitivity via the SNS during cold exposure. In response to thermal sensory input from the periphery during cold exposure, the brain engages a series of adaptive responses that increase SNS outflow to thermogenic tissues (i.e., brown adipose tissue, skeletal muscle, heart) as needed to meet the increased demands for heat production in order to maintain core temperature. At the same time, cold exposure increases SNS outflow to the pancreas, which potently inhibits insulin secretion via activation of α-ARs on pancreatic β-cells. Our findings demonstrate that the effect of cold exposure to increase insulin sensitivity is offset by a proportionate decline in glucose-induced insulin secretion such that glucose tolerance remains unchanged. Moreover, the effects of cold exposure on insulin sensitivity and insulin secretion are rapidly reversed by systemic α-AR blockade and by returning animals to room temperature. These findings implicate a key role for the brain, via the SNS, in the rapid, highly coordinated, and reciprocal changes of insulin secretion and insulin sensitivity that preserve glucose homeostasis in the setting of cold exposure. Gregory J. Morton et al. Diabetes 2017;66:823-834 ©2017 by American Diabetes Association