(A) Maintenance of body temperature, body fat stores, and blood glucose levels within narrow physiological limits requires seamless integration of systems governing thermoregulation, energy homeostasis, and glucose homeostasis. This integration is coordinated by the brain, and it is dependent upon accurate sensing by the brain of external temperature (1), body fat content (2), and the blood glucose level (3). (B) During cold exposure, the increased demand for heat production is met through markedly increased rates of glucose utilization by thermogenic tissues. Energy homeostasis is preserved by a centrally mediated increase in food intake, while glucose homeostasis preserved by centrally mediated inhibition of insulin secretion (to avert hypoglycemia). Impaired sensing of the relevant afferent input results in a compensatory increase in the defended level of the regulated variable. In the case of T2D, impaired brain glucose sensing is hypothesized to raise the defended blood glucose level into the diabetic range, with inhibition of insulin secretion playing a key role.