Leptin and insulin are both secreted in proportion to energy availability. Whereas leptin secretion is indicative of adipose mass and thus is more chronic in nature, insulin secretion reflects both acute and chronic nutritional status. The findings of Morioka et al. (5) validate the existence of an adipose tissue–islet endocrine feedback loop. Insulin is both potently lipogenic and functions in the CNS to reduce nutrient intake. Leptin also acts on the CNS to reduce nutrient intake and directly on β cells in lean animals to inhibit insulin secretion. The findings of both Morioka et al. (5) and Covey et al. (6) suggest that as body weight increases, leptin signaling protects the β cell from the adverse effects of overnutrition. Thus, glucose and energy homeostasis should both be considered in a very broad manner that simultaneously takes into account the effects of glucose, insulin, and leptin in multiple tissues.