Role for Insulin Signaling in Catecholaminergic Neurons in Control of Energy Homeostasis

Dopaminergic midbrain neurons integrate signals on food palatability and food-associated reward into the complex control of energy homeostasis. To define the role of insulin receptor (IR) signaling in this circuitry, we inactivated IR signaling in tyrosine hydroxylase (Th)-expressing cells of mice (IR ΔTh). IR inactivation in Th-expressing cells of mice resulted in increased body weight, increased fat mass, and hyperphagia. While insulin acutely stimulated firing frequency in 50% of dopaminergic VTA/SN neurons, this response was abolished in IR ΔTh mice. Moreover, these mice exhibited an altered response to cocaine under food-restricted conditions. Taken together, these data provide in vivo evidence for a critical role of insulin signaling in catecholaminergic neurons to control food intake and energy homeostasis. ► IR signaling in Th cells is critical in long-term control of fat mass and feeding ► Insulin increases firing frequency of a substantial subset of DA VTA/SN neurons ► Insulin controls activity of the reward dopaminergic circuitry ► Insulin modulates cocaine-evoked locomotor activity