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Neuropeptide Y (NPY)/Agouti-related protein (AgRP) neurons in the arcuate nucleus of the hypothalamus are part of a neuroendocrine feedback loop that regulates feeding behavior and glucose homeostasis. NPY/AgRP neurons sense peripheral signals (including the hormones leptin, insulin, and ghrelin) and integrate those signals with inputs from other brain regions. These inputs modify both long-term changes in gene transcription and acute changes in the electrical activity of these neurons, leading to a coordinated response to maintain energy and glucose homeostasis. However, the mechanisms by which the hormones insulin and leptin acutely modify the electrical activity of these neurons remain unclear. In this study, we show that loss of the phosphoinositide 3-kinase catalytic subunits p110α and p110β in AgRP neurons abrogates the leptin- and insulin-induced inhibition of AgRP neurons. Moreover, continual disruption of p110α and p110β in AgRP neurons results in increased weight gain. The increased adiposity was concomitant with a hypometabolic phenotype: decreased energy expenditure independent of changes in food intake. Deficiency of p110α and p110β in AgRP neurons also impaired glucose homeostasis and insulin sensitivity. In summary, these data highlight the requirement of both p110α and p110β in AgRP neurons for the proper regulation of energy balance and glucose homeostasis., Deficiency of both p110α and p110β in AgRP neurons abrogates acute inhibition of leptin and insulin as well as proper energy balance and glucose homeostasis.