The hypothalamic neuronal circuits that modulate energy homeostasis become mature and functional during early postnatal life. However, the molecular mechanism underlying this developmental process remains largely unknown. Here we use a mouse genetic approach to investigate the role of gamma-protocadherins (Pcdh-γs) in hypothalamic neuronal circuits. First, we show that rat insulin promoter (RIP)-Cre conditional knockout mice lacking Pcdh-γs in a broad subset of hypothalamic neurons are obese and hyperphagic. Second, specific deletion of Pcdh-γs in anorexigenic proopiomelanocortin (POMC) expressing neurons also leads to obesity. Using cell lineage tracing, we show that POMC and RIP-Cre expressing neurons do not overlap but interact with each other in the hypothalamus. Moreover, excitatory synaptic inputs are reduced in Pcdh-γ deficient POMC neurons. Genetic evidence from both knockout models shows that Pcdh-γs can regulate POMC neuronal function autonomously and non-autonomously through cell–cell interaction. Taken together, our data demonstrate that Pcdh-γs regulate the formation and functional integrity of hypothalamic feeding circuitry in mice.