Multiple regulatory pathways exist to control the expression levels of neuropeptides in response to body weight and energy availability changes. Since many neuropeptides are first synthesized in a pro-neuropeptide form, the availability of processing enzymes in a neuron can control the amount of active mature neuropeptide produced at any given time. In this review, we will focus on the regulation of prohormone convertase 1 (PC1) and prohormone convertase 2 (PC2), as well as downstream neuropeptide genes. Evidence from our laboratory suggests that Nescient helix-loop-helix 2 (Nhlh2) regulates the transcription of PC1 and PC2, possibly in conjunction with the leptin-stimulated transcription factor, STAT3. Furthermore, Nhlh2 itself is a target of leptin and other energy availability signals, with high levels of expression during energy surplus, and low levels of expression in conditions of reduced energy availability such as food deprivation or cold exposure. Overall, coordinate regulation of Nhlh2, PC1, PC2 and downstream hypothalamic neuropeptides such as thyrotropin releasing hormone (TRH) and pro-opiomelanocortin (POMC) does lead to energy balance modulation and ensuing long-term changes in body weight.