Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis
We show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity.  Lepr inactivation in PNOC neurons increases Npy expression in a subset of hypothalamic PNOC neurons that do not express Agrp and selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOCARC neurons and overexpression of Npy in PNOCARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPYARC neurons as an additional critical mediator of leptin action and  a promising target for obesity therapeutics. Overall design: BacTRAP based RNA sequencing. We crossed control and Pnoc Lepr deletion mice with ROSA-STOP-L10a-bactrap mice, allowing for Cre-dependent expression of the fusion protein of the ribosomal protein L10a tagged with GFP specifically in PNOC neurons. From 12 week old L10a-bactrap animals, we harvested hypothalamic samples and used an anti-GFP antibody to precipitate ribosomes of PNOC neurons (4 pooled animals per sample). Deep mRNA sequencing of RNA associated with immunopurified ribosomes from PNOC neurons yielded a detailed translational profile of hypothalamic PNOC neurons.