Energy metabolism and bone homeostasis share several neuronal regulatory 
pathways. Within the ventral hypothalamus (VHT), the orexigenic neurons 
co-express Agouti-related peptide (AgRP) and neuropeptide Y (NPY) and the 
anorexigenic neurons co-express, α-melanocyte stimulating hormone derived from 
proopiomelanocortin (POMC), and cocaine and amphetamine-regulated transcript 
(CART). These neurons regulate both processes, yet their relative contribution 
is unknown. Previously, using genetically targeted activator protein (AP1) 
alterations as a tool, we showed in adult mice that AgRP or POMC neurons are 
capable of inducing whole-body energy catabolism and bone accrual, with 
different effects on bone resorption. Here, we investigated whether co-residing 
neurons exert similar regulatory effects. We show that AP1 antagonists targeted 
to NPY-producing or CART-producing neurons in adult mice stimulate energy 
expenditure, reduce body weight gain and adiposity and promote trabecular bone 
formation and mass, yet again via different effects on bone resorption, as 
measured by serum level of carboxy-terminal collagen type I crosslinks (CTX). In 
addition, AP1 antagonists promote neurite expansion, increasing neurite number, 
length, and surface area in primary hypothalamic neuronal cultures. Overall, our 
data demonstrate that the orexigenic NPY and anorexigenic CART neurons both have 
the capacity to stimulate energy burning state and increase bone mass. © 2020 
American Society for Bone and Mineral Research.