Nos1 neurons in the paraventricular hypothalamic area modulate lipid metabolism via the sympathetic nervous system in male mice.

The selection of the appropriate energy substrate under different physiological conditions is a key aspect of the energy metabolism homeostasis. We here show that Nos1 (nitric oxide synthase 1)-expressing cells in the paraventricular hypothalamic nucleus (PVH) serve as a pivotal node for controlling whole-body fat consumption in male mice. Nos1 neurons account for ~30% of PVH neurons that convey signals via polysynaptic pathways to individual peripheral tissues, including skeletal muscle and brown (BAT) and white (WAT) adipose tissues. Activation of these Nos1 neurons in the PVH area induces WAT lipolysis and fat oxidation in other peripheral tissues via the sympathetic nervous system, thereby increasing whole-body fat consumption. Inhibition of these neurons abolishes the increase in fat consumption during the light period, whereas long-term silencing lead to obesity independent of energy intake. These neurons are also necessary for cold-induced thermogenesis in BAT and the rapid increase in fat consumption elicited by food deprivation or other stressors. Nos1 neurons in the PVH area are therefore essential for controlling fat consumption and energy homeostasis.