Altered function of arcuate leptin receptor expressing neuropeptide Y neurons depending on energy balance

OBJECTIVE: One of leptin's main targets in the hypothalamus are neuropeptide Y (NPY) neurons, with selective deletion of leptin receptors (Lepr) specifically in Npy neurons resulting in major alterations of energy partitioning between fat and bone mass. However, the specific action of these Npy+/Lepr+ neurons compared to Npy-negative Lepr (Npy−/Lepr+) neurons in regard to energy homeostasis regulation is unknown. METHODS: Specific AAV viral vectors were generated using DREADD and INTRSECT technology and used in male Lepr(Cre/+) and Lepr(Cre/+);Npy(Flp/+) mice to assess the effect of activating either all Lepr neurons or specifically Npy+/Lepr+ or Npy−/Lepr+ neurons only on feeding, energy homeostasis control, and body composition. RESULTS: Selective stimulation of Npy+/Lepr+ neurons led to an immediate decrease in respiratory quotient followed by a delayed increase in food intake in standard chow fed, but interestingly not in high fat diet (HFD) fed mice. In addition, stimulation of Npy+/Lepr+ neurons led to a robust increase in brown adipose tissue thermogenesis and improved glucose tolerance. These effects were not observed in standard chow fed mice when Npy−/Lepr+ expressing neurons were specifically activated, suggesting the effects of leptin on these parameters are driven by NPY. However, under HFD condition when leptin levels are elevated, the stimulation of the Npy−/Lepr+ neurons increased food intake, physical activity and energy expenditure. Interestingly, chronic stimulation of Npy-positive Lepr neurons was able to increase bone mass independently of bodyweight, whilst chronic stimulation of the Npy−/Lepr+ neurons resulted in increased bodyweight and fat mass with proportionate increases in bone mass. CONCLUSIONS: Together, these data indicate that leptin signalling through Npy-positive Lepr-expressing neurons controls energy partitioning via stimulation of thermogenesis, energy expenditure, and the use of fat as a fuel source. However, under prolonged HFD, leptin resistance may occur and actions of leptin signalling through Npy-negative Lepr hypothalamic neurons may exacerbate excess food intake.