Introduction: The deletion of leptin receptors specifically in neuropeptide Y (NPY) neurons has been shown to alter the balance of energy partitioning between fat and bone mass, however the involvement of NPY and the underlying mechanisms involved in this process are unclear. We sought to investigate whether energy homeostasis can be altered by stimulating leptin-responsive NPY neurons using viral ‘designer receptor exclusively activated by designer drugs’ (DREADD) technology.
Materials and methods: In order to specifically target DREADD receptor expression to only NPY neurons that are also expressing leptin receptors, we generated stimulatory pAAV-Creon/Flpon hM3Dq-mCherry vectors that are only expressed in cells which co-express both Cre and Flp. We injected this vector bilaterally into the arcuate nucleus of LepRCre/+;NPYFlp/+ mice. In addition, we also used a Creon/Flpoff version of the virus in LepRCre/+;NPYFlp/+ mice to specifically target those neurons expressing the leptin receptor but not NPY. Following recovery, mice were assessed for energy homeostasis parameters in metabolic cages and thermogenesis was measured with a thermal imaging camera following CNO or control saline stimulation.
Results: The specific DREADD stimulation of LepR-expressing NPY neurons led to an increase in energy expenditure and a decrease in respiratory quotient with a delayed increase in food intake. In addition, CNO stimulation of LepR-NPY neurons led to a robust increase in brown adipose tissue thermogenesis. These effects were not observed when non-NPY LepR expressing neurons were stimulated, suggesting the effects of leptin on these parameters are driven by NPY.
Conclusion: Leptin acting on NPY neurons in the hypothalamus may control energy partitioning via actions to stimulate thermogenesis, energy expenditure, food intake, and the use of fat as a fuel source.