In addition to its role in determining sleep need, Salt-inducible kinase 3 (Sik3) is likely to regulate energy homeostasis since mice mutant for exon 13 of the Sik3 gene (Sleepy) display an obese phenotype. The main objective of this project is to identify the role of SIK3 in the central nervous system in the regulation of energy balance. To achieve this, neuron-specific mutant mice lines for the Sleepy gene were generated, as well as viral genetic approaches in Sik3-ex13 floxed mice were used to identify the brain regions involved in SIK3 actions. Our data showed that Vglut2-specific Sleepy mice also show an obese phenotype, suggesting dependency of glutamatergic signaling. SIK3 gain of function, by AAV injection in Sik3-ex13 floxed mice, in the ventromedial nucleus of the hypothalamus induced feeding-independent increase in body weight, associated with altered glucose homeostasis. On the other hand, SIK3 in the paraventricular nucleus of the hypothalamus caused hyperphagia and reduced energy expenditure leading to an obese phenotype. Overall, these data suggest a role of SIK3 in the regulation of energy metabolism in a nucleus-specific manner.