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Many studies show that genetics play a major contribution to the onset of obesity. Human genome-wide association studies (GWASs) have identified hundreds of genes that are associated with obesity. However, the majority of them have not been functionally validated. <i>SEC16B</i> has been identified in multiple obesity GWASs but its physiological role in energy homeostasis remains unknown. Here, we use <i>Drosophila</i> to determine the physiological functions of <i>dSec16</i> in energy metabolism. Our results showed that global RNAi of <i>dSec16</i> increased food intake and triglyceride (TAG) levels. Furthermore, this TAG increase was observed in flies with a specific RNAi of <i>dSec16</i> in insulin-like peptide producing cells (IPCs) with an alteration of endocrine peptides. Together, our study demonstrates that <i>dSec16</i> acting in IPCs controls energy balance and advances the molecular understanding of obesity.