Coordination between Drosophila Arc1 and a specific population of brain neurons regulates organismal fat

• Unbiased screen identifies neurons that prevent obesity in fly larvae.
• E347 brain neurons control body fat and expression of Arc1 in nearby neurons.
• Mutation of Arc1, a learning/memory factor, alters metabolism and drives fat storage.
• Arc1 is required for E347 neuronal control of body fat.

The brain plays a critical yet incompletely understood role in regulating organismal fat. We performed a neuronal silencing screen in Drosophila larvae to identify brain regions required to maintain proper levels of organismal fat. When used to modulate synaptic activity in specific brain regions, the enhancer-trap driver line E347 elevated fat upon neuronal silencing, and decreased fat upon neuronal activation. Unbiased sequencing revealed that Arc1 mRNA levels increase upon E347 activation. We had previously identified Arc1 mutations in a high-fat screen. Here we reveal metabolic changes in Arc1 mutants consistent with a high-fat phenotype and an overall shift toward energy storage. We find that Arc1-expressing cells neighbor E347 neurons, and manipulating E347 synaptic activity alters Arc1 expression patterns. Elevating Arc1 expression in these cells decreased fat, a phenocopy of E347 activation. Finally, loss of Arc1 prevented the lean phenotype caused by E347 activation, suggesting that Arc1 activity is required for E347 control of body fat. Importantly, neither E347 nor Arc1 manipulation altered energy-related behaviors. Our results support a model wherein E347 neurons induce Arc1 in specific neighboring cells to prevent excess fat accumulation.