The Mitochondrial Brown Adipose Tissue Maintenance Factor Nipsnap1 Interfaces Directly with the Beta-Oxidation Protein Machinery.

Background: The activation of brown adipose tissue (BAT) is associated with improved metabolic health in humans. We previously identified the mitochondrial protein 4-Nitrophenylphosphatase Domain and Non-Neuronal SNAP25-Like 1 (Nipsnap1) as a novel regulatory factor that integrates with lipid metabolism and is critical to sustain the long-term activation of BAT, but the precise mechanism and function of Nipsnap1 is unknown. Objectives: Define how the regulatory factor Nipsnap1 integrates with lipid metabolism. Methods: We generated adeno-associated viral (AAV) constructs that overexpress Nipsnap1 in the thermogenic fat of mice. We then measured both whole-body and cellular mitochondrial metabolism and mapped the first Nipsnap1 interacting protein-protein network. Results: Herein, we show that adipose-specific overexpression of Nipsnap1 in mice increases energy expenditure through the utilization of lipids as an energy substrate. The increase in energy expenditure results in reduced weight gain. Additionally, we show that Nipsnap1 overexpression in primary adipocytes increases lipid beta-oxidation. Moreover, we mapped the first protein- protein network of Nipsnap1 in brown adipocytes and show that Nipsnap1 interacts with proteins that regulate both peroxisomal and mitochondrial fatty acid beta-oxidation. Conclusion: This study elucidates a mechanistic function of Nipsnap1 in thermogenic fat where Nipsnap1 facilitates a functional connection between peroxisomal and mitochondrial beta-oxidation pathways. By enhancing lipid utilization as energy substrates, Nipsnap1 plays a pivotal role in sustaining thermogenic fat activation to increase energy expenditure. These findings underscore the potential of Nipsnap1 as a therapeutic target for metabolic health.