Tsai Pei-Yin, Qu Yue, Walter Claire, Liu Yang, Cheng Chloe, Barrow Joeva J
Division of Nutritional Sciences, Cornell University, Ithaca, NY, United States.
Department of Biomedical Sciences, Cornell University, Ithaca, NY, United States.
J Nutr. 2025 Jul;155(7):2154-2163. doi: 10.1016/j.tjnut.2025.05.026. Epub 2025 May 23.
The activation of brown adipose tissue (BAT) is associated with improved metabolic health in humans. We previously identified the mitochondrial protein 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 are unknown.
The study aims to define the function of the regulatory factor Nipsnap1 in lipid metabolism by identifying its specific protein-protein interactions and regulatory role in fatty acid β-oxidation.
We used adeno-associated viral (AAV) vectors to overexpress Nipsnap1 in the thermogenic adipose tissue of male C57BL/6J mice and assessed whole-body energy metabolism using metabolic cages. Mitochondrial respiration in primary brown adipocytes was measured by Seahorse assay after AAV-Nipsnap1 infection. To further investigate molecular mechanisms, an immunoprecipitation assay was performed to identify Nipsnap1-interacting proteins.
We showed that adipose-specific overexpression of Nipsnap1 in mice elicits a 20% increase in energy expenditure through the utilization of lipids as an energy substrate as evidenced by the shift of the respiratory exchange ratio to 0.7 (P < 0.001). Additionally, we showed that Nipsnap1 overexpression in primary adipocytes increases lipid β-oxidation by 39% to increase cellular energy expenditure (P < 0.05). Moreover, we mapped the first protein-protein network of Nipsnap1 in brown adipocytes and showed that Nipsnap1 interacts with proteins such as solute carrier family 25 member 20 and enoyl-coenzyme A (CoA) hydratase and 3-hydroxyacyl CoA dehydrogenase that regulate both mitochondrial and peroxisomal fatty acid β-oxidation, respectively.
This study elucidates a mechanistic function of Nipsnap1 in thermogenic fat where Nipsnap1 facilitates a functional connection between peroxisomal and mitochondrial β-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.
棕色脂肪组织（BAT）的激活与人类代谢健康的改善相关。我们之前鉴定出线粒体蛋白Nipsnap1是一种与脂质代谢整合的新型调节因子，对维持BAT的长期激活至关重要，但Nipsnap1的确切机制和功能尚不清楚。
本研究旨在通过鉴定其特定的蛋白质-蛋白质相互作用以及在脂肪酸β氧化中的调节作用，来明确调节因子Nipsnap1在脂质代谢中的功能。
我们使用腺相关病毒（AAV）载体在雄性C57BL/6J小鼠的产热脂肪组织中过表达Nipsnap1，并使用代谢笼评估全身能量代谢。在AAV-Nipsnap1感染后，通过海马实验测量原代棕色脂肪细胞中的线粒体呼吸。为了进一步研究分子机制，进行免疫沉淀实验以鉴定与Nipsnap1相互作用的蛋白质。
我们发现，在小鼠中脂肪特异性过表达Nipsnap1会使能量消耗增加20%，这是通过将脂质用作能量底物实现的，呼吸交换率转变为0.7就证明了这一点（P < 0.001）。此外，我们发现原代脂肪细胞中Nipsnap1的过表达使脂质β氧化增加39%，从而增加细胞能量消耗（P < 0.05）。此外，我们绘制了棕色脂肪细胞中Nipsnap1的首个蛋白质-蛋白质网络，并表明Nipsnap1与溶质载体家族25成员20以及烯酰辅酶A（CoA）水合酶和3-羟酰基辅酶A脱氢酶等蛋白质相互作用，这些蛋白质分别调节线粒体和过氧化物酶体脂肪酸β氧化。
本研究阐明了Nipsnap1在产热脂肪中的机制功能，其中Nipsnap1促进了过氧化物酶体和线粒体β氧化途径之间的功能连接。通过增强脂质作为能量底物的利用，Nipsnap1在维持产热脂肪激活以增加能量消耗方面发挥着关键作用。这些发现强调了Nipsnap1作为代谢健康治疗靶点的潜力。
