Department of Biology, Indiana University-Indianapolis, Indianapolis, Indiana, United States.
Medical Neurosciences and Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, Indiana, United States.
Am J Physiol Endocrinol Metab. 2024 Aug 1;327(2):E155-E171. doi: 10.1152/ajpendo.00099.2023. Epub 2024 Apr 17.
Spinophilin is an F-actin binding and protein phosphatase 1 (PP1) targeting protein that acts as a scaffold of PP1 to its substrates. Spinophilin knockout () mice have decreased fat mass, increased lean mass, and improved glucose tolerance, with no difference in feeding behaviors. Although spinophilin is enriched in neurons, its roles in nonneuronal tissues, such as β cells of the pancreatic islets, are unclear. We have corroborated and expanded upon previous studies to determine that mice have decreased weight gain and improved glucose tolerance in two different models of obesity. We have identified multiple putative spinophilin-interacting proteins isolated from intact pancreas and observed increased interactions of spinophilin with exocrine, ribosomal, and cytoskeletal protein classes that normally act to mediate peptide hormone production, processing, and/or release in Lepr and/or high-fat diet-fed (HFF) models of obesity. In addition, we have found that spinophilin interacts with proteins from similar classes in isolated islets, suggesting a role for spinophilin in the pancreatic islet. Consistent with a pancreatic β cell type-specific role for spinophilin, using our recently described conditional spinophilin knockout mice, we found that loss of spinophilin specifically in pancreatic β cells improved glucose tolerance without impacting body weight in chow-fed mice. Our data further support the role of spinophilin in mediating pathophysiological changes in body weight and whole body metabolism associated with obesity. Our data provide the first evidence that pancreatic spinophilin protein interactions are modulated by obesity and that loss of spinophilin specifically in pancreatic β cells impacts whole body glucose tolerance. To our knowledge, these data are the first to demonstrate that obesity impacts spinophilin protein interactions in the pancreas and identify spinophilin specifically in pancreatic β cells as a modulator of whole body glucose tolerance.
螺旋肌球蛋白是一种 F-肌动蛋白结合蛋白和蛋白磷酸酶 1（PP1）靶向蛋白，作为 PP1 与其底物的支架。螺旋肌球蛋白敲除（）小鼠的脂肪量减少，瘦肉量增加，葡萄糖耐量改善，摄食量无差异。尽管螺旋肌球蛋白在神经元中富集，但它在非神经元组织（如胰岛β细胞）中的作用尚不清楚。我们已经证实并扩展了以前的研究，以确定在两种不同的肥胖模型中，螺旋肌球蛋白缺失的小鼠体重增加减少，葡萄糖耐量提高。我们已经从完整的胰腺中鉴定出多个假定的螺旋肌球蛋白相互作用蛋白，并观察到螺旋肌球蛋白与外分泌、核糖体和细胞骨架蛋白类别的相互作用增加，这些蛋白通常在肥胖的 Lepr 和/或高脂肪饮食喂养（HFF）模型中起作用，以介导肽激素的产生、加工和/或释放。此外，我们发现螺旋肌球蛋白与分离胰岛中的类似类别的蛋白相互作用，提示螺旋肌球蛋白在胰岛中的作用。与螺旋肌球蛋白在胰腺β细胞中具有特定的作用一致，使用我们最近描述的条件性螺旋肌球蛋白敲除小鼠，我们发现螺旋肌球蛋白在胰腺β细胞中的特异性缺失改善了葡萄糖耐量，而不影响喂食普通饮食的小鼠的体重。我们的数据进一步支持了螺旋肌球蛋白在介导与肥胖相关的体重和全身代谢的病理生理变化中的作用。我们的数据首次提供了证据，表明肥胖会调节胰腺螺旋肌球蛋白蛋白相互作用，并且螺旋肌球蛋白在胰腺β细胞中的特异性缺失会影响全身葡萄糖耐量。据我们所知，这些数据首次表明肥胖会影响胰腺中的螺旋肌球蛋白蛋白相互作用，并确定胰腺β细胞中的螺旋肌球蛋白特异性作为全身葡萄糖耐量的调节剂。
