FoxO1 Deacetylation Decreases Fatty Acid Oxidation in beta-cells and Sustains Insulin Secretion in Diabetes

Pancreatic beta-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state beta-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to beta-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylation-dependent nuclear translocation to forestall the progression of these abnormalities. However, how deacetylated FoxO exert their actions remains unclear. To address this question, we analyzed islet function in mice homozygous for knock-in alleles encoding deacetylated FoxO1 (6KR). Islets expressing 6KR mutant FoxO1 have enhanced insulin secretion in vivo and ex vivo, and decreased fatty acid oxidation ex vivo. Remarkably, the gene expression signature associated with FoxO1 deacetylation differs from wild-type by only ~2% of the > 4,000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for beta-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects beta-cell function by limiting mitochondrial lipid utilization, and raise the possibility that inhibition of fatty acid oxidation in β-cells is beneficial to diabetes treatment. Examined 2 different feeding state and 2 different genotypes

胰腺β细胞（Pancreatic beta-cell）功能障碍可促成2型糖尿病（Type 2 diabetes）的发生与进展。在此状态下，β细胞会丧失代谢灵活性，无法选择以碳水化合物或脂质作为线粒体氧化（Mitochondrial oxidation）的底物，此类改变最终会引发β细胞去分化。本研究团队曾提出，叉头框O蛋白（FoxO）可通过去乙酰化依赖的核转位（Nuclear translocation）被激活，以延缓这类异常的进展，但目前仍不明确去乙酰化后的FoxO如何发挥其调控作用。为解答这一问题，我们对携带编码去乙酰化FoxO1（6KR）的纯合敲入等位基因（Knock-in alleles）的小鼠开展了胰岛功能分析。结果显示，表达6KR突变型FoxO1的胰岛在体内（In vivo）及体外（Ex vivo）实验中均表现出胰岛素分泌增强，而体外脂肪酸氧化（Fatty acid oxidation）水平降低。值得注意的是，在超过4000个受复食（Re-feeding）调控的基因中，与FoxO1去乙酰化相关的基因表达特征仅与野生型（Wild-type）存在约2%的差异，但这一微小的基因集合却涵盖了维持β细胞特性、脂质代谢以及线粒体脂肪酸与溶质转运所需的关键基因。本研究数据支持“去乙酰化FoxO1通过限制线粒体脂质利用以保护β细胞功能”这一假说，并提示抑制β细胞脂肪酸氧化或可有益于糖尿病治疗。本研究共考察了2种喂养状态（Feeding state）与2种基因型（Genotypes）。