FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes

Abstract

Pancreatic ␤-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state ␤-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to ␤-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylationdependent 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 ϳ2% of the >4000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for ␤-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects ␤-cell function by limiting mitochondrial lipid utilization and raise the possibility that inhibition of fatty acid oxidation in ␤-cells is beneficial to diabetes treatment.

When β‐cells fail: lessons from dedifferentiation

“…However, it is equally important to note that Foxo activation is limited in time, as the deacetylated nuclear protein has decreased stability . As Foxo levels decrease, the stage is set for dedifferentiation through the loss of gene expression networks necessary to the maintenance of β‐cell characteristics …”

“…Experimental animal studies show that Foxo activation in the early phases of diabetes preserves the balance between glucose and lipids in the generation of acyl‐CoA for mitochondrial oxidation. Foxo maintains the activation state of the maturity onset diabetes of youth (MODY) genes Hnf4, Hnf1 and Pdx1, and suppresses the fatty acid oxidation network supervised by nuclear receptor Pparα, to curtail generation of lipid‐derived acyl‐CoA (Figure ) …”

HDAC4 mutations cause diabetes and induce β‐cell FoxO1 nuclear exclusion

“…In this report, we found dramatically increasing levels of acetylation FoxO1 and obvious nuclear export of both HDAC4 and FoxO1, but the location of Pdx1 remains unchanging, indicating the HDAC4 mutations disrupt the deacetylation of FoxO1, but not the pdx1. We therefore hypothesize FoxO1 is deacetylated not only by Sirt1, Sirt2, and Sirt6, but also by HDAC4 in the pancreas (Daitoku et al, ; Kim‐Muller et al, ; Kitamura et al, ; Song, Wang, Ka, Bae, & Park, ). The regulation of FoxO1 to β‐cell compensation to overnutrition and obesity (Zhang et al, ) was thereafter disrupted by the FoxO1 deacetylation failure in the diabetic patients harboring HDAC4 mutations.…”

“…Deacetylated FoxO1 protects β-cell function by limiting mitochondrial lipid utilization through decreasing fatty acid oxidation and enhancing insulin secretion in the context of diabetes (Kim-Muller et al, 2016); which is in consist in the findings that the levels of acetylated FoxO1 are markedly increased in pancreatic tissues of diabetic, compared to healthy rats (Ding et al, 2014). We found elevated levels of acetylated FoxO1 in the pancreatic β-cells exposed to the HDAC4 mutations compared to the wild type, indicating the failure of FoxO1 deacetylation in the diabetic patients.…”

Deterioration of insulin release rate response to glucose during oral glucose tolerance test is associated with an increased risk of incident diabetes in normal glucose tolerance subjects

“…Identification of b-cell function impairment in subjects with NGT could have great importance for the prevention and early diagnosis of risk subjects for diabetes. The failure of b-cell response to metabolic stress, such as high glucose stimulation, has been attributed to different biological mechanisms, one of which is b-cell dedifferentiation (14), and is considered to play an important role in the development of T2D (14,27). The capacity of b-cell response to glucose is an inherent feature of b-cell response and a key regulator for the glucose homeostasis (28,29).…”