Foxo1 integrates insulin signaling with mitochondrial function in the liver

Cheng, Zhiyong; Guo, Shaodong; Copps, Kyle D.; Dong, Xiaochen; Kollipara, Ramya; Rodgers, Joseph T.; DePinho, Ronald A.; Puigserver, Pere; White, Morris F.

doi:10.1038/nm.2049

Cited by 292 publications

(360 citation statements)

References 33 publications

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“…Thus, the ability of 6KR to tune down expression of solute carriers might be part of a protective function. Interestingly, the mitochondrial gene expression signature of FoxO1 in ␤-cells appears to differ substantially from that in liver (39). Whether this depends on different levels of deacetylation in the two organs is an interesting question that will have to be addressed in subsequent studies.…”

Section: Discussionmentioning

confidence: 99%

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

Kim-Muller

Kim

Fan

et al. 2016

Journal of Biological Chemistry

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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.

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Section: Discussionmentioning

confidence: 99%

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

Kim-Muller

Kim

Fan

et al. 2016

Journal of Biological Chemistry

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“…Apart from the relationship with PGC1A, the present study found no relationship between GIR and downstream factors, including PGC1α protein production, nuclear respiratory factor-1 (NRF1), mitochondrial transcription factor A (TFAM) or mitochondrial genes and proteins. Post-transcriptional regulation of PGC1α, such as acetylation [47], may in part account for the dissociation between gene expression and protein abundance and the expected downstream effects.…”

Section: Discussionmentioning

confidence: 99%

Effect of exercise training on insulin sensitivity, mitochondria and computed tomography muscle attenuation in overweight women with and without polycystic ovary syndrome

et al. 2012

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Aims/hypothesis Polycystic ovary syndrome (PCOS) is an insulin resistant (IR) state. Increased skeletal muscle lipid content and impaired mitochondrial biogenesis have been implicated in the pathogenesis of IR. We investigated whether differences in these variables explain the IR of women affected by PCOS and whether improvements in IR with exercise are reflected by changes in these variables. Methods Sixteen PCOS and 13 non-PCOS overweight women were assessed, and eight PCOS and seven non-PCOS women were reassessed after 12 weeks of moderate and vigorous exercise training. Outcomes included insulin sensitivity (glucose infusion rate [GIR]), skeletal muscle gene expression and protein abundance, enzyme activity of selected mitochondrial components, and computed tomography (CT) attenuation-estimated muscle lipid. Results GIR was lower in women with PCOS versus those without (p 00.01) and increased with exercise in both groups. Baseline CT muscle attenuation suggested a trend to less muscle lipid in PCOS, which increased with exercise training, with a difference in the change in muscle lipid (p00.01, age-corrected), compared with non-PCOS women. GIR correlated with PGC1A gene expression across the whole group; skeletal muscle expression of mitochondrial biogenesis markers was not different between groups at baseline, or after training. Neither lipid changes nor mitochondrial changes correlated with changes in GIR. Conclusions/interpretation Differences in IR in women with and without PCOS were not explained by differences in skeletal muscle lipid or mitochondrial parameters. Improvements in IR with exercise were dissociated from mitochondrial parameters. CT muscle attenuation suggested a differential capacity of PCOS muscle to store lipid compared with non-PCOS.

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“…6,7 As FoxO1 was implicated in mitochondrial regulation, 12,20 we asked if AS1842856 interferes with mitochondrial function in adipocytes. Western blot analysis of mitochondrial proteins revealed 2.6-fold (P < 0.01) upregulation of respiration chain complex I (C1) and 3.9-fold (P < 0 .01) elevation of complex III (C3) in matured adipocytes when compared with pre-adipocytes ( Fig.…”

Section: As1842856 Reduced Mitochondrial Protein Levelsmentioning

confidence: 99%

“…Oil Red O retained in the cells was extracted with isopropanol, and quantified by the absorbance (O. D.) at 510 nm. 28 Western blot For cell lysates, the cells were washed with ice-cold PBS (Caisson Labs) and lysed with a Bullet Blender Ò (Next Advance, Inc..), in PLC lysis buffer: 20,29 (30 mM Hepes, pH 7.5, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl2, 1 mM EGTA, 10 mM NaPPi, 100 mM NaF, 1 mM Na3VO4) supplemented with protease inhibitor cocktail (Roche), 1 mM PMSF, 10 mM TSA (Trichostatin A, Selleckchem) and 5 mM Nicotinamide (Alfa Aesar). Total protein concentrations of the cell lysates were determined using the DC protein assay (Bio-Rad).…”

Section: Oil Red O Stainingmentioning

confidence: 99%

“…[15][16][17][18] FoxO1 haploinsufficiency protects mice from diet induced insulin resistance and diabetes. 15,19 In the liver, activated FoxO1 can regulate lipid metabolism by manipulating mitochondrial function, 20,21 and it also increases blood glucose by upregulating glucose 6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK), the gluconeogenic enzymes that promote glucose production. 22 These multiple roles in regulating metabolism demonstrate the great potential to target FoxO1 for new therapeutics for obesity and T2DM.…”

Section: Introductionmentioning

confidence: 99%

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Targeting FoxO1 with AS1842856 Suppresses Adipogenesis

et al. 2014

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Abbreviations: AS1842856, 5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid BMI, basal media I; BMII, basal media II; C1, mitochondrial complex I; C3, mitochondrial complex III; DMI, differentiation media I; DMII, differentiation media II; FoxO1, forkhead box O1; G6P, glucose 6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; PPARg, peroxisome proliferator-activated receptor gamma; T2DM, type 2 diabetes mellitus.Hyperplasia (i.e., increased adipogenesis) contributes to excess adiposity, the hallmark of obesity that can trigger metabolic complications. As FoxO1 has been implicated in adipogenic regulation, we investigated the kinetics of FoxO1 activation during adipocyte differentiation, and tested the effects of FoxO1 antagonist (AS1842856) on adipogenesis. We found for the first time that the kinetics of FoxO1 activation follows a series of sigmoid curves, and reveals the phases relevant to clonal expansion, cell cycle arrest, and the regulation of PPARg, adiponectin, and mitochondrial proteins (complexes I and III). In addition, multiple activation-inactivation transitions exist in the stage of terminal differentiation. Importantly, persistent inhibition of FoxO1 with AS1842856 almost completely suppressed adipocyte differentiation, while selective inhibition in specific stages had differential effects on adipogenesis. Our data present a new view of FoxO1 in adipogenic regulation, and suggest AS1842856 can be an anti-obesity agent that warrants further investigation.

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Foxo1 integrates insulin signaling with mitochondrial function in the liver

Cited by 292 publications

References 33 publications

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

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

Effect of exercise training on insulin sensitivity, mitochondria and computed tomography muscle attenuation in overweight women with and without polycystic ovary syndrome

Targeting FoxO1 with AS1842856 Suppresses Adipogenesis

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