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.2011 Jul 31;17(8):961-7.
doi: 10.1038/nm.2378.

Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner

Affiliations

Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner

Utpal B Pajvani et al. Nat Med..

Erratum in

Abstract

Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate this function. Altered Notch signaling is evident in tumorigenesis, and Notch antagonists are in clinical testing for application in cancer. Here we report that FoxO1 and Notch coordinately regulate hepatic glucose metabolism. Combined haploinsufficiency of FoxO1 and Notch1 markedly raises insulin sensitivity in diet-induced insulin resistance, as does liver-specific knockout of the Notch transcriptional effector Rbp-Jκ. Conversely, Notch1 gain-of-function promotes insulin resistance in a FoxO1-dependent manner and induces glucose-6-phosphatase expression. Pharmacological blockade of Notch signaling with γ-secretase inhibitors raises insulin sensitivity after in vivo administration in lean mice and in obese, insulin-resistant mice. The data identify a heretofore unknown metabolic function of Notch and suggest that Notch inhibition is beneficial in diabetes treatment, in part by helping to offset excessive FoxO1-driven hepatic glucose production.

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Figures

Figure 1
Figure 1
Metabolic characterization ofFoxo1+/− andFoxo1+/−:Notch1+/− mice. (a) Notch1 cleavage and (b) Notch target gene expression in livers from 8-wk-old male WT mice after increasing length of fast, or refeeding after 24hr fast. (c) Glucose and (d) insulin levels in mice fed either HFD or standard chow and fasted for 16 h, or fasted for 16 h, then refed for 2 h. (e) Intraperitoneal glucose tolerance tests (IPGTT) in HFD-fed mice following 16-h fast. (f) Insulin tolerance tests in HFD-fed mice following 4-h fast. (g) Pyruvate tolerance test in HFD-fed mice following 16-h fast. (h) Glucose production in primary hepatocytes from WT,FoxO1+/− andFoxo1+/−:Notch1+/− mice in the presence (HGP) or absence of pyruvate and lactate (glycogenolysis, Gly). The difference between these two values was assumed to reflect gluconeogenesis (Gng). (i) Western blots of insulin signaling proteins in livers from HFD-fed WT,FoxO1+/− andFoxo1+/−:Notch1+/− mice. All animals were 16-wk old. *P < 0.05 vs. WT,&P < 0.05 vs.Foxo1+/− (n = 7–8 each genotype).
Figure 2
Figure 2
Hyperinsulinemic-euglycemic clamps and gene expression studies inFoxo1+/−:Notch1+/− mice. (a) Glucose infusion rate (GIR), (b) hepatic glucose production (HGP) and glucose disposal rate (Rd) from clamp studies in 12-wk-old, HFD-fed WT,Foxo1+/− andFoxo1+/−:Notch1+/− male mice. (c)14C-2-deoxy-glucose (2-DOG) uptake during the final 5 min of the clamp. (d) Hepatic glycogen content in clamped livers. Gene expression in 16-wk-old, (e) chow-fed or (f) HFD-fed WT,Foxo1+/− andFoxo1+/−:Notch1+/− male mice sacrificed after a 16-h fast. All genes were normalized by 18s rRNA. *P < 0.05, **P < 0.01, ***P < 0.001 vs. WT;&P < 0.05 vs.Foxo1+/− (n = 7–8 each genotype).
Figure 3
Figure 3
Metabolic characteristics ofL-Rbpj mice. (a) Growth curves, (b) body composition andad libitum (c) insulin and (d) glucose levels of HFD-fedL-Rbpj mice and cre-negative controls (Cre−) measured every 2–4 wk. (e) IPGTT in 16-h fasted, HFD-fed Cre− andL-Rbpj mice. (f) Western blots for hepatic p−Akt, total Akt and G6pc from fasted, HFD-fed, 16-wk old Cre− andL-Rbpj (Cre +) mice. *P<0.05 vs. Cre− n = 8 each genotype).
Figure 4
Figure 4
Notch1 regulation ofG6Pc transcription in hepatocytes, and hepatic insulin sensitivityin vivo. (a) mRNA levels in primary hepatocytes from 12-wk-old WT male mice transduced with FoxO1-ADA (FoxO1), Notch1-IC (N1-IC) and/or GFP adenoviruses (MOI=5). (b)G6pc promoter luciferase reporter assays, following transduction with GFP or N1-IC, or (c) incubation with Delta-like ligand-4 (rDLL4). N1-IC or rDLL4 treatment-induced luciferase activity in constructs containing both Rbp-Jk (denoted with “R”) and FoxO1 binding sites (−1227bp), but not constructs lacking the sites (−499) or containing mutated FoxO1 sites (−1227-mut). Numbers refer to nucleotides upstream of transcription start site. (d) Chromatin immunoprecipitation (ChIP) at theG6pc promoter using anti-Rbp-Jk or control antibody in livers from fasted control (Cre−),L-Foxo1 andL-Rbpj mice. (e)G6pc ChIP assays from liver of WT mice fasted for 16 h or refed for 2 h following a 16-h fast. *P<0.05vs. control IgG (n = 4). (f) Glucose and (g) insulin levels determined 7 days after N1-IC delivery in mice fasted for 16-h or refed for 2 h following a 16-h fast. (h) mRNA levels in livers of mice transduced with either N1-IC or GFP adenoviruses. (i) Insulin levels and (j) hepatic gene expression in 2-h refedL-Rbpj male mice and Cre− controls transduced with either N1-IC or GFP adenoviruses. *P < 0.05, *P < 0.01, ***P < 0.001vs. GFP;&P < 0.05 vs. Cre− n = 5–8 each genotype).
Figure 5
Figure 5
Effects of GSI in primary hepatocytes. (a) Western blot analysis of Notch1 cleavage at Val1744 following incubation with increasing doses of EDTA in the presence or absence of GSI. (b) qPCR analysis of Notch targets in vehicle (No tx) or EDTA-treated hepatocytes in the presence or absence of GSI. (c) Gene expression and (d) glucose production in the absence (No tx) or presence of GSI. Hepatocytes were treated with cAMP and dexamethasone for 3 h to stimulate gluconeogenic gene expression and glucose output. (e) Dose-response curve for insulin inhibition of glucose production from primary hepatocytes incubated in the presence or absence of GSI. (f) Glucose production in the absence (No tx) or presence of GSI in primary hepatocytes from control (Cre−), FoxO1-deficient (L-Foxo1) and Rbp-Jκ-deficient mice (L-Rbpj). (g) GSI-dependent regulation of gene expression in hepatocytes transduced with FoxO1 shRNA adenovirus. *P<0.05 vs. No tx;&P<0.05 vs. cAMP/dexamethasone (n = 4). One experiment representative of 3 individual experiments is shown.
Figure 6
Figure 6
Insulin-sensitizing effects of dibenzazepine (GSI) treatment. (a) IPGTT and (b) hepatic gene expression in 16-h fasted, chow-fed lean mice following a single dose of GSI (GSI 1d) or 5 consecutive days of GSI treatment (GSI 5d). (c)Ad libitum glucose and (d) insulin levels in diet-induced obese (DIO) andob/ob mice following a 5-day course of either vehicle or GSI. (e) IPGTT inob/ob mice following a 5-day course of vehicle or GSI. (f) IPGTT, (g) ad lib glucose and (h) insulin levels in DIO mice treated with either vehicle or GSI every third day, or (i) every second day (arrows). (j) Western blots of Akt and IRS1 phosphorylation in livers isolated after 5 days treatment with either vehicle or GSI. *P<0.05, *P<0.01, ***P<0.001 vs. vehicle,&P<0.05 vs. GSI 1d (n = 6 each group).
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Comment in

References

    1. Accili D. Lilly lecture 2003: the struggle for mastery in insulin action: from triumvirate to republic. Diabetes. 2004;53:1633–1642. - PubMed
    1. Kahn SE, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–2443. - PubMed
    1. Kim-Muller JY, Accili D. Cell biology. Selective insulin sensitizers. Science. 2011;331:1529–1531. - PubMed
    1. Haeusler RA, Kaestner KH, Accili D. FoxOs function synergistically to promote hepatic glucose production. J Biol Chem. 2010 - PMC - PubMed
    1. Nakae J, et al. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet. 2002;32:245–253. - PubMed

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