Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling

Abstract

Summary Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of Glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of Glucokinase is unknown; and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here we report that SIN3A is the insulin-sensitive FOXO1 corepressor of Glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of Glucokinase, without affecting other FOXO1 target genes, and lowers glycemia without concurrent steatosis. To extend this work, we executed a small molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes. In addition to identifying a novel mode of insulin action, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out adverse effects of insulin sensitizers.

PDK4‐Deficiency Reprograms Intrahepatic Glucose and Lipid Metabolism to Facilitate Liver Regeneration in Mice

“…The deletion of FOXO1 rescues loss‐of‐AKT‐impaired LR, which is consistent with our finding that FOXO1 has a suppressive role in LR by inhibiting CD36 expression. The transcription repression function of FOXO1 on CD36 might depend on co‐repressors . In summary, the PDK4/AMPK/FOXO1/CD36 axis is critical to resection‐induced LR, and pharmacological inhibition of PDK4 might improve LR efficiency.…”

“…The transcription repression function of FOXO1 on CD36 might depend on co-repressors. (45,46) In summary, the PDK4/AMPK/ FOXO1/CD36 axis is critical to resection-induced LR, and pharmacological inhibition of PDK4 might improve LR efficiency.…”

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

“…Except for its critical regulatory role of insulin signaling in liver (Langlet et al, 2017), FoxO1 maintains β-cell mass (Kitamura et al, 2002;Okamoto et al, 2006), β-cell identity, and proper β-cell function (Kawamori et al, 2006;Talchai, Xuan, Kitamura, DePinho, & Accili, 2012). Impaired FoxO activity causes MODY-like diabetes through the reduced metabolic flexibility of β-cells (Kim-Muller et al, 2014).…”

Dysregulation of the Mitochondrial Proteome Occurs in Mice Lacking Adiponectin Receptor 1

“…Adiponectin is an adipose-derived hormone which comprises 0.01% of all plasma proteins. Despite its known protective functions in the body, which include anti-inflammatory, anti-atherosclerotic and anti-fibrotic effects (1), its primary physiological role may be the ability to improve systemic insulin sensitivity. Its role in regulating glucose homeostasis therefore suggests that the observed decrease in serum levels of adiponectin in non-insulin dependent (type 2) diabetes mellitus (NIDDM) is involved in the pathogenesis of insulin resistance and ultimately NIDDM (2,3).…”