FoxO1 Plays an Important Role in Regulating β-Cell Compensation for Insulin Resistance in Male Mice

Zhang, Ting; Kim, Dae Hyun; Xiao, Xianmin; Lee, Sojin; Gong, Zhaohui; Muzumdar, Radhika; Calabuig-Navarro, Virtu; Yamauchi, Jun; Harashima, Hideyoshi; Wang, Rennian; Bottino, Rita; Álvarez-Pérez, Juan Carlos; Garcı́a-Ocaña, Adolfo; Gittes, George K.; Dong, H. Henry

doi:10.1210/en.2015-1852

Cited by 64 publications

(48 citation statements)

References 66 publications

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“…However, contradictory reports have called the generality of these observations into question. Mice lacking Foxo1 either in beta cells or throughout the entire pancreas show no increase in beta cell proliferation either on a chow or high-fat diet (Kobayashi et al, 2012), and mice overexpressing FoxO1 fed a high-fat diet actually showed increased beta cell proliferation (Zhang et al, 2016). These results suggest that FoxO1 might inhibit beta cell replication only when the insulin receptor is completely absent, which is a unique and rare state.…”

Section: Regulation Of Metabolism By Foxo1mentioning

confidence: 92%

Fox transcription factors: from development to disease

2016

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Forkhead box (Fox) transcription factors are evolutionarily conserved in organisms ranging from yeast to humans. They regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with human disease and, as such, various animal models have been generated to study the function of these transcription factors in mechanistic detail. In many cases, the absence of even a single Fox transcription factor is lethal. In this Primer, we provide an overview of the Fox family, highlighting several key Fox transcription factor families that are important for mammalian development.

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Section: Regulation Of Metabolism By Foxo1mentioning

confidence: 92%

Fox transcription factors: from development to disease

2016

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“…In addition, APOC3-tg islets had increased expression of Irs2 (Fig. 5H), whose function is critical for ␤-cell function and mass regulation (47,48). In contrast, no significant differences were seen in Glut2 and Gck expression in islets of high fat-fed APOC3-tg mice.…”

Section: Apoc3 In Nonalcoholic Fatty Liver Diseasementioning

confidence: 93%

APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

Cheng

Yamauchi

Lee

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinNonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 (APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretion versus fatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and nonesterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro-and anti-inflammatory cytokines. APOC3 neither exacerbated dietinduced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity. Nonalcoholic fatty liver disease (NAFLD)4 is characterized by excessive lipid deposition in the liver of subjects with little alcohol consumption. Patients with NAFLD are at heightened risk of developing steatohepatitis with potential complications of fibrosis and cirrhosis (1-4). Currently, NAFLD affects about 30% of the general population, and its prevalence is increasing along with the rising epidemic of obesity in both adults and children (1, 5-10). Although it is known that NAFLD results from increased lipogenesis and decreased fatty acid oxidation in the liver, accompanied often by hepatic overproduction of TG-rich very low density lipoprotein (VLDL-TG), genetic factors that tip the balance of these three intertwining pathways in hepatic lipid metabolism at the expense of NAFLD are incompletely characterized.Apolipoprotein C3 (APOC3) (79 amino acids in length) is one of the most abundant apolipoproteins in the blood, where it is present as an exchangeable moiety between high density lipoproteins (HDLs) and triglyceride (TG)-rich particles, such as VLDL and chylomicrons (11). Secreted mainly from the liver and to a lesser extent from the intestine, AP...

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“…This renders β-cells more vulnerable to oxidative stress, accounting in part for β-cell dysfunction in diabetes. In this context, Zhang and co-workers show that FoxO1 stimulates β-cell expression of Sod1, catalase (Cat) and glutathione peroxidase 1 (Gpx1), contributing to improved β-cell survival and function in the presence of oxidative stress (Zhang et al 2016). Kibbe and colleagues report that FoxO1 protects β-cells from oxidative stress by inhibiting the expression of thioredoxin-interacting protein (TXNIP), a cytosolic factor whose deregulation is associated with β-cell apoptosis (Kibbe et al 2013).…”

Section: Foxo Integration Of Oxidative Stress To Cell Survivalmentioning

confidence: 99%

FoxO integration of insulin signaling with glucose and lipid metabolism

Lee

Dong

2017

Journal of Endocrinology

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254

177

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The forkhead box O family consists of FoxO1, FoxO3, FoxO4 and FoxO6 proteins in mammals. Expressed ubiquitously in the body, the four FoxO isoforms share in common the amino DNA binding domain, known as “forkhead box” domain. They mediate the inhibitory action of insulin or insulin-like growth factor on key functions involved in cell metabolism, growth, differentiation, oxidative stress, senescence, autophagy and aging. Genetic mutations in FoxO genes or abnormal expression of FoxO proteins are associated with metabolic disease, cancer or altered lifespan in humans and animals. Of the FoxO family, FoxO6 is the least characterized member and is shown to play pivotal roles in the liver, skeletal muscle and brain. Altered FoxO6 expression is associated with the pathogenesis of insulin resistance, dietary obesity and type 2 diabetes, and risk of neurodegeneration disease. FoxO6 is evolutionally divergent from other FoxO isoforms. FoxO6 mediates insulin action on target genes in a mechanism that is fundamentally different from other FoxO members. Here we focus our review on the role of FoxO6, in contrast with other FoxO isoforms, in health and disease. We review the distinctive mechanism by which FoxO6 integrates insulin signaling to hepatic glucose and lipid metabolism. We highlight the importance of FoxO6 dysregulation in the dual pathogenesis of fasting hyperglycemia and hyperlipidemia in diabetes. We review the role of FoxO6 in memory consolidation and its contribution to neurodegeneration disease and aging. We discuss the potential therapeutic option of pharmacological FoxO6 inhibition for improving glucose and lipid metabolism in diabetes.

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FoxO1 Plays an Important Role in Regulating β-Cell Compensation for Insulin Resistance in Male Mice

Cited by 64 publications

References 66 publications

Fox transcription factors: from development to disease

Fox transcription factors: from development to disease

APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

FoxO integration of insulin signaling with glucose and lipid metabolism

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