Targeting Forkhead Box O1 from the Concept to Metabolic Diseases: Lessons from Mouse Models

Cheng, Zhiyong; White, Morris F.

doi:10.1089/ars.2010.3370

Cited by 174 publications

(183 citation statements)

References 127 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…Based on our data, combined with that of previous reports [33,34], we propose a model for the mechanism of FOXQ1 action on hepatic gluconeogenesis (Fig. 8).…”

Section: Resultssupporting

confidence: 77%

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

et al. 2016

View full text Add to dashboard Cite

Aim/hypothesis Hepatic forkhead box q1 (FOXQ1) expression levels are regulated by nutritional and pathophysiological status. In this study we investigated the role of FOXQ1 in the regulation of hepatic gluconeogenesis. Methods We used multiple mouse and cell models to study the role of FOXQ1 in regulating expression of gluconeogenic genes, and cellular and hepatic glucose production. Results Expression of hepatic FOXQ1 was regulated by fasting in normal mice and was dysregulated in diabetic mice. Overexpression of FOXQ1 in primary hepatocytes inhibited expression of gluconeogenic genes and decreased cellular glucose output. Hepatic FOXQ1 rescue in db/db and high-fat diet-induced obese mice markedly decreased blood glucose level and improved glucose intolerance. In contrast, wildtype C57 mice with hepatic FOXQ1 deficiency displayed increased blood glucose levels and impaired glucose tolerance. Interestingly, studies into molecular mechanisms indicated that FOXQ1 interacts with FOXO1, thereby blocking FOXO1 activity on hepatic gluconeogenesis, preventing it from directly binding to insulin response elements mapped in the promoter region of gluconeogenic genes. Conclusions/interpretation FOXQ1 is a novel factor involved in regulating hepatic gluconeogenesis, and the decreased FOXQ1 expression in liver may contribute to the development of type 2 diabetes.

show abstract

“…Based on our data, combined with that of previous reports [33,34], we propose a model for the mechanism of FOXQ1 action on hepatic gluconeogenesis (Fig. 8).…”

Section: Resultssupporting

confidence: 77%

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…After transfecting the effective siSOCS3 into the hepatocytes of IUGR rats, insulin sensitivity was restored and demonstrated a significantly greater downregulation in the transcriptional expressions of G6Pase and PEPCK than those without siSOCS3 treatment. Furthermore, phosphorylated Akt2 levels in CG-IUGR liver cells were elevated after transfection, and subsequently forkhead box O1 was inactivated by phosphorylation to inhibit the transcription of G6Pase and PEPCK (31). Therefore, we confirmed that knocking down the expression of SOCS3 ameliorates the insulin signaling pathway and decreases hepatic glucose production by downregulating the transcriptional expressions of gluconeogenesis genes in primary hepatocytes of CG-IUGR rats.…”

Section: Articlessupporting

confidence: 62%

Downregulating SOCS3 with siRNA ameliorates insulin signaling and glucose metabolism in hepatocytes of IUGR rats with catch-up growth

Zheng

Wang

et al. 2012

Pediatr Res

View full text Add to dashboard Cite

Background: Individuals with intrauterine growth retardation (IUGR) who demonstrate a catch-up in body weight are prone to insulin resistance. high expressions of suppressor of cytokine signaling 3 (sOcs3) are thought to aggravate insulin resistance. We hypothesized that downregulating sOcs3 expression via small interfering RNa (siRNa) might have beneficial effects on insulin-resistant hepatocytes of catch-up growth IUGR rats (cG-IUGRs). Methods: an IUGR rat model was employed via maternal nutritional restriction. after evaluating metabolic states of cG-IUGR offspring, effective SOCS3-specific siRNa (sisOcs3) was transfected into cultured hepatocytes using liposomes. mRNa levels of sOcs3, insulin receptor substrates (IRss), phosphatidylinositol 3-kinase (PI3K), and akt2, key gluconeogenesis genes, were assessed via real-time PcR. Protein expression and phosphorylation changes were evaluated via western blot. results: cG-IUGR hepatocytes showed increases in sOcs3 and gluconeogenic gene expressions, and decreases in IRs1 and PI3K expressions as compared with controls. after transfecting cG-IUGR hepatocytes with sisOcs3, protein levels of IRs1, PI3K, and phosphorylated akt2 were higher as compared with those of untransfected cG-IUGR cells. Transcriptional suppression effects of gluconeogenesis genes were more obvious in sisOcs3-treated cells after insulin stimulation. conclusion: additional insights were provided to understand mechanisms of insulin resistance in cG-IUGR rats. Downregulating sOcs3 might improve insulin signaling transduction and ameliorate hepatic glucose metabolism in insulin-resistant cG-IUGR rats in vitro.W orldwide epidemiological data have shown that intrauterine growth retardation (IUGR), low birth weight, and subsequent adulthood obesity are highly correlated with the development of metabolic syndrome, which comprises hypertension, cardiovascular disease, type 2 diabetes mellitus, and dyslipidemia. Insulin resistance is considered to be a fundamental contributor to metabolic syndrome (1-3). The underlying causes of IUGR are complicated. In developed countries, poor placental function and cigarette smoking during pregnancy are the most common factors causing IUGR, although maternal malnutrition is the major determinant of IUGR in developing countries (4). Approximately 85-90% of infants with IUGR demonstrate catch-up growth during the first 2 y, and those who display a catch-up in body weight are more prone to insulin resistance (5). However, the underlying molecular mechanisms that result in insulin resistance in individuals with catch-up IUGR are still not fully understood.Suppressor of cytokine signaling (SOCS)-family proteins have been identified as inhibitors of cytokine-induced signaling pathways in various tissues and serve as physiological regulatory feedback loops (6). Suppressor of cytokine signaling 3 (SOCS3) is highly expressed in the liver, skeletal muscle, and adipose tissue of animal models with insulin resistance (7,8). Studies have also shown that SOCS3 plays an important role...

show abstract

“…This factor is known to control expression of the enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in the liver, both regulatory enzymes of gluconeogenesis. 21 Consistent with changes in FoxO1, both PEPCK and G6Pase were increased in liver of obB2KO mice. Conversely, intraportal injection of BK in lean mice acutely decreased FoxO1 and PEPCK mRNA expression in the liver.…”

mentioning

confidence: 60%

“…G6Pase and PEPCK are important regulatory enzymes for activation of the gluconeogenesis pathway and both enzymes are transcriptionally controlled by FoxO1. 21 The 25-hydroxycholesterol 7-alpha-hydroxylase (CYP7b1) expression is dramatically decreased. Additionally, we found a decrease in the expression of glucokinase (GCK) mRNA in obB2KO.…”

Section: Expression Of Gluconeogenesis Regulatory Enzymes Is Increasementioning

confidence: 99%

Bradykinin inhibits hepatic gluconeogenesis in obese mice

Barros

Haro

Russo

et al. 2012

Laboratory Investigation

View full text Add to dashboard Cite

The kallikrein-kinin system (KKS) has been previously linked to glucose homeostasis. In isolated muscle or fat cells, acute bradykinin (BK) stimulation was shown to improve insulin action and increase glucose uptake by promoting glucose transporter 4 translocation to plasma membrane. However, the role for BK in the pathophysiology of obesity and type 2 diabetes remains largely unknown. To address this, we generated genetically obese mice (ob/ob) lacking the BK B2 receptor (obB2KO). Despite similar body weight or fat accumulation, obB2KO mice showed increased fasting glycemia (162.3±28.2 mg/dl vs 85.3±13.3 mg/dl), hyperinsulinemia (7.71±1.75 ng/ml vs 4.09±0.51 ng/ml) and impaired glucose tolerance when compared with ob/ob control mice (obWT), indicating insulin resistance and impaired glucose homeostasis. This was corroborated by increased glucose production in response to a pyruvate challenge. Increased gluconeogenesis was accompanied by increased hepatic mRNA expression of forkhead box protein O1 (FoxO1, four-fold), peroxisome proliferator-activated receptor gamma co-activator 1-alpha (seven-fold), phosphoenolpyruvate carboxykinase (PEPCK, three-fold) and glucose-6-phosphatase (eight-fold). FoxO1 nuclear exclusion was also impaired, as the obB2KO mice showed increased levels of this transcription factor in the nucleus fraction of liver homogenates during random feeding. Intraportal injection of BK in lean mice was able to decrease the hepatic mRNA expression of FoxO1 and PEPCK. In conclusion, BK modulates glucose homeostasis by affecting hepatic glucose production in obWT. These results point to a protective role of the KKS in the pathophysiology of type 2 diabetes mellitus. KEYWORDS: bradykinin; gluconeogenesis; kinin receptor; leptin; ob/ob; obesity The pathophysiology of type 2 diabetes mellitus (T2DM) involves innumerous metabolic and endocrine alterations, including changes in the carbohydrate, lipid and protein metabolisms. T2DM is directly linked with insulin resistance and the inability of pancreatic beta cells to compensate for these changes. 1 There is also a strong association between T2DM and obesity 1,2 that persists independently of gender or ethnic group. In this interaction, the weight gain of obese subjects seems to precede the development of T2DM. 3 Kinins are vasoactive peptides produced in the circulatory system and other tissues by the action of serine proteases called kallikreins. The kallikrein-kinin system (KKS) modulates pain, vasodilatation, vascular permeability, inflammation and edema and has been linked to insulin resistance. [4][5][6][7] Bradykinin (BK), the agonist of the constitutively expressed BK B2 receptor (BKB2R), has been reported to increase glucose uptake in skeletal muscle and adipose tissue. 8 At the same time, the kinin B1 receptor and its agonist, the des-arg 9 -kinin, have been shown to control leptin sensitivity 7 and insulin secretion. 9 Despite evidence that acute BK stimulation improves glucose uptake, the role for BK and BKB2R in the pathophysiology of T2DM is s...

show abstract

Targeting Forkhead Box O1 from the Concept to Metabolic Diseases: Lessons from Mouse Models

Cited by 174 publications

References 127 publications

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

Downregulating SOCS3 with siRNA ameliorates insulin signaling and glucose metabolism in hepatocytes of IUGR rats with catch-up growth

Bradykinin inhibits hepatic gluconeogenesis in obese mice

Contact Info

Product

Resources

About