Hepatic Expression of a Targeting Subunit of Protein Phosphatase-1 in Streptozotocin-diabetic Rats Reverses Hyperglycemia and Hyperphagia Despite Depressed Glucokinase Expression

Yang, Ruojing; Newgard, Christopher B.

doi:10.1074/jbc.m213112200

Cited by 26 publications

(23 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, rats overexpressing this constitutively active LGS mutant had the capacity to remove the excess of glucose in blood and then deliver it to glycogen synthesis more efficiently than the other groups. However, a permanent activation of LGS could potentially cause the saturation of the liver capacity to store glycogen, thus limiting its glycemia-lowering effects (8). The results obtained with liver-specific transgenic mice chronically expressing the activated mutant LGS largely reproduce the observations from the experiments with rats: increased LGS activity and glycogen accumulation in the fed state, capacity to mobilize glycogen stores upon fasting, and improved glucose tolerance when these mice were challenged with a glucose load.…”

Section: Journal Of Biological Chemistry 37175supporting

confidence: 76%

“…Similarly, G L targeting subunit overexpression in the livers of streptozotocin-induced diabetic rats causes a large increase in liver glycogen stores but only a transient decrease in blood glucose levels. The glycemia-reducing effect can be prolonged in time by using a truncated version of the scaffolding proteins G M and G L , termed G M ⌬C, which does not compromise the response to glycogenolytic signals (7)(8)(9).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Hepatic Overexpression of a Constitutively Active Form of Liver Glycogen Synthase Improves Glucose Homeostasis

Ros

Zafra

Valles-Ortega

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

In this study, we tested the efficacy of increasing liver glycogen synthase to improve blood glucose homeostasis. The overexpression of wild-type liver glycogen synthase in rats had no effect on blood glucose homeostasis in either the fed or the fasted state. In contrast, the expression of a constitutively active mutant form of the enzyme caused a significant lowering of blood glucose in the former but not the latter state. Moreover, it markedly enhanced the clearance of blood glucose when fasted rats were challenged with a glucose load. Hepatic glycogen stores in rats overexpressing the activated mutant form of liver glycogen synthase were enhanced in the fed state and in response to an oral glucose load but showed a net decline during fasting. In order to test whether these effects were maintained during long term activation of liver glycogen synthase, we generated liver-specific transgenic mice expressing the constitutively active LGS form. These mice also showed an enhanced capacity to store glycogen in the fed state and an improved glucose tolerance when challenged with a glucose load. Thus, we conclude that the activation of liver glycogen synthase improves glucose tolerance in the fed state without compromising glycogenolysis in the postabsorptive state. On the basis of these findings, we propose that the activation of liver glycogen synthase may provide a potential strategy for improvement of glucose tolerance in the postprandial state.The liver responds to an increase in blood glucose concentration in the postprandial state by net uptake of glucose and conversion to glycogen, which is subsequently mobilized in the postabsorptive state to maintain blood glucose homeostasis. Various attempts have been made to improve blood glucose homeostasis through the modulation of the expression or activity of proteins involved in the control of liver glycogen metabolism. Glucokinase (GK) 3 catalyzes the first step in hepatic glucose metabolism and exerts high control on liver glycogen synthesis (1). Previous studies using either transgenic models (2, 3) or adenoviral vectors targeting the liver (4) demonstrated improved glucose tolerance and/or a lowering of blood glucose in basal conditions. However, GK overexpression also increases flux through glycolysis, and in some circumstances this leads to hypertriglyceridemia (4). An alternative approach to modulating liver glycogen metabolism without stimulating glycolysis and triglyceride formation is through modifying the enzymes that are involved exclusively in glycogen synthesis and degradation or regulatory proteins that may affect the activity of the former, such as protein targeting to glycogen (PTG) (5). Overexpression of PTG in the liver by means of an adenoviral vector increases glucose tolerance without perturbing lipid homeostasis (6). However, a limitation of this experimental model is that it leads to the progressive accumulation of glycogen because PTG promotes the inactivation of glycogen phosphorylase (GP) also during fasting, and consequently there is ne...

show abstract

Section: Journal Of Biological Chemistry 37175supporting

confidence: 76%

mentioning

confidence: 99%

Hepatic Overexpression of a Constitutively Active Form of Liver Glycogen Synthase Improves Glucose Homeostasis

Ros

Zafra

Valles-Ortega

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In addition, increased fatty acid oxidation might be involved in the decreased food intake, because administration of peroxisome proliferator-activated receptor (PPAR)-␣ agonists reportedly reduces food intake amounts, but not in mice deficient in PPAR-␣ (28). Furthermore, streptozotocin-induced hyperphagia was reportedly reversed by hepatic expression of protein phosphatase-1 (29), suggesting that altering hepatic metabolism modulates appetite. Vagal pathways from the liver to the brain mediate the fat-induced changes in hypothalamic neuropeptides and feeding behavior in diabetic rats (30).…”

Section: Discussionmentioning

confidence: 98%

Dissipating Excess Energy Stored in the Liver Is a Potential Treatment Strategy for Diabetes Associated With Obesity

et al. 2005

View full text Add to dashboard Cite

For examining whether dissipating excess energy in the liver is a possible therapeutic approach to high-fat diet-induced metabolic disorders, uncoupling protein-1 (UCP1) was expressed in murine liver using adenoviral vectors in mice with high-fat diet-induced diabetes and obesity, and in standard diet-fed lean mice. Once diabetes with obesity developed, hepatic UCP1 expression increased energy expenditure, decreased body weight, and reduced fat in the liver and adipose tissues, resulting in markedly improved insulin resistance and, thus, diabetes and dyslipidemia. Decreased expressions of enzymes for lipid synthesis and glucose production and activation of AMP-activated kinase in the liver seem to contribute to these improvements. Hepatic UCP1 expression also reversed high-fat diet-induced hyperphagia and hypothalamic leptin resistance, as well as insulin resistance in muscle. In contrast, intriguingly, in standard diet-fed lean mice, hepatic UCP1 expression did not significantly affect energy expenditure or hepatic ATP contents. Furthermore, no alterations in blood glucose levels, body weight, or adiposity were observed. These findings suggest that ectopic UCP1 in the liver dissipates surplus energy without affecting required energy and exerts minimal metabolic effects in lean mice. Thus, enhanced UCP expression in the liver is a new potential therapeutic target for the metabolic syndrome. Diabetes 54:322-332, 2005 A n explosive increase in the number of diabetic patients, which has become a major public health concern in most industrialized countries in recent decades (1), is mainly the result of excess energy intake and physical inactivity. When food intake chronically exceeds metabolic needs, efficient metabolism causes excess energy storage and results in obesity, a common condition associated with diabetes, hyperlipidemia, and premature heart disease. Excess energy in cells lowers the response to insulin, namely insulin resistance. However, the major treatment modalities for diabetes, including insulin injection and oral sulfonylureas, aim at lowering blood glucose levels by driving glucose into cells in peripheral tissues such as muscle and fat. This further exacerbates insulin resistance when energy intake is in excess, resulting in a vicious cycle. Therefore, novel therapies that promote increased energy expenditure are needed.Inefficient metabolism, such as the generation of heat instead of ATP, is a potential treatment strategy for type 2 diabetes associated with obesity. Uncoupling proteins (UCPs) were discovered members of the mitochondrial inner membrane carrier family. These proteins leak protons into the mitochondrial matrix, dissipating energy as heat rather than allowing it to be captured in ATP (2). UCP1 (thermogenin) was originally identified in brown adipose tissue and demonstrated to mediate nonshivering thermogenesis. UCP1 plays an important role in mediating cold exposure-induced thermogenesis (3) and is also a likely regulator of diet-induced thermogenesis (4).Several laboratories have r...

show abstract

“…Increasing G L activity by overexpression was found in cultured primary human myotubes (26) as well as in primary hepatocytes (27) to stimulate glycogen synthase activity and to exhibit a high glycogenic effect. The effects of increasing activity of different glycogen targeting subunits by hepatic overexpression have also been studied in ani- mal models (28,29). Despite the profound effects of hepatic G L overexpression on glycogen stores in the livers of these animal models, no or only modest and transient effects on hyperglycemia are reported.…”

Section: Discussionmentioning

confidence: 99%

Molecular Recognition of the Protein Phosphatase 1 Glycogen Targeting Subunit by Glycogen Phosphorylase

Pautsch

Stadler

Wissdorf

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Disrupting the interaction between glycogen phosphorylase and the glycogen targeting subunit (G L ) of protein phosphatase 1 is emerging as a novel target for the treatment of type 2 diabetes. To elucidate the molecular basis of binding, we have determined the crystal structure of liver phosphorylase bound to a G L -derived peptide. The structure reveals the C terminus of G L binding in a hydrophobically collapsed conformation to the allosteric regulator-binding site at the phosphorylase dimer interface. G L mimics interactions that are otherwise employed by the activator AMP. Functional studies show that G L binds tighter than AMP and confirm that the C-terminal Tyr-Tyr motif is the major determinant for G L binding potency. Our study validates the G L -phosphorylase interface as a novel target for small molecule interaction.Diabetes is one of the major public health problems. Approximately 194 million people worldwide, or 5.1%, in the age group 20 -79 were estimated to have diabetes in 2003. This estimate is expected to increase to some 333 million, or 6.3% of the adult population, by 2025 (1). Type 2 diabetes, the most common form of diabetes is characterized by defects in insulin secretion, insulin resistance, and elevated hepatic glucose production. Both increased gluconeogenesis and increased glycogenolysis contribute to excessive hepatic glucose output despite hyperglycemia (2). Several novel pharmacological strategies are aiming to treat hyperglycemia by normalizing or increasing depleted glycogen stores (3). For example, drug discovery has focused on competitive as well as allosteric inhibition of glycogen phosphorylase activity (4).Glycogen phosphorylase (GP) 2 is an important allosteric enzyme in carbohydrate metabolism that catalyzes phosphorolysis of an ␣-1,4-glycosidic bond of glycogen to glucose-1-phosphate. In humans there are three GP isoforms (liver, muscle, and brain GP), which are named after the tissues where they are predominantly expressed. Glycogen phosphorylase is a homodimer that cycles between two conformations: active (R) and inactive (T) state. Phosphorylation of Ser 14 by phosphorylase kinase and active site as well as allosteric binders modulate the equilibrium between both states (5), but the isozymes differ in their responsiveness to regulatory mechanisms. In the liver, phosphorylation is the major regulator of GP activation. Conversion of unphosphorylated liver GPb to phosphorylated GPa fully activates the enzyme. AMP stimulates liver GPb by 10 -20%, whereas it does not further activate GPa (6). In contrast, AMP activates the unphosphorylated muscle isoform to 80% of the maximal activity and increases the activity of phosphorylated muscle GPa by a further 10%. Crystallographic studies have shown endogenous and synthetic modulators bound to four major sites (see Fig. 1a): active site (7), purine site (8), central cavity (9), and allosteric AMP site (10, 11).Important for glycogen metabolism is the strong reciprocal control between GPa and glycogen synthase activity. Activation of...

show abstract

Hepatic Expression of a Targeting Subunit of Protein Phosphatase-1 in Streptozotocin-diabetic Rats Reverses Hyperglycemia and Hyperphagia Despite Depressed Glucokinase Expression

Cited by 26 publications

References 33 publications

Hepatic Overexpression of a Constitutively Active Form of Liver Glycogen Synthase Improves Glucose Homeostasis

Hepatic Overexpression of a Constitutively Active Form of Liver Glycogen Synthase Improves Glucose Homeostasis

Dissipating Excess Energy Stored in the Liver Is a Potential Treatment Strategy for Diabetes Associated With Obesity

Molecular Recognition of the Protein Phosphatase 1 Glycogen Targeting Subunit by Glycogen Phosphorylase

Contact Info

Product

Resources

About