Hepatic Overexpression of ATP Synthase β Subunit Activates PI3K/Akt Pathway to Ameliorate Hyperglycemia of Diabetic Mice

Wang, Chunjiong; Chen, Zhenzhen; Li, Sha; Zhang, Yuan; Shi, Jia; Li, Jing; Chi, Yujing; Miao, Yifei; Guan, Youfei; Yang, Jichun

doi:10.2337/db13-1096

Cited by 49 publications

(57 citation statements)

References 56 publications

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“…Because glucose oxidation was higher in PTG OE fed an HFD, we addressed hepatic ATP content. It is known that this parameter is reduced in the livers of HFD-induced diabetic mice (29). The ATP content in the livers of HFD-fed mice was significantly reduced, and PTG overexpression resulted in an ATP content similar to that of mice fed a standard diet (Fig.…”

Section: Hfd-fed Ptg Oe Mice Have a Lower Food Intake And Reduced Obementioning

confidence: 86%

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

et al. 2014

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We generated mice that overexpress protein targeting to glycogen (PTG) in the liver (PTG OE ), which results in an increase in liver glycogen. When fed a high-fat diet (HFD), these animals reduced their food intake. The resulting effect was a lower body weight, decreased fat mass, and reduced leptin levels. Furthermore, PTG overexpression reversed the glucose intolerance and hyperinsulinemia caused by the HFD and protected against HFD-induced hepatic steatosis. Of note, when fed an HFD, PTG OE mice did not show the decrease in hepatic ATP content observed in control animals and had lower expression of neuropeptide Y and higher expression of proopiomelanocortin in the hypothalamus. Additionally, after an overnight fast, PTG OE animals presented high liver glycogen content, lower liver triacylglycerol content, and lower serum concentrations of fatty acids and b-hydroxybutyrate than control mice, regardless of whether they were fed an HFD or a standard diet. In conclusion, liver glycogen accumulation caused a reduced food intake, protected against the deleterious effects of an HFD, and diminished the metabolic impact of fasting. Therefore, we propose that hepatic glycogen content be considered a potential target for the pharmacological manipulation of diabetes and obesity.Liver glycogen acts as an energy store in times of nutritional sufficiency for use in times of need. The metabolism of this polysaccharide in the liver is controlled by the activities of two key enzymes: glycogen synthase (GS) and glycogen phosphorylase (GP) (1). GS is phosphorylated at multiple sites, which induces its inactivation, whereas GP is activated by phosphorylation at a single site. Both enzymes are also regulated allosterically (2,3).Glycogen-targeting subunits bind to glycogen and protein phosphatase 1 (PP1) and facilitate the dephosphorylation of GS and GP, thus activating the former and inactivating the latter. Six genes encode glycogen-targeting subunits (4). Among these, protein targeting to glycogen (PTG) (PPP1R3C or PPP1R5), which is expressed in many tissues, has been shown to control glycogen stores in various animal models (5-7).Adenoviral PTG overexpression in the liver of normal rats increases glycogen and improves glucose tolerance without perturbing lipid metabolism (8). In a diabeticfocused approach, Yang and Newgard (9) showed that adenoviral expression of PTG in the liver of STZ-diabetic rats increased glycogen content and reversed hyperglycemia and hyperphagia. Through a different approach, we reported that hepatic adenoviral expression of an active form of liver GS (LGS), which also increases glycogen content, in STZ-diabetic rats reduced food intake and hyperglycemia (10).Russek (11) was the first to propose a hepatostatic theory of food intake, which was further redefined as a glycogenostatic model by Flatt (12). This model predicts that individuals consume food to a level that maintains glycogen levels in the body (12). In fact, many lines of experimental evidence establish a correlation between the size of liver ...

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Section: Hfd-fed Ptg Oe Mice Have a Lower Food Intake And Reduced Obementioning

confidence: 86%

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

et al. 2014

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“…After 8 weeks of treatment, mice were fasted for 6 h (8:00 AM to 2:00 PM), and the oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) experiments were performed as previously described (Chen et al, 2014b; Wang C. et al, 2014). Briefly, the animals were orally administered with glucose (2 g kg -1 body weight) or intraperitoneally administrated with insulin (0.75 U kg -1 body weight), and blood glucose levels were monitored over a 2 h period using Omron Glucometer.…”

Section: Methodsmentioning

confidence: 99%

Astragaloside IV Attenuates Podocyte Apoptosis Mediated by Endoplasmic Reticulum Stress through Upregulating Sarco/Endoplasmic Reticulum Ca2+-ATPase 2 Expression in Diabetic Nephropathy

Guo

Chu

et al. 2016

Front. Pharmacol.

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Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) plays a central role in the pathogenesis of diabetes. This protein has been recognized as a potential target for diabetic therapy. In this study, we identified astragaloside IV (AS-IV) as a potent modulator of SERCA inhibiting renal injury in diabetic status. Increasing doses of AS-IV (2, 6, and 18 mg kg-1 day-1) were administered intragastrically to db/db mice for 8 weeks. Biochemical and histopathological approaches were conducted to evaluate the therapeutic effects of AS-IV. Cultured mouse podocytes were used to further explore the underlying mechanism in vitro. AS-IV dose-dependently increased SERCA activity and SERCA2 expression, and suppressed ER stress-mediated and mitochondria-mediated apoptosis in db/db mouse kidney. AS-IV also normalized glucose tolerance and insulin sensitivity, improved renal function, and ameliorated glomerulosclerosis and renal inflammation in db/db mice. In palmitate stimulated podocytes, AS-IV markedly improved inhibitions of SERCA activity and SERCA2 expression, restored intracellular Ca2+ homeostasis, and attenuated podocyte apoptosis in a dose-dependent manner with a concomitant abrogation of ER stress as evidenced by the downregulation of GRP78, cleaved ATF6, phospho-IRE1α and phospho-PERK, and the inactivation of both ER stress-mediated and mitochondria-mediated apoptotic pathways. Furthermore, SERCA2b knockdown eliminated the effect of AS-IV on ER stress and ER stress-mediated apoptotic pathway, whereas its overexpression exhibited an anti-apoptotic effect. Our data obtained from in vivo and in vitro studies demonstrate that AS-IV attenuates renal injury in diabetes subsequent to inhibiting ER stress-induced podocyte apoptosis through restoring SERCA activity and SERCA2 expression.

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“…From a functional standpoint, the β‐subunit of the ATP synthase (β‐F 1 ‐ATPase) forms the catalytic site of the ATP synthase, and therefore has a direct role among the rest of the subunits of the enzyme in determining the capacity for ATP production. Characteristically, lower β‐F 1 ‐ATPase expression is associated with lower ATP content in liver in animal models of diabetes (Wang et al., ).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial ATP synthase β‐subunit production rate and ATP synthase specific activity are reduced in skeletal muscle of humans with obesity

Tran

Langlais

Hoffman

et al. 2018

Experimental Physiology

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The content of the beta subunit of the ATP synthase (β-F1-ATPase), which forms the catalytic site of the enzyme ATP synthase, is reduced in muscle of obese humans, along with reduced capacity for ATP synthesis. We studied 18 young (37 ± 8 years old) subjects of which nine were lean (BMI = 23 ± 2 kg/m2) and nine were obese (BMI = 34 ± 3 kg/m2) to determine the fractional synthesis rate (FSR) and gene expression of β-F1-ATPase, as well as the specific activity of the ATP synthase. FSR of β-F1-ATPase was determined using a combination of isotope tracer infusion and muscle biopsies. Gene expression of β-F1-ATPase and specific activity of the ATP synthase were determined in the muscle biopsies. When compared to lean, obese subjects had lower muscle β-F1-ATPase FSR (0.10 ± 0.05 vs 0.06 ± 0.03 %/hr; P < 0.05) and protein expression (P < 0.05), but not mRNA expression (P > 0.05). Across subjects, abundance of β-F1-ATPase correlated with the FSR of β-F1-ATPase (P < 0.05). The specific activity of muscle ATP synthase was lower in the obese when compared to lean subjects (0.035 ± 0.004 vs 0.042 ± 0.007 arbitrary units; P < 0.05), but this difference was not significant after the activity of the ATP synthase was adjusted to the β-F1-ATPase content (P > 0.05). Obesity impairs the synthesis of β-F1-ATPase in muscle at the translational level, reducing the content of β-F1-ATPase in parallel with reduced capacity for ATP generation via the ATP synthase complex.

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Hepatic Overexpression of ATP Synthase β Subunit Activates PI3K/Akt Pathway to Ameliorate Hyperglycemia of Diabetic Mice

Cited by 49 publications

References 56 publications

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

Astragaloside IV Attenuates Podocyte Apoptosis Mediated by Endoplasmic Reticulum Stress through Upregulating Sarco/Endoplasmic Reticulum Ca2+-ATPase 2 Expression in Diabetic Nephropathy

Mitochondrial ATP synthase β‐subunit production rate and ATP synthase specific activity are reduced in skeletal muscle of humans with obesity

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