-
Zhidan Wu,
Ping Jiao, Xueming Huang,
Bin Feng,
Yajun Feng,
Shengyong Yang,
Phillip Hwang,
Jing Du,
Yaohui Nie,
Guozhi Xiao,
Haiyan Xu
[show abstract]
[hide abstract]
ABSTRACT: Insulin resistance results in dysregulated hepatic gluconeogenesis that contributes to obesity-related hyperglycemia and progression of type 2 diabetes mellitus (T2DM). Recent studies show that MAPK phosphatase-3 (MKP-3) promotes gluconeogenic gene transcription in hepatoma cells, but little is known about the physiological role of MKP-3 in vivo. Here, we have shown that expression of MKP-3 is markedly increased in the liver of diet-induced obese mice. Consistent with this, adenovirus-mediated MKP-3 overexpression in lean mice promoted gluconeogenesis and increased fasting blood glucose levels. Conversely, shRNA knockdown of MKP-3 in both lean and obese mice resulted in decreased fasting blood glucose levels. In vitro experiments identified forkhead box O1 (FOXO1) as a substrate for MKP-3. MKP-3-mediated dephosphorylation of FOXO1 at Ser256 promoted its nuclear translocation and subsequent recruitment to the promoters of key gluconeogenic genes. In addition, we showed that PPARγ coactivator-1α (PGC-1α) acted downstream of FOXO1 to mediate MKP-3-induced gluconeogenesis. These data indicate that MKP-3 is an important regulator of hepatic gluconeogenesis in vivo and suggest that inhibition of MKP-3 activity may provide new therapies for T2DM.
The Journal of clinical investigation 10/2010; 120(11):3901-11. · 15.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: PPARdelta (peroxisome proliferator-activated receptor delta) is a regulator of lipid metabolism and has been shown to induce fatty acid oxidation (FAO). PPARdelta transgenic and knock-out mice indicate an involvement of PPARdelta in regulating mitochondrial biogenesis and oxidative capacity; however, the precise mechanisms by which PPARdelta regulates these pathways in skeletal muscle remain unclear. In this study, we determined the effect of selective PPARdelta agonism with the synthetic ligand, GW501516, on FAO and mitochondrial gene expression in vitro and in vivo. Our results show that activation of PPARdelta by GW501516 led to a robust increase in mRNA levels of key lipid metabolism genes. Mitochondrial gene expression and function were not induced under the same conditions. Additionally, the activation of Pdk4 transcription by PPARdelta was coactivated by PGC-1alpha. PGC-1alpha, but not PGC-1beta, was essential for full activation of Cpt-1b and Pdk4 gene expression via PPARdelta agonism. Furthermore, the induction of FAO by PPARdelta agonism was completely abolished in the absence of both PGC-1alpha and PGC-1beta. Conversely, PGC-1alpha-driven FAO was independent of PPARdelta. Neither GW501516 treatment nor knockdown of PPARdelta affects PGC-1alpha-induced mitochondrial gene expression in primary myotubes. These results demonstrate that pharmacological activation of PPARdelta induces FAO via PGC-1alpha. However, PPARdelta agonism does not induce mitochondrial gene expression and function. PGC-1alpha-induced FAO and mitochondrial biogenesis appear to be independent of PPARdelta.
Journal of Biological Chemistry 06/2009; 284(28):18624-33. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1alpha) is a master regulator of mitochondrial biogenesis and plays an important role in several other aspects of energy metabolism. To identify upstream regulators of PGC-1alpha gene transcription, 10,000 human full-length cDNAs were screened for induction of the PGC-1alpha promoter. A number of activators of PGC-1alpha transcription were found; the most potent activator was the transducer of regulated CREB (cAMP response element-binding protein) binding protein (TORC) 1, a coactivator of CREB. The other two members of the TORC family, TORC2 and TORC3, also strongly activated PGC-1alpha transcription. TORCs dramatically induced PGC-1alpha gene transcription through CREB. Forced expression of TORCs in primary muscle cells induced the endogenous mRNA of PGC-1alpha and its downstream target genes in the mitochondrial respiratory chain and TCA cycle. Importantly, these changes in gene expression resulted in increased mitochondrial oxidative capacity measured by cellular respiration and fatty acid oxidation. Finally, we demonstrated that the action of TORCs in promoting mitochondrial gene expression and function requires PGC-1alpha. Previous studies had indicated that TORCs function as a calcium- and cAMP-sensitive coincidence detector and mediate individual and synergistic effects of these two pathways. Our results, together with previous findings, strongly suggest that TORCs play a key role in linking these external signals to the transcriptional program of adaptive mitochondrial biogenesis by activating PGC-1alpha gene transcription.
Proceedings of the National Academy of Sciences 10/2006; 103(39):14379-84. · 9.68 Impact Factor
-
Brian Hubbard,
Holger Doege,
Sandhya Punreddy,
Hui Wu, Xueming Huang,
Virendar K Kaushik,
Robin L Mozell,
John J Byrnes,
Alain Stricker-Krongrad,
Chieh J Chou,
Louis A Tartaglia,
Harvey F Lodish,
Andreas Stahl,
Ruth E Gimeno
[show abstract]
[hide abstract]
ABSTRACT: Fatty Acid Transport Protein 5 (FATP5) is a liver-specific member of the FATP/Slc27 family, which has been shown to exhibit both fatty acid transport and bile acid-CoA ligase activity in vitro. Here, we investigate its role in bile acid metabolism and body weight homeostasis in vivo by using a novel FATP5 knockout mouse model.
Bile acid composition was analyzed by mass spectroscopy. Body weight, food intake, energy expenditure, and fat absorption were determined in animals fed either a low- or a high-fat diet.
Although total bile acid concentrations were unchanged in bile, liver, urine, and feces of FATP5 knockout mice, the majority of gallbladder bile acids was unconjugated, and only a small percentage was conjugated. Primary, but not secondary, bile acids were detected among the remaining conjugated forms in FATP5 deletion mice, suggesting a specific requirement for FATP5 in reconjugation of bile acids during the enterohepatic recirculation. Fat absorption in FATP5 deletion mice was largely normal, and only a small increase in fecal fat was observed on a high-fat diet. Despite normal fat absorption, FATP5 deletion mice failed to gain weight on a high-fat diet because of both decreased food intake and increased energy expenditure.
Our findings reveal an important role for FATP5 in bile acid conjugation in vivo and an unexpected function in body weight homeostasis, which will require further analysis. FATP5 deletion mice provide a new model to study the intersection of bile acid metabolism, lipid metabolism, and body weight regulation.
Gastroenterology 05/2006; 130(4):1259-69. · 11.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Insulin is a key hormone that controls glucose homeostasis. In liver, insulin suppresses gluconeogenesis by inhibiting the transcriptions of phosphoenolpyruvate carboxylase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. In insulin resistance and type II diabetes there is an elevation of hepatic gluconeogenesis, which contributes to hyperglycemia. To search for novel genes that negatively regulate insulin signaling in controlling metabolic pathways, we screened a cDNA library derived from the white adipose tissue of ob/ob mice using a reporter system comprised of the PEPCK promoter placed upstream of the alkaline phosphatase gene. The mitogen-activated dual specificity protein kinase phosphatase 3 (MKP-3) was identified as a candidate gene that antagonized insulin suppression on PEPCK gene transcription from this screen. In this study, we showed that MKP-3 was expressed in insulin-responsive tissues and that its expression was markedly elevated in the livers of insulin-resistant obese mice. In addition, MKP-3 can activate PEPCK promoter in synergy with dexamethasone in hepatoma cells. Furthermore, ectopic expression of MKP-3 in hepatoma cells by adenoviral infection increased the expression of PEPCK and G6Pase genes and led to elevated glucose production. Taken together, our data strongly suggests that MKP-3 plays a role in regulating gluconeogenic gene expression and hepatic gluconeogenesis. Therefore, dysregulation of MKP-3 expression and/or function in liver may contribute to the pathogenesis of insulin resistance and type II diabetes.
Journal of Biological Chemistry 11/2005; 280(43):36013-8. · 4.77 Impact Factor
