Peroxisome Proliferator-activated Receptor-γ Coactivator-1α Expression Research Articles

Physical exercise improves mitochondrial function in ovariectomized rats.

Estrogen deficiency causes metabolic disorders in humans and rodents, including in part due to changes in energy expenditure. We have shown previously that skeletal muscle mitochondrial function is compromised in ovariectomized (Ovx) rats. Since physical exercise is a powerful strategy to improve skeletal muscle mitochondrial content and function, we hypothesize that exercise training would counteract the deficiency-induced skeletal muscle mitochondrial dysfunction in Ovx rats. We report that exercised Ovx rats, at 60-65% of maximal exercise capacity for 8 weeks, exhibited less fat accumulation and body weight gain compared with sedentary controls. Treadmill exercise training decreased muscle lactate production, indicating a shift to mitochondrial oxidative metabolism. Furthermore, reduced soleus muscle mitochondrial oxygen consumption confirmed that estrogen deficiency is detrimental to mitochondrial function. However, exercise restored mitochondrial oxygen consumption in Ovx rats, achieving similar levels as in exercised control rats. Exercise-induced skeletal muscle peroxisome proliferator-activated receptor-γ coactivator-1α expression was similar in both groups. Therefore, the mechanisms by which exercise improves mitochondrial oxygen consumption appears to be different in Ovx-exercised and sham-exercised rats. While there was an increase in mitochondrial content in sham-exercised rats, demonstrated by a greater citrate synthase activity, no induction was observed in Ovx-exercised rats. Normalizing mitochondrial respiratory capacity by citrate synthase activity indicates a better oxidative phosphorylation efficiency in the Ovx-exercised group. In conclusion, physical exercise sustains mitochondrial function in ovarian hormone-deficient rats through a non-conventional mitochondrial content-independent manner.

Ciclopirox inhibits NLRP3 inflammasome activation via protecting mitochondria and ameliorates imiquimod-induced psoriatic inflammation in mice

The maturation and secretion of interleukin-1β (IL-1β) mediated by NLRP3 inflammasome activation plays an important role in the progression of many inflammatory diseases. Inhibition of NLRP3 inflammasome activation may be a promising strategy to treat these inflammation-driven diseases, such as psoriasis. As a broad-spectrum antifungal agent, ciclopirox (CPX) is widely used in the treatment of dermatomycosis. Although CPX has been reported to have anti-inflammatory effects in many studies, there has been little research into its underlying mechanisms. In our study, CPX reduced lipopolysaccharide (LPS)/nigericin-induced NLRP3 inflammasome activation (IC50: 1.684 μM). Mechanistically, CPX upregulated peroxisome proliferator-activated receptor-γ coactivator-1α expression (by 82.7% at 5 μM and 87.5% at 10 μM) to protect mitochondria. Our studies showed that CPX reduced mitochondrial reactive oxygen species production, increased mitochondrial membrane potential, elevated mitochondrial biosynthesis, and up-regulated intracellular adenosine triphosphate level. Furthermore, treatment with CPX promoted the up-regulation of mRNA expression, which involved mitochondrial biosynthesis (NRF1, NRF2, TFAM) and antioxidation (SOD1 and CAT). In addition, CPX ameliorated inflammatory response in imiquimod-induced psoriasis mice. This study provides a potential pharmacological mechanism for CPX to treat psoriasis and other NLRP3-driven inflammatory diseases.

C-type natriuretic peptide is a pivotal regulator of metabolic homeostasis

Thermogenesis and adipogenesis are tightly regulated mechanisms that maintain lipid homeostasis and energy balance; dysfunction of these critical processes underpins obesity and contributes to cardiometabolic disease. C-type natriuretic peptide (CNP) fulfills a multimodal protective role in the cardiovascular system governing local blood flow, angiogenesis, cardiac function, and immune cell reactivity. Herein, we investigated a parallel, preservative function for CNP in coordinating metabolic homeostasis. Global inducible CNP knockout mice exhibited reduced body weight, higher temperature, lower adiposity, and greater energy expenditure in vivo. This thermogenic phenotype was associated with increased expression of uncoupling protein-1 and preferential lipid utilization by mitochondria, a switch corroborated by a corresponding diminution of insulin secretion and glucose clearance. Complementary studies in isolated murine and human adipocytes revealed that CNP exerts these metabolic regulatory actions by inhibiting sympathetic thermogenic programming via Gi-coupled natriuretic peptide receptor (NPR)-C and reducing peroxisome proliferator-activated receptor-γ coactivator-1α expression, while concomitantly driving adipogenesis via NPR-B/protein kinase-G. Finally, we identified an association between CNP/NPR-C expression and obesity in patient samples. These findings establish a pivotal physiological role for CNP as a metabolic switch to balance energy homeostasis. Pharmacological targeting of these receptors may offer therapeutic utility in the metabolic syndrome and related cardiovascular disorders.

Local myostatin inhibition improves skeletal muscle glucose uptake in insulin-resistant high-fat diet-fed mice.

Myostatin inhibition is thought to improve whole body insulin sensitivity and mitigate the development of insulin resistance in models of obesity. However, although myostatin is known to be a major regulator of skeletal muscle mass, the direct effects of myostatin inhibition in muscle on glucose uptake and the mechanisms that may underlie this are still unclear. We investigated the effect of local myostatin inhibition by adeno-associated virus-mediated overexpression of the myostatin propeptide on insulin-stimulated skeletal muscle glucose disposal in chow-fed or high fat diet-fed mice and evaluated the molecular pathways that might mediate this. We found that myostatin inhibition improved glucose disposal in obese high fat diet-fed mice alongside the induction of muscle hypertrophy but did not have an impact in chow-fed mice. This improvement was not associated with greater glucose transporter or peroxisome proliferator-activated receptor-γ coactivator-1α expression or 5' AMP-activated protein kinase activation as previously suggested. Instead, transcriptomic analysis suggested that the improvement in glucose disposal was associated with significant enrichment in genes involved in fatty acid metabolism and translation of mitochondrial genes. Thus, myostatin inhibition improves muscle insulin-stimulated glucose disposal in obese high fat diet-fed mice independent of muscle hypertrophy, potentially involving previously unidentified pathways.

Upregulation of miR-181a impairs hepatic glucose and lipid homeostasis.

The contributions of altered post-transcriptional gene silencing to the development of metabolic disorders remain poorly understood thus far. The objective of this study was to evaluate the roles of miR-181a in the regulation of hepatic glucose and lipid metabolism. MiR-181a is abundantly expressed in the liver, and we found that blood and hepatic miR-181a levels were significantly increased in patients and dairy cows with non-alcoholic fatty liver disease, as well as in high-fat diet and ob/ob mice. We determined that sirtuin1 is a target of miR-181a. Moreover, we found that hepatic sirtuin1 and peroxisome proliferator-activated receptor-γ coactivator-1α expression levels are downregulated, and acetylated peroxisome proliferator-activated receptor-γ coactivator-1α expression levels are upregulated in patients and dairy cows with non-alcoholic fatty liver disease, as well as in high-fat diet and ob/ob mice. MiR-181a overexpression inhibits the sirtuin1-peroxisome proliferator-activated receptor-γ coactivator-1α pathway, reduces insulin sensitivity, and increases gluconeogenesis and lipid synthesis in dairy cow hepatocytes and HepG2 cells. Conversely, silencing of miR-181a over-activates the sirtuin1-peroxisome proliferator-activated receptor-γ coactivator-1α pathway, increases insulin sensitivity and glycogen content, and decreases gluconeogenesis and lipid synthesis in hepatocytes, even under non-esterified fatty acids treatment conditions. Furthermore, miR-181a overexpression or sirtuin1 knockdown in mice increases lipid accumulation and decreases insulin sensitivity and glycogen content in the liver. Taken together, these findings indicate that increased hepatic miR-181a impairs glucose and lipid homeostasis by silencing sirtuin1 in non-alcoholic fatty liver disease.

Arginase-2 mediates renal ischemia-reperfusion injury.

Novel therapeutic interventions for preventing or attenuating kidney injury following ischemia-reperfusion injury (IRI) remain a focus of significant interest. Currently, there are no definitive therapeutic or preventive approaches available for ischemic acute kidney injury (AKI). Our objective is to determine 1) whether renal arginase activity or expression is increased in renal IRI, and 2) whether arginase plays a role in development of renal IRI. The impact of arginase activity and expression on renal damage was evaluated in male C57BL/6J (wild type) and arginase-2 (ARG2)-deficient (Arg2-/- ) mice subjected to bilateral renal ischemia for 28 min, followed by reperfusion for 24 h. ARG2 expression and arginase activity significantly increased following renal IRI, paralleling the increase in kidney injury. Pharmacological blockade or genetic deficiency of Arg2 conferred kidney protection in renal IRI. Arg2-/- mice had significantly attenuated kidney injury and lower plasma creatinine and blood urea nitrogen levels after renal IRI. Blocking arginases using S-(2-boronoethyl)-l-cysteine (BEC) 18 h before ischemia mimicked arginase deficiency by reducing kidney injury, histopathological changes and kidney injury marker-1 expression, renal apoptosis, kidney inflammatory cell recruitment and inflammatory cytokines, and kidney oxidative stress; increasing kidney nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation, kidney peroxisome proliferator-activated receptor-γ coactivator-1α expression, and mitochondrial ATP; and preserving kidney mitochondrial ultrastructure compared with vehicle-treated IRI mice. Importantly, BEC-treated eNOS-knockout mice failed to reduce blood urea nitrogen and creatinine following renal IRI. These findings indicate that ARG2 plays a major role in renal IRI, via an eNOS-dependent mechanism, and that blocking ARG2 activity or expression could be a novel therapeutic approach for prevention of AKI.

Skeletal Muscle Alterations Are Exacerbated in Heart Failure With Reduced Compared With Preserved Ejection Fraction

Background— A greater understanding of the different underlying mechanisms between patients with heart failure with reduced (HFrEF) and with preserved (HFpEF) ejection fraction is urgently needed to better direct future treatment. However, although skeletal muscle impairments, potentially mediated by inflammatory cytokines, are common in both HFrEF and HFpEF, the underlying cellular and molecular alterations that exist between groups are yet to be systematically evaluated. The present study, therefore, used established animal models to compare whether alterations in skeletal muscle (limb and respiratory) were different between HFrEF and HFpEF, while further characterizing inflammatory cytokines. Methods and Results— Rats were assigned to (1) HFrEF (ligation of the left coronary artery; n=8); (2) HFpEF (high-salt diet; n=10); (3) control (con: no intervention; n=7). Heart failure was confirmed by echocardiography and invasive measures. Soleus tissue in HFrEF, but not in HFpEF, showed a significant increase in markers of (1) muscle atrophy (ie, MuRF1, calpain, and ubiquitin proteasome); (2) oxidative stress (ie, higher nicotinamide adenine dinucleotide phosphate oxidase but lower antioxidative enzyme activities); (3) mitochondrial impairments (ie, a lower succinate dehydrogenase/lactate dehydrogenase ratio and peroxisome proliferator-activated receptor-γ coactivator-1α expression). The diaphragm remained largely unaffected between groups. Plasma concentrations of circulating cytokines were significantly increased in HFrEF for tumor necrosis factor-α, whereas interleukin-1β and interleukin-12 were higher in HFpEF. Conclusions— Our findings suggest, for the first time, that skeletal muscle alterations are exacerbated in HFrEF compared with HFpEF, which predominantly reside in limb, rather than in respiratory, muscle. This disparity may be mediated, in part, by the different circulating inflammatory cytokines that were elevated between HFpEF and HFrEF.

Thyroid hormone activation by type2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-γ coactivator-1α expression in skeletal muscle.

In skeletal muscle, physical exercise and thyroid hormone mediate the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a) expression that is crucial to skeletal muscle mitochondrial function. The expression of type 2 deiodinase (D2), which activates thyroid hormone in skeletal muscle is upregulated by acute treadmill exercise through a β-adrenergic receptor-dependent mechanism. Pharmacological block of D2 or disruption of the Dio2 gene in skeletal muscle fibres impaired acute exercise-induced PGC-1a expression. Dio2 disruption also impaired muscle PGC-1a expression and mitochondrial citrate synthase activity in chronically exercised mice. Thyroid hormone promotes expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a), which mediates mitochondrial biogenesis and oxidative capacity in skeletal muscle (SKM). Skeletal myocytes express the type 2 deiodinase (D2), which generates 3,5,3'-triiodothyronine (T3 ), the active thyroid hormone. To test whether D2-generated T3 plays a role in exercise-induced PGC-1a expression, male rats and mice with SKM-specific Dio2 inactivation (SKM-D2KO or MYF5-D2KO) were studied. An acute treadmill exercise session (20min at 70-75% of maximal aerobic capacity) increased D2 expression/activity (1.5- to 2.7-fold) as well as PGC-1a mRNA levels (1.5- to 5-fold) in rat soleus muscle and white gastrocnemius muscle and in mouse soleus muscle, which was prevented by pretreatment with 1mg(100g body weight)(-1) propranolol or 6mg(100g body weight)(-1) iopanoic acid (5.9- vs. 2.8-fold; P<0.05), which blocks D2 activity . In the SKM-D2KO mice, acute treadmill exercise failed to induce PGC-1a fully in soleus muscle (1.9-vs. 2.8-fold; P<0.05), and in primary SKM-D2KO myocytes there was only a limited PGC-1a response to 1μm forskolin (2.2- vs. 1.3-fold; P<0.05). Chronic exercise training (6weeks) increased soleus muscle PGC-1a mRNA levels (∼25%) and the mitochondrial enzyme citrate synthase (∼20%). In contrast, PGC-1a expression did not change and citrate synthase decreased by ∼30% in SKM-D2KO mice. The soleus muscle PGC-1a response to chronic exercise was also blunted in MYF5-D2KO mice. In conclusion, acute treadmill exercise increases SKM D2 expression through a β-adrenergic receptor-dependent mechanism. The accelerated conversion of T4 to T3 within myocytes mediates part of the PGC-1a induction by treadmill exercise and its downstream effects on mitochondrial function.

Curcumin regulates peroxisome proliferator-activated receptor-γ coactivator-1α expression by AMPK pathway in hepatic stellate cells in vitro

Curcumin exerts an inhibitory effect on hepatic stellate cell (HSC) activation, a key step for liver fibrogenesis, and on liver fibrosis by up-regulation of peroxisome proliferator-activated receptor-γ (PPARγ) expression. PPARγ plays a crucial role in suppression of HSC activation. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) functions as a co-activator for PPARγ. Therefore, researches on the effect of curcumin on PGC-1α might contribute to understanding of the mechanisms underlying curcumin inhibition of HSC activation and liver fibrosis through PPARγ. The present study aimed to investigate the effect of curcumin on PGC-1α expression in HSCs in vitro and examine the underlying molecular mechanisms by western blot, reat-time PCR, and transfection. Our results showed that curcumin stimulation increased PGC-1α expression and the effects of curcumin on PGC-1α expression were correlated with the activation of adenosine monophosphate-activated protein kinase (AMPK). Curcumin increased superoxide dimutase-2 (SOD2) transcription and activity by AMPK/PGC-1α axis. Moreover, PGC-1α was demonstrated to inhibit α1(I) collagen (a marker for liver fibrosis) transcription in cultured HSCs. These results demonstrated the promotion effect of curcumin on PGC-1α expression through AMPK pathway, which led to the increases in PPARγ activity and in SOD-2 transcription and activity. These data might suggest a possible new explanation for the inhibitory effect of curcumin on HSC activation and on liver fibrogenesis.

Study of peroxisome proliferator-activated receptor-γ coactivator-1α expression and cytoapoptosis in masseter muscles of unilateral chewing rat

To investigate the changes of peroxisome proliferator- activated receptor-γ coactivator -1α (PGC-1α) mRNA and cytoapoptosis in the rats' masseter muscle which had been influenced by unilateral chewing, and to explore the theoretical foundation of changes in masticatory muscles induced by unilateral chewing. The animal models were established by extracting the Wistar rats' left maxillary molars. Thirty- six female Wistar rats were randomly divided into four groups of 2, 4, 6 and 8 weeks, nine each. In each group there were six rats with molar extracted and three as control. The Ca²⁺ level was detected by atomic spectrophotometric method. The relative expression of PGC-1α mRNA was detected by real- time fluorescent quantitative PCR. The apoptosis index was detected by Hoechst staining. The Ca²⁺ level in the muscle on the extraction side were significantly higher than that in the controls in the beginning stage of unilateral chewing, and reached the peak at the 4th week [(43.62 ± 2.36) µg/g]. The relative expressions of PGC-1α increased from the beginning and reached the maximum level at the 4th week [extraction side: (1.57 ± 0.10); non-extraction side: (1.92 ± 0.06)], while the relative expressions of PGC-1α in 6 and 8 weeks decreased gradually [extraction side: (1.06 ± 0.08), (1.08 ± 0.07); non- extraction side: (1.09 ± 0.10), (1.11 ± 0.08)]. The changes of apoptosis index on non- extraction side increased continually and peaked at the 6th week [(38.56 ± 1.64)%]. PGC-1α and cytoapoptosis played important roles in different stages of tissue remodeling induced by unilateral chewing.

Role of estrogen on skeletal muscle mitochondrial function in ovariectomized rats: a time course study in different fiber types

Postmenopausal women are prone to develop obesity and insulin resistance, which might be related to skeletal muscle mitochondrial dysfunction. In a rat model of ovariectomy (OVX), skeletal muscle mitochondrial function was examined at short- and long-term periods after castration. Mitochondrial parameters in the soleus and white gastrocnemius muscle fibers were analyzed. Three weeks after surgery, there were no differences in coupled mitochondrial respiration (ATP synthesis) with pyruvate, malate, and succinate; proton leak respiration; or mitochondrial reactive oxygen species production. However, after 3 wk of OVX, the soleus and white gastrocnemius muscles of the OVX animals showed a lower use of palmitoyl-carnitine and glycerol-phosphate substrates, respectively, and decreased peroxisome proliferator-activated receptor-γ coactivator-1α expression. Estrogen replacement reverted all of these phenotypes. Eight weeks after OVX, ATP synthesis was lower in the soleus and white gastrocnemius muscles of the OVX animals than in the sham-operated and estrogen-treated animals; however, when normalized by citrate synthase activity, these differences disappeared, indicating a lower muscle mitochondria content. No differences were observed in the proton leak parameter. Mitochondrial alterations did not impair the treadmill exercise capacity of the OVX animals. However, blood lactate levels in the OVX animals were higher after the physical test, indicating a compensatory extramitochondrial ATP synthesis system, but this phenotype was reverted by estrogen replacement. These results suggest early mitochondrial dysfunction related to lipid substrate use, which could be associated with the development of the overweight phenotype of ovariectomized animals.

Metabolic Gene Remodeling and Mitochondrial Dysfunction in Failing Right Ventricular Hypertrophy Secondary to Pulmonary Arterial Hypertension

Right ventricular (RV) dysfunction (RVD) is the most frequent cause of death in patients with pulmonary arterial hypertension. Although abnormal energy substrate use has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in RVD remain incomplete. Thus, we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy. Two different rat models of RV hypertrophy were studied. The model of RVD (SU5416/hypoxia) exhibited a significantly decreased gene expression of peroxisome proliferator-activated receptor-γ coactivator-1α, peroxisome proliferator-activated receptor-α and estrogen-related receptor-α. The expression of multiple peroxisome proliferator-activated receptor-γ coactivator-1α target genes required for fatty acid oxidation was similarly decreased. Decreased peroxisome proliferator-activated receptor-γ coactivator-1α expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of transcription factor A, mitochondrial, and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that, in RVD tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from RVD tissue had a significantly reduced ADP-stimulated (state 3) rate for complex I. Conversely, functional RV hypertrophy in the pulmonary artery banding model showed normal expression of peroxisome proliferator-activated receptor-γ coactivator-1α, whereas the expression of fatty acid oxidation genes was either preserved or unregulated. Moreover, pulmonary artery banding-RV tissue exhibited preserved transcription factor A mitochondrial expression and mitochondrial respiration despite elevated RV pressure-overload. Right ventricular dysfunction, but not functional RV hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload.

Biphasic modulation of the mitochondrial electron transport chain in myocardial ischemia and reperfusion

Mitochondrial electron transport chain (ETC) is the major source of reactive oxygen species during myocardial ischemia-reperfusion (I/R) injury. Ischemic defect and reperfusion-induced injury to ETC are critical in the disease pathogenesis of postischemic heart. The properties of ETC were investigated in an isolated heart model of global I/R. Rat hearts were subjected to ischemia for 30 min followed by reperfusion for 1 h. Studies of mitochondrial function indicated a biphasic modulation of electron transfer activity (ETA) and ETC protein expression during I/R. Analysis of ETAs in the isolated mitochondria indicated that complexes I, II, III, and IV activities were diminished after 30 min of ischemia but increased upon restoration of flow. Immunoblotting analysis and ultrastructural analysis with transmission electron microscopy further revealed marked downregulation of ETC in the ischemic heart and then upregulation of ETC upon reperfusion. No significant difference in the mRNA expression level of ETC was detected between ischemic and postischemic hearts. However, reperfusion-induced ETC biosynthesis in myocardium can be inhibited by cycloheximide, indicating the involvement of translational control. Immunoblotting analysis of tissue homogenates revealed a similar profile in peroxisome proliferator-activated receptor-γ coactivator-1α expression, suggesting its essential role as an upstream regulator in controlling ETC biosynthesis during I/R. Significant impairment caused by ischemic and postischemic injury was observed in the complexes I- III. Analysis of NADH ferricyanide reductase activity indicated that injury of flavoprotein subcomplex accounts for 50% decline of intact complex I activity from ischemic heart. Taken together, our findings provide a new insight into the molecular mechanism of I/R-induced mitochondrial dysfunction.

Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression

OBJECTIVEThe peroxisome proliferator–activated receptor-γ coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1α show that this coactivator is important for activating the programs of gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and lipid secretion during times of nutrient deprivation. However, how moderate changes in PGC-1α activity affect metabolism and energy homeostasis has yet to be determined.RESEARCH DESIGN AND METHODSTo identify key metabolic pathways that may be physiologically relevant in the context of reduced hepatic PGC-1α levels, we used the Cre/Lox system to create mice heterozygous for PGC-1α specifically within the liver (LH mice).RESULTSThese mice showed fasting hepatic steatosis and diminished ketogenesis associated with decreased expression of genes involved in mitochondrial β-oxidation. LH mice also exhibited high circulating levels of triglyceride that correlated with increased expression of genes involved in triglyceride-rich lipoprotein assembly. Concomitant with defects in lipid metabolism, hepatic insulin resistance was observed both in LH mice fed a high-fat diet as well as in primary hepatocytes.CONCLUSIONSThese data highlight both the dose-dependent and long-term effects of reducing hepatic PGC-1α levels, underlining the importance of tightly regulated PGC-1α expression in the maintenance of lipid homeostasis and glucose metabolism.

Short-term inhibition of peroxisome proliferator-activated receptor-γ coactivator-1α expression reverses diet-induced diabetes mellitus and hepatic steatosis in mice

The coactivator of nuclear receptors, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) has been implicated in a series of events that contribute to the control of glucose metabolism. We have recently reported the use of a PGC-1alpha antisense oligonucleotide (PGC-1alphaAS) that inhibits up to 60% of PGC-1alpha expression in pancreatic islets, leading to increased insulin secretion. This oligonucleotide was used in this study to try to ameliorate diet-induced type 2 diabetes in a genetically predisposed mouse strain (Swiss mice). Glucose and insulin tolerance tests, euglycaemic-hyperinsulinaemic clamp, immunoprecipitation assays, immunoblotting assays and immunohistochemistry were used in this investigation. Swiss mice became obese and overtly diabetic after 8 weeks of feeding with chow containing 24% saturated fat. One daily dose (1.0 nmol) of PGC-1alphaAS significantly reduced glucose and increased insulin blood levels without affecting food intake and body weight. These effects were accompanied by a reduced area under the glucose curve during an intraperitoneal glucose tolerance test, an increased constant of glucose decay (K(itt)) during an insulin tolerance test, and an increased glucose consumption rate during a euglycaemic-hyperinsulinaemic clamp. Moreover, mice treated with PGC-1alphaAS presented an outstanding reduction of macroscopic and microscopic features of hepatic steatosis. These effects were accompanied by reduced expression or function of a series of proteins involved in lipogenesis. PGC-1alpha is an attractive target for pharmacological therapeutics in type 2 diabetes mellitus and diet-induced hepatic steatosis.

The developmental regulation of peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression in the liver is partially dissociated from the control of gluconeogenesis and lipid catabolism.

The developmental regulation of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) gene expression was studied in mice and compared with that of marker genes of liver energy metabolism. The PGC-1alpha gene was highly expressed in fetal liver compared with that in adults and remained high in neonatal liver. The regulation of PGC-1alpha gene expression during the fetal and early neonatal periods was dissociated from that of gluconeogenic genes, i.e. the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. Only under the effects of starvation was PGC-1alpha gene expression induced in parallel to phosphoenolpyruvate carboxykinase and G6Pase mRNAs during the perinatal period. Furthermore, the PGC-1alpha gene was not regulated as part of the developmental program of gene expression associated with the maturation of hepatic gluconeogenesis, as revealed by the impaired PEPCK and G6Pase gene expression but unaltered PGC-1alpha mRNA levels in CCAAT/enhancer-binding protein-alpha-null fetus and neonates. Regulation of the PGC-1alpha gene and that of mitochondrial 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase, acyl-coenzyme A oxidase, and long-chain acyl-coenzyme dehydrogenase, marker genes of lipid catabolism, were dissociated in fetuses and neonates. The expression of lipid catabolism genes was down-regulated in fasted neonates, whereas PGC-1alpha was oppositely regulated. The independent regulation of PGC-1alpha and lipid catabolism genes was also found in peroxisome proliferator-activated receptor-alpha-null neonates, in which PGC-1alpha mRNA levels were unaffected whereas gene expression for 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase and acyl-coenzyme A oxidase was impaired. Thus, regulation of the PGC-1alpha gene is partially dissociated from the patterns of regulation of hepatic genes encoding enzymes involved in gluconeogenesis and lipid catabolism during fetal ontogeny and in response to the initiation of lactation.