Peroxisome Proliferator-activated Receptor-γ Coactivator-1β Research Articles

Expressions of mitochondria-related genes in pregnant women with subclinical hypothyroidism, and expressions of miRNAs in maternal and cord blood

BackgroundSubclinical hypothyroidism in pregnancy and definition by upper thyrotropin (TSH) cutoff are controversial. As mitochondria are influenced by thyroid hormones, the purpose in this study was to measure expression of mitochondria-related genes in euthyroid and subclinical hypothyroid pregnant women to obtain more knowledge of potential metabolic consequences of maternal subclinical hypothyroidism. In addition, we wished to test if applied TSH-cutoff significantly changed our results of expressed gene-levels. Moreover, we aimed to identify potential microRNA-biomarkers for subclinical hypothyroidism – markers that could be traced to offspring as well.MethodsFrom a cohort of at-term pregnant women undergoing planned cesarean section, 77 women had expression levels of the mitochondria-related genes Peroxisome Proliferator-activated Receptor-γ coactivator-1β (PGC-1β), mitochondrial Transcription Factor A (TFAM), Superoxide Dismutase 2 (SOD2) and Nuclear Respiratory Factor 2 (NRF-2) determined by qPCR from blood sampled in prior to delivery. Two TSH-cutoff levels defining subclinical hypothyroidism (> 3.0 and > 3.7 mIU/L) were applied for the procession of results, generating two data analyses of the same cohort. In 22 pairwise maternal-cord samples (subclinical hypothyroid/euthyroid-rate 0.5, TSH-cutoff > 3.0 mIU/L), microRNA-expressions (miRNA) were analyzed.ResultsAll gene expressions were lower in the subclinical hypothyroid group regardless of applied TSH-cutoff, but insignificant except for PGC-1β at TSH cutoff > 3.0 mIU/L. Two miRNAs (hsa-let-7d-3p and hsa-miR-345-5p) were upregulated in blood from women and offspring (cord blood) with subclinical hypothyroidism.ConclusionsA trend towards decreased mitochondrial gene expressions in subclinical hypothyroidism were demonstrated. The miRNAs hsa-let-7d-3p and hsa-miR-345-5p might be potential markers of maternal subclinical hypothyroidism. However, larger studies are needed to verify the findings.

Adipose tissue-specific ablation of PGC-1β impairs thermogenesis in brown fat.

ABSTRACTImpaired thermogenesis observed in mice with whole-body ablation of peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β; officially known as PPARGC1B) may result from impaired brown fat (brown adipose tissue; BAT) function, but other mechanism(s) could be involved. Here, using adipose-specific PGC-1β knockout mice (PGC-1β-AT-KO mice) we aimed to learn whether specific PGC-1β ablation in adipocytes is sufficient to drive cold sensitivity. Indeed, we found that warm-adapted (30°C) mutant mice were relatively sensitive to acute cold exposure (6°C). When these mice were subjected to cold exposure for 7 days (7-day-CE), adrenergic stimulation of their metabolism was impaired, despite similar levels of thermogenic uncoupling protein 1 in BAT in PGC-1β-AT-KO and wild-type mice. Gene expression in BAT of mutant mice suggested a compensatory increase in lipid metabolism to counteract the thermogenic defect. Interestingly, a reduced number of contacts between mitochondria and lipid droplets associated with low levels of L-form of optic atrophy 1 was found in BAT of PGC-1β-AT-KO mice. These genotypic differences were observed in warm-adapted mutant mice, but they were partially masked by 7-day-CE. Collectively, our results suggest a role for PGC-1β in controlling BAT lipid metabolism and thermogenesis.This article has an associated First Person interview with the first author of the paper.

Flunarizine inhibits osteoclastogenesis by regulating calcium signaling and promotes osteogenesis.

Many bone diseases such as osteoporosis and periodontitis are caused by hyperactivation of osteoclasts. Calcium (Ca2+ ) signals are crucial for osteoclast differentiation and function. Thus, the blockade of Ca2+ signaling may be a strategy for regulating osteoclast activity and has clinical implications. Flunarizine (FN) is a Ca2+ channel antagonist that has been used for reducing migraines. However, the role of FN in osteoclast differentiation and function remains unknown. Here, we investigated whether FN regulates osteoclastogenesis and elucidated the molecular mechanism. FN inhibited osteoclast differentiation along with decreased expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and attenuated osteoclast maturation and bone resorption. FN inhibition of osteoclast differentiation was restored by ectopic expression of constitutively active NFATc1. FN reduced calcium oscillations and its inhibition of osteoclast differentiation and resorption function was reversed by ionomycin, an ionophore that binds Ca2+ . FN also inhibited Ca2+ /calmodulin-dependent protein kinase IV (CaMKIV) and calcineurin leading to a decrease in the cAMP-responsive element-binding protein-dependent cFos and peroxisome proliferator-activated receptor-γ coactivator 1β expression, and NFATc1 nuclear translocation. These results indicate that FN inhibits osteoclastogenesis via regulating CaMKIV and calcineurin as a Ca2+ channel blocker. In addition, FN-induced apoptosis in osteoclasts and promoted osteogenesis. Furthermore, FN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting that it has therapeutic potential for treating inflammatory bone diseases and postmenopausal osteoporosis.

Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis.

Cinchonine (CN) has been known to exert antimalarial, antiplatelet, and antiobesity effects. It was also recently reported to inhibit transforming growth factor β-activated kinase 1 (TAK1) and protein kinase B (AKT) through binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). However, its role in bone metabolism remains largely unknown. Here, we showed that CN inhibits osteoclast differentiation with decreased expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key determinant of osteoclastogenesis. Immunoblot and quantitative real-time polymerase chain reaction analysis as well as the reporter assay revealed that CN inhibits nuclear factor-κB and activator protein-1 by regulating TAK1. CN also attenuated the activation of AKT, cyclic AMP response element-binding protein, and peroxisome proliferator-activated receptor-γ coactivator 1β (PGC1β), an essential regulator of mitochondrial biogenesis. Collectively, these results suggested that CN may inhibit TRAF6-mediated TAK1 and AKT activation, which leads to downregulation of NFATc1 and PGC1β resulting in the suppression of osteoclast differentiation. Interestingly, CN not only inhibited the maturation and resorption function of differentiated osteoclasts but also promoted osteoblast differentiation. Furthermore, CN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting its therapeutic potential for treating inflammation-induced bone diseases and postmenopausal osteoporosis.

Apical sodium-dependent bile acid transporter inhibition with volixibat improves metabolic aspects and components of non-alcoholic steatohepatitis in Ldlr-/-.Leiden mice.

Interruption of bile acid recirculation through inhibition of the apical sodium-dependent bile acid transporter (ASBT) is a promising strategy to alleviate hepatic cholesterol accumulation in non-alcoholic steatohepatitis (NASH), and improve the metabolic aspects of the disease. Potential disease-attenuating effects of the ASBT inhibitor volixibat (5, 15, and 30 mg/kg) were investigated in high-fat diet (HFD)-fed Ldlr-/-.Leiden mice over 24 weeks. Plasma and fecal bile acid levels, plasma insulin, lipids, and liver enzymes were monitored. Final analyses included liver histology, intrahepatic lipids, mesenteric white adipose tissue mass, and liver gene profiling. Consistent with its mechanism of action, volixibat significantly increased the total amount of bile acid in feces. At the highest dose, volixibat significantly attenuated the HFD-induced increase in hepatocyte hypertrophy, hepatic triglyceride and cholesteryl ester levels, and mesenteric white adipose tissue deposition. Non-alcoholic fatty liver disease activity score (NAS) was significantly lower in volixibat-treated mice than in the HFD controls. Gene profiling showed that volixibat reversed the inhibitory effect of the HFD on metabolic master regulators, including peroxisome proliferator-activated receptor-γ coactivator-1β, insulin receptor, and sterol regulatory element-binding transcription factor 2. Volixibat may have beneficial effects on physiological and metabolic aspects of NASH pathophysiology.

OR-025 Association study between Chinese excellent long-distance female athletes’ PGC-1β genetic polymorphism and aerobic capacity

Objective Peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β) is mainly expressed in mitochondria-rich tissues, which involved in skeletal muscle mitochondrial biosynthesis and energy metabolism processes such as fatty acid transport and oxidation, hepatic gluconeogenesis. PGC-1β is Previous studies have shown that this genetic polymorphism is associated with the athletic ability of elite endurance athletes. Therefore, based on the previous research, the relationship between PGC-1β gene polymorphism and aerobic exercise ability of elite female long-distance runners was discussed to provide new effective indicators for athletes' selection of materials, and improve the accuracy and advancement of athletes' selection of materials.
 Methods 56 Chinese elite female long-distance runners were selected, and venous blood was extracted to analyze the gene polymorphism of specific gene locus. The subjects were tested for aerobic endurance index and lung function index, wherein the aerobic endurance index included maximum oxygen uptake, relative maximal oxygen uptake relative value, anaerobic threshold and anaerobic threshold relative value, and lung function indicators including vital capacity, Time lung capacity, minute ventilation and maximum ventilation . Subsequently, the cross-sectional association study method was used to analyze the association between four genotypes locus of PGC-1β including rs32579, rs2161257, rs1544744 and rs10783180 in 56 subjects.
 Results 1) All four polymorphic locus were tested by H-W balance, indicating that the subjects were representative of the population. 2) rs32579 locus: There were no significant differences in lung function indicators and aerobic exercise capacity between different genotype athletes. 3) rs2161257 locus: There were no significant differences in lung function indicators and aerobic exercise capacity between different genotype athletes. 4) rs1544744 locus: There were no significant differences in lung function indicators and aerobic exercise capacity between different genotype athletes. 5) rs10783180 locus: There is a significant difference in the relative values of anaerobic threshold and anaerobic threshold between different genotype athletes. The anaerobic threshold of AG genotype athletes was 2156.35±227.69 ml/min and the anaerobic threshold of athletes with GG genotype was 2143.41±217.30 ml/min. So the anaerobic threshold of AG genotype athletes was significantly greater than the anaerobic threshold of GG genotype athletes. The Anaerobic threshold relative value for AG genotype athletes was 50.99±3.99 ml/kg/min, while the anaerobic threshold relative value for athletes with GG genotype was 48.12±4.25 ml/kg/min. The anaerobic threshold relative value of AG genotype athletes was significantly greater than that of GG genotype athletes
 Other indicators showed no significant difference.
 Conclusions The rs10783180 polymorphism is associated with the athletic ability of elite endurance athletes. The population carrying AG genotype may have higher anaerobic threshold value and relative value of anaerobic threshold, which may become more excellent endurance athletes. Rs10783180 polymorphic locus AG genotype can be used as a molecular genetic marker to predict the relative value of anaerobic threshold and anaerobic threshold of Chinese Han women's long-distance runners in northern China.

Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β−/−) murine hearts

IntroductionAgeing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors. Materials and methodsPro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-γ coactivator-1β knockout (Pgc-1β−/−) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA. Results and discussionYoung and aged Pgc-1β−/− showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT. Both young and old, regularly-paced, Pgc-1β-/- hearts showed slowed maximum action potential (AP) upstrokes, (dV/dt)max (∼157 vs. 120–130 V s-1), prolonged AP latencies (by ∼20%) and shortened refractory periods (∼58 vs. 51 ms) but similar AP durations (∼50 ms at 90% recovery) compared to WT. However, Pgc-1β-/- genotype and age each influenced extrasystolic AP latencies during PES. Young and aged WT ventricles displayed distinct, but Pgc-1β−/− ventricles displayed similar dependences of AP latency upon (dV/dt)max resembling aged WT. They also independently increased myocardial fibrosis. AP wavelengths combining activation and recovery terms paralleled contrasting arrhythmic incidences in Pgc-1β-/- and WT hearts. Mitochondrial dysfunction thus causes pro-arrhythmic Pgc-1β−/− phenotypes by altering AP conduction through reducing (dV/dt)max and causing age-dependent fibrotic change.

Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis.

Kelch-like ECH-associated protein 1 (Keap1) binds to nuclear factor E2 p45-related factor 2 (Nrf2), a transcription factor for antioxidant enzymes, to suppress Nrf2 activation. The role of oxidative stress in many diseases supports the possibility that processes that are associated with Nrf2 activation might offer therapeutic potential. Nrf2 deficiency induces osteoclastogenesis, which is responsible for bone loss, by activating receptor activator of NF-κB ligand (RANKL)-mediated signaling; however, the effects of Keap1 deficiency remain unclear. By using Keap1-deficient newborn mice, we observed that talus and calcaneus bone formation was partially retarded and that osteoclast number was reduced in vivo without severe gross abnormalities. In addition, Keap1-deficient macrophages were unable to differentiate into osteoclasts in vitrovia attenuation of RANKL-mediated signaling and expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), a key transcription factor that is involved in osteoclastogenesis. Furthermore, Keap1 deficiency up-regulated the expression of Mafb, a negative regulator of NFATc1. RANKL-induced mitochondrial gene expression is required for down-regulation of IFN regulatory factor 8 (IRF-8), a negative transcriptional regulator of NFATc1. Our results indicate that Keap1 deficiency down-regulated peroxisome proliferator-activated receptor-γ coactivator 1β and mitochondrial gene expression and up-regulated Irf8 expression. These results suggest that the Keap1/Nrf2 axis plays a critical role in NFATc1 expression and osteoclastogenic progression.-Sakai, E., Morita, M., Ohuchi, M., Kido, M. A., Fukuma, Y., Nishishita, K., Okamoto, K., Itoh, K., Yamamoto, M., Tsukuba, T. Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis.

Hypolipidemic effect of oleanolic acid is mediated by the miR-98-5p/PGC-1β axis in high-fat diet-induced hyperlipidemic mice.

Oleanolic acid (OA) is an active component of the traditional Chinese herb Olea europaea L. and has been found to exhibit a significant lipid-lowering effect; however, its direct molecular target is still unknown, which limits its clinical application and the possible structure modification to improve its beneficial functions. In this regard, we carried out the present study to identify potential hepatic targets of OA to mediate its lipid-lowering effect. We found that both acute and chronic OA treatments reduced serum levels of triglycerides, total cholesterol, and LDL cholesterol, and decreased hepatic expression levels of peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β), which is an important regulator in maintaining hepatic lipid homeostasis, and its downstream target genes. Of note, liver-specific knockdown of PGC-1β recapitulated the hypolipidemic effects of OA. At the molecular level, OA accelerated mRNA degradation of PGC-1β. Microarray analysis revealed a host of microRNAs that potentially mediate OA-induced PGC-1β mRNA degradation, among which, miR-98-5p significantly inhibited activity of Pgc-1β 3' UTR as well as PGC-1β expression and promoted its mRNA degradation. Conversely, miR-98-5p inhibitors blunted the inhibitory effects of OA on PGC-1β expression. Collectively, our data demonstrated that OA ameliorated hyperlipidemia, likely via regulation of the miR-98-5p/PGC-1β axis.-Chen, S., Wen, X., Zhang, W., Wang, C., Liu, J., Liu, C. Hypolipidemic effect of oleanolic acid is mediated by the miR-98-5p/PGC-1β axis in high-fat diet-induced hyperlipidemic mice.

Molecular responses in the telomere-mitochondrial axis of ageing in the elderly: A candidate gene approach

Experimental evidence shows that telomere shortening induces mitochondrial damage but so far studies in humans are scarce. Here, we investigated the association between leukocyte telomere length (LTL) and mitochondrial DNA (mtDNA) content in elderly and explored possible intermediate mechanisms by determining the gene expression profile of candidate genes in the telomere-mitochondrial axis of ageing.Among 166 non-smoking elderly, LTL, leukocyte mtDNA content and expression of candidate genes: sirtuin1 (SIRT1), tumor protein p53 (TP53), peroxisome proliferator-activated receptor γ-coactivator1α (PGC-1α), peroxisome proliferator-activated receptor γ-coactivator1β (PGC-1β), nuclear respiratory factor 1 (NRF1) and nuclear factor, erythroid 2 like 2 (NRF2), using a quantitave real time polymerase chain assay (qPCR). Statistical mediation analysis was used to study intermediate mechanisms of the telomere-mitochondrial axis of ageing.LTL correlated with leukocyte mtDNA content in our studied elderly (r=0.23, p=0.0047). SIRT1 gene expression correlated positively with LTL (r=0.26, p=0.0094) and leukocyte mtDNA content (r=0.43, p<0.0001). The other studied candidates showed significant correlations in the telomere-mitochondrial interactome but not independent from SIRT1. SIRT1 gene expression was estimated to mediate 40% of the positive association between LTL and leukocyte mtDNA content.The key finding of our study was that SIRT1 expression plays a pivotal role in the telomere-mitochondrial interactome.

PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine.

The mucosa of the small intestine is renewed completely every 3-5 d throughout the entire lifetime by small populations of adult stem cells that are believed to reside in the bottom of the crypts and to migrate and differentiate into all the different populations of intestinal cells. When the cells reach the apex of the villi and are fully differentiated, they undergo cell death and are shed into the lumen. Reactive oxygen species (ROS) production is proportional to the electron transfer activity of the mitochondrial respiration chain. ROS homeostasis is maintained to control cell death and is finely tuned by an inducible antioxidant program. Here we show that peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β) is highly expressed in the intestinal epithelium and possesses dual activity, stimulating mitochondrial biogenesis and oxygen consumption while inducing antioxidant enzymes. To study the role of PGC-1β gain and loss of function in the gut, we generated both intestinal-specific PGC-1β transgenic and PGC-1β knockout mice. Mice overexpressing PGC-1β present a peculiar intestinal morphology with very long villi resulting from increased enterocyte lifespan and also demonstrate greater tumor susceptibility, with increased tumor number and size when exposed to carcinogens. PGC-1β knockout mice are protected from carcinogenesis. We show that PGC-1β triggers mitochondrial respiration while protecting enterocytes from ROS-driven macromolecule damage and consequent apoptosis in both normal and dysplastic mucosa. Therefore, PGC-1β in the gut acts as an adaptive self-point regulator, capable of providing a balance between enhanced mitochondrial activity and protection from increased ROS production.

Role of retinol binding protein 4 in hepatic steatosis

Using HepG2 cell, Xia et al.1 revealed that retinol binding protein 4 (RBP4) activated critical lipogenic transcription factors of sterol regulatory element-binding protein-1c (SREBP-1c) and liver X receptor through the stimulation of peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β). The stimulatory effect of RBP4 on SREBP-1c activity associated with hepatic lipogenesis was ensured also in vivo. Xia et al. conclude that the activation of SREBP-1c by RBP4 is fully dependent on up-regulation of PGC-1β, because RBP4 did not exhibit lipogenic effect in PGC-1β-knockout mice. In the associated editorial,2 Dr. Maher raises an important question of whether RBP4 is directly linked to hepatic lipogenesis, but neither Xia et al. or Maher address the issue about the unidentified hepatic receptor of RBP4. The only known receptor for RBP4 is a receptor stimulated by retinoic acid-6 (STRA6), which is expressed in several tissues, including retina, brain, spleen, thymus, female genital tract, testis, muscle, and placental endothelial cells (and in small quantities in heart and lung), whereas STRA6 has not been identified in the liver.3 Until the discovery of the hepatic receptor of RBP4, the metabolic link between RBP4 and fat is not confirmed. Recently, Alapatt et al.4 reported that RBP4 receptor-2 (RBPR2), which is primarily expressed in the liver and intestine and induced in adipose tissue in obese mice, is likely to mediate effects of RBP4 on insulin action and glucose homeostasis in the capacity of an RBP4 receptor. To define the role of RBP4 in lipid metabolism, it would be necessary to investigate the effect of RBP4 also under the condition of knockdown of RBPR2. PGC-1β has been thought to be a coactivator of lipogenic transcription factors, leading to lipogenesis. However, a recent study suggests that PGC-1β plays dual roles in regulating hepatic fatty acid metabolism by controlling the expression of programs of genes involved in both fatty acid oxidation and de novo fatty acid synthesis, because PGC-1β-deficient mice were outwardly normal, but exhibited a significant increase in hepatic triglyceride content at 6 weeks of age.5 The lipogenic effects of RBP4 shown by Xia et al. might be time-dependent. Tetsuji Fujita, M.D. Department of Surgery Jikei University School of Medicine Tokyo, Japan

Retinol binding protein 4 stimulates hepatic sterol regulatory element-binding protein 1 and increases lipogenesis through the peroxisome proliferator-activated receptor-γ coactivator 1β-dependent pathway

Recent studies have revealed the essential role of retinol binding protein 4 (RBP4) in insulin resistance. However, the impact of RBP4 on aberrant lipogenesis, the common hepatic manifestation in insulin resistance states, and the underlying mechanism remain elusive. The present study was designed to examine the effect of RBP4 on sterol regulatory element-binding protein (SREBP-1) and hepatic lipogenesis. Treatment with human retinol-bound RBP4 (holo-RBP4) significantly induced intracellular triglyceride (TAG) synthesis in HepG2 cells and this effect is retinol-independent. Furthermore, RBP4 treatment enhanced the levels of mature SREBP-1 and its nuclear translocation, thereby increasing the expression of lipogenic genes, including fatty acid synthase (FAS), acetyl coenzyme A carboxylase-1 (ACC-1), and diacylglycerol O-acyltransferase 2 (DGAT-2). Stimulation of HepG2 cells with RBP4 strongly up-regulated the expression of transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β) at both the messenger RNA (mRNA) and protein levels. The transcriptional activation of PGC-1β is necessary and sufficient for the transcriptional activation of SREBP-1 in response to RBP4. The cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) was identified as the target transcription factor involved in the RBP4-mediated up-regulation of PGC-1β transcription as a result of phosphorylation on Ser133. Furthermore, in vivo RBP4 infusion induced SREBP-1c activation and consequently accelerated hepatic lipogenesis and plasma TAG in C57BL/6J mice, a phenomenon not observed in Ppargc1b knockout mice. These findings reveal a novel mechanism by which RBP4 achieves its effects on hepatic lipid metabolism.

PGC‐1β Modulates the Expression of Genes Involved in Mitochondrial Function and Adipogenesis During Preadipocyte Differentiation

This study determined the expression of genes involved in mitochondrial function and adipogenesis at mRNA and protein levels by transfecting rat differentiating preadipocytes with siRNA/Lipofectamine complex and pcDNA-PGC-1β (peroxisome proliferator-activated receptor-γ coactivator-1β)/Lipofectamine complex, respectively, to further elucidate the role of PGC-1β in white preadipocyte differentiation. The results showed that the transfection of PGC-1β siRNA inhibited the expressions of mitochondrial genes malate dehydrogenase, carnitine palmitoyltransferase 1, nuclear respiratory factor 1, ATP synthesis, adipocyte differentiation key transcription factor peroxisome proliferator-activated receptor-γ, sterol regulatory element binding protein 1c and fatty acid synthetase, whereas the triglyceride synthesis was retarded (p < 0.05). Furthermore, overexpression of PGC-1β up-regulated the expressions of adipogenic and mitochondrial biosynthetic marker genes and promoted triglyceride accumulation during 3T3-L1 adipocyte differentiation. These observations suggest that PGC-1β modulates the expression of mitochondrial function and adipogenesis-related genes and affects white preadipocyte differentiation.

Estrogen related receptor α-induced adipogenesis is PGC-1β-dependent

Previous report showed that Estrogen related receptor α (ERRα) knockout mice had a significant reduction in adipose tissue deposition. Although it was reported that ERRα could promote adipogenesis in several immortalized preadipocytes cell lines, the mechanism behind which is still unclear to date. Besides, the expression pattern of ERRα in white adipose tissue is rarely examined. Here, we show that the expression of ERRα in primary cultured adipocytes is closely associated with adipogenesis. Besides, we found that peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β) play an important role in regulating ERRα-induced adipogenesis. ERRα-induced adipogenesis was greatly attenuated when knocking down PGC-1β expression, while rescued by overexpression of PGC-1β. However, PGC-1β could still promote adipogenesis when suppressing ERRα expression. Furthermore, we demonstrated that ERRα could transcriptionally active PGC-1β expression and then enhance the formation of sterol-regulatory-element-binding protein-1c (SREBP-1c)/PGC-1β complex and peroxisome proliferator-activated receptor-γ (PPARγ)/PGC-1β complex. Taken together, these results indicate that ERRα-induced adipogenesis is triggered by modulating the expression of PGC-1β.

Aging-Associated Changes in Physical Performance and Energy Metabolism in the Senescence-Accelerated Mouse

The aim of the study was to clarify the aging-associated changes in physical performance and energy metabolism in senescence-accelerated prone mouse (SAMP1). The endurance of aged SAMP1 was significantly lower by 28% than the age-matched senescence-resistant mouse (SAMR1). Oxygen consumption and fat oxidation in aged SAMP1 were lower by 19% and 22%, respectively. Peroxisome proliferator-activated receptor-γ coactivator-1β and medium-chain acyl coenzyme A dehydrogenase messenger RNA expression was significantly lower in aged SAMP1. Aged SAMP1 exhibited higher plasma glucose, insulin, leptin, and lower adiponectin concentrations. Aged SAMP1 also had higher malondialdehyde levels in plasma and tissues and lower peroxisome proliferator-activated receptor-γ messenger RNA and protein levels in adipose tissue. These results indicate that physical performance and energy expenditure decrease earlier with aging in SAMP1, accompanied by decreased fatty acid catabolism in muscle and liver and increased inflammation and oxidative stress in adipose tissue. SAMP1 could thus be a useful accelerated functional depression model for studying physical performance and energy metabolism.

PGC-1β regulates angiogenesis in skeletal muscle

Aerobic metabolism requires oxygen and carbon sources brought to tissues via the vasculature. Metabolically active tissues such as skeletal muscle can regulate blood vessel density to match metabolic needs; however, the molecular cues that coordinate these processes remain poorly understood. Here we report that the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β), a potent regulator of mitochondrial biology, induces angiogenesis in skeletal muscle. PGC-1β induces the expression of vascular endothelial growth factor (VEGF) in cell culture and in vivo. The induction of VEGF by PGC-1β requires coactivation of the orphan nuclear receptor estrogen-related receptor-α (ERRα) and is independent of the hypoxia-inducible factor (HIF) pathway. In coculture experiments, overexpression of PGC-1β in skeletal myotubes increases the migration of adjacent endothelial cells, and this depends on VEGF signaling. Transgenic expression of PGC-1β in skeletal myocytes dramatically increases muscular vessel density. Taken together, these data indicate that PGC-1β is a potent regulator of angiogenesis, thus providing a novel link between the regulations of oxidative metabolism and vascular density.

Induction of ketosis in rats fed low-carbohydrate, high-fat diets depends on the relative abundance of dietary fat and protein

Low-carbohydrate/high-fat diets (LC-HFDs) in rodent models have been implicated with both weight loss and as a therapeutic approach to treat neurological diseases. LC-HFDs are known to induce ketosis; however, systematic studies analyzing the impact of the macronutrient composition on ketosis induction and weight loss success are lacking. Male Wistar rats were pair-fed for 4 wk either a standard chow diet or one of three different LC-HFDs, which only differed in the relative abundance of fat and protein (percentages of fat/protein in dry matter: LC-75/10; LC-65/20; LC-55/30). We subsequently measured body composition by nuclear magnetic resonance (NMR), analyzed blood chemistry and urine acetone content, evaluated gene expression changes of key ketogenic and gluconeogenic genes, and measured energy expenditure (EE) and locomotor activity (LA) during the first 4 days and after 3 wk on the respective diets. Compared with chow, rats fed with LC-75/10, LC-65/20, and LC-55/30 gained significantly less body weight. Reductions in body weight were mainly due to lower lean body mass and paralleled by significantly increased fat mass. Levels of β-hydroxybutyate were significantly elevated feeding LC-75/10 and LC-65/20 but decreased in parallel to reductions in dietary fat. Acetone was about 16-fold higher with LC-75/10 only (P < 0.001). In contrast, rats fed with LC-55/30 were not ketotic. Serum fibroblast growth factor-21, hepatic mRNA expression of hydroxymethylglutaryl-CoA-lyase, peroxisome proliferator-activated receptor-γ coactivator-1α, and peroxisome proliferator-activated receptor-γ coactivator-1β were increased with LC-75/10 only. Expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase was downregulated by 50-70% in LC-HF groups. Furthermore, EE and LA were significantly decreased in all groups fed with LC-HFDs after 3 wk on the diets. In rats, the absence of dietary carbohydrates per se does not induce ketosis. LC-HFDs must be high in fat, but also low in protein contents to be clearly ketogenic. Independent of the macronutrient composition, LC-HFD-induced weight loss is not due to increased EE and LA.

Stearoyl CoA desaturase‐1 mediates the pro‐lipogenic effects of dietary saturated fat

Dietary saturated fats have often been implicated in the promotion of obesity and related disorders. It has been shown recently that saturated fats act through the transcription factor SREBP-1c (sterol regulatory element-binding protein-1c) and its requisite coactivator, peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β), to exert their pro-lipogenic effects. We show here that a diet high in the saturated fat stearate induces lipogenic genes in wild-type mice, with the induction of the Scd1 (stearoyl-CoA desaturase-1) gene preceding that of other lipogenic genes. However, in Scd1-/- mice, stearate does not induce lipogenesis, and Srebp-1c and Pgc-1β levels are markedly reduced. Instead, genes of fatty acid oxidation such as Cpt-1 (carnitine palmitoyltransferase-1) as well as Pgc-1α are induced. Mitochondrial fatty acid oxidation is increased, and white adipose tissue and hepatic glycogen stores are depleted in stearate-fed Scd1-/- mice. Furthermore, AMP-activated protein kinase is also induced by stearate feeding in Scd1-/- mice. These results indicate that the desaturation of saturated fats such as stearate by SCD is an essential step mediating their induction of lipogenesis. In the absence of SCD1, stearate promotes oxidation, leading to protection from saturated fat-induced obesity. SCD1 thus serves as a molecular switch in the promotion or prevention of lipid-induced disorders brought on by consumption of excess saturated fat.

PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta) is believed to control mitochondrial oxidative energy metabolism by activating specific target transcription factors including estrogen-related receptors and nuclear respiratory factor 1, yet its physiological role is not yet clearly understood. To define its function in vivo, we generated and characterized mice lacking the functional PGC-1beta protein [PGC-1beta knockout (KO) mice]. PGC-1beta KO mice are viable and fertile and show no overt phenotype under normal laboratory conditions. However, the KO mice displayed an altered expression in a large number of nuclear-encoded genes governing mitochondrial and metabolic functions in multiple tissues including heart, skeletal muscle, brain, brown adipose tissue, and liver. In contrast to PGC-1alpha KO mice that are reportedly hyperactive, PGC-1beta KO mice show greatly decreased activity during the dark cycle. When acutely exposed to cold, the KO mice developed abnormal hypothermia and morbidity. Furthermore, high-fat feeding induced hepatic steatosis and increased serum triglyceride and cholesterol levels in the KO mice. These results suggest that PGC-1beta in mouse plays a nonredundant role in controlling mitochondrial oxidative energy metabolism.