Peroxisome Proliferator-activated Receptor-γ Coactivator Research Articles

Acupuncture modulates the AMPK/PGC-1 signaling pathway to facilitate mitochondrial biogenesis and neural recovery in ischemic stroke rats

AimsThe main objective of this study was to investigate the role and mechanism of acupuncture on anti-nerve injury in the acute phase by regulating mitochondrial energy metabolism via monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) axis in rat ischemic stroke.Main methodsMiddle cerebral artery occlusion (MCAO) was established by middle cerebral artery occlusion/reperfusion. One-week of acupuncture was performed during the acute phase of ischemic stroke. The neurological function and brain tissue integrity were evaluated. Mitochondrial function (intracellular ATP level and the activity of mitochondrial respiratory chain complex I) and the level of NADH oxidase (NOX) were detected by enzymatic chemistry. Next, the potential molecular mechanisms were explored by western blotting, fluorescence quantitative PCR and immunohistochemistry method.Key findings(1) Acupuncture treatment for MCAO/R rats showed a significant improvement in the infarcted tissue accompanied by functional recovery in Zea-Longa score and balance beam score outcomes, motor function performances. (2) Acupuncture increased the levels of ATP and mitochondrial respiratory chain complex I, decreased the NOX levels in cerebral ischemia established by suture-occluded method. (3) Acupuncture reduced the necrosis dissolution of neuronal cells and meningeal edema, while promoting angiogenesis. (4) Quantitative immunohistochemical staining results showed acupuncture can increase the expression of AMPK, p-AMPK and the mitochondrial transcription factor PGC-1α, NRF2, TFAM and uncoupling protein 2 (UCP2). Meanwhile, acupuncture treatment up-regulated the expression of the corresponding protein. (5) Subsequently, acupuncture enhanced AMPK phosphorylation as well as the expression of PGC-1α, NRF2, TFAM and UCP2, implicated in mitochondrial synthesis and cellular apoptosis. (6) Finally, injections of AMPK antagonists and activators confirmed AMPK as a therapeutic target for the anti-nerve damage effects of acupuncture.SignificanceAcupuncture intervention relieved ischemic stroke progression in MCAO rats by promoting energy metabolism and mitochondrial biogenesis in the brain and alleviating neuronal apoptosis, which was mediated by eliciting AMPK/PGC-1α axis, among them AMPK is a therapeutic target.

Imeglimin modulates mitochondria biology and facilitates mitokine secretion in 3T3-L1 adipocytes

AimsImeglimin, a novel antidiabetic drug, has recently been reported to affect pancreatic β-cells and hepatocytes. Adipose tissue plays a crucial role in systemic metabolism. However, its effect on adipocytes remains unexplored. Herein, we investigated the effects of imeglimin on adipocytes, particularly in the mitochondria. Main methodsThe 3T3-L1 adipocytes were treated with imeglimin. Mitochondrial respiratory complex I activity and NAD+, NADH, and AMP levels were measured. Protein expression levels were determined by western blotting, mitochondrial DNA and mRNA expression levels were determined using quantitative polymerase chain reaction, and secreted adipocytokine and mitokine levels were determined using adipokine array and enzyme-linked immunosorbent assay. Key findingsImeglimin inhibited complex I activity, decreased the NAD+/NADH ratio, and increased AMP levels, which were associated with the enhanced phosphorylation of AMP-activated protein kinase. In addition, imeglimin increased the mitochondrial DNA content and levels of mitochondrial transcription factor A and peroxisome proliferator-activated receptor-γ coactivator 1-α mRNA, which were abolished by Ly294002, a phosphoinositide 3-kinase inhibitor. Furthermore, imeglimin facilitated the expression levels of markers of the mitochondrial unfolded protein response, and the gene expression and secretion of two mitokines, fibroblast growth factor 21 and growth differentiation factor 15. The production of both mitokines was transcriptionally regulated and abolished by phosphoinositide 3-kinase and Akt inhibitors. SignificanceImeglimin modulates mitochondrial biology in adipocytes and may exert a mitohormetic effect through mitokine secretion.

Irisin, A Fascinating and Multifunctional Protein: Implication for Health

BACKGROUND: Fibronectin type III domain-containing protein 5 (FNDC5), or also known as irisin, has been identified for two decades but almost completely disregarded for 10 years. It is present in skeletal muscle, heart, and brain, and in reaction to exercise can transform white adipose tissue into brown. Since then, irisin has gained a lot of attention for its potencies in treating metabolic disorders. In this review article, the potential future of irisin especially on metabolism and aging process will be discussed.CONTENT: Sedentary lifestyle is acknowledged as risk factor for type 2 diabetes mellitus, obesity, immune system issues, asthma, and neurological or heart illness. Irisin is secreted by muscle cells when exercising, produced after the proteolytic cleavage of FNDC5 protein. Irisin has positive impacts on maintaining physiological balance including reducing inflammation, keeping the bone homeostasis, as well as influencing metabolic processes and the neurological system function. Due to these many and advantageous characteristics, irisin could be a possible choice for preventing and managing disorders associated with modern society, and finding the agents to increase irisin can be beneficial.SUMMARY: Irisin offers a fresh potential basis for kinesitherapy and shows promise as a therapeutic target due to its various biological activities. Irisin pathway can be activated through dietary changes, the use of natural substances and drugs and can interact with this signalling pathway which involved peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and uncoupling protein mRNA 1 (UCP1) to resolve obesity and its metabolic comorbidities.KEYWORDS: irisin, FNDC5, exercise, inflammation, obesity, nervous system

Lycopene as a Therapeutic Agent against Aflatoxin B1-Related Toxicity: Mechanistic Insights and Future Directions.

Aflatoxin (AFT) contamination poses a significant global public health and safety concern, prompting widespread apprehension. Of the various AFTs, aflatoxin B1 (AFB1) stands out for its pronounced toxicity and its association with a spectrum of chronic ailments, including cardiovascular disease, neurodegenerative disorders, and cancer. Lycopene, a lipid-soluble natural carotenoid, has emerged as a potential mitigator of the deleterious effects induced by AFB1 exposure, spanning cardiac injury, hepatotoxicity, nephrotoxicity, intestinal damage, and reproductive impairment. This protective mechanism operates by reducing oxidative stress, inflammation, and lipid peroxidation, and activating the mitochondrial apoptotic pathway, facilitating the activation of mitochondrial biogenesis, the endogenous antioxidant system, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (KEAP1) and peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) pathways, as well as regulating the activities of cytochrome P450 (CYP450) enzymes. This review provides an overview of the protective effects of lycopene against AFB1 exposure-induced toxicity and the underlying molecular mechanisms. Furthermore, it explores the safety profile and potential clinical applications of lycopene. The present review underscores lycopene's potential as a promising detoxification agent against AFB1 exposure, with the intent to stimulate further research and practical utilization in this domain.

Skeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α

Aim/hypothesisThe peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) plays a critical role in the maintenance of glucose, lipid and energy homeostasis by orchestrating metabolic programs in multiple tissues in response to environmental cues. In skeletal muscles, PGC-1α dysregulation has been associated with insulin resistance and type 2 diabetes but the underlying mechanisms have remained elusive. This research aims to understand the role of TET3, a member of the ten-eleven translocation (TET) family dioxygenases, in PGC-1α dysregulation in skeletal muscles in obesity and diabetes.MethodsTET expression levels in skeletal muscles were analysed in humans with or without type 2 diabetes, as well as in mouse models of high-fat diet (HFD)-induced or genetically induced (ob/ob) obesity/diabetes. Muscle-specific Tet3 knockout (mKD) mice were generated to study TET3’s role in muscle insulin sensitivity. Genome-wide expression profiling (RNA-seq) of muscle tissues from wild-type (WT) and mKD mice was performed to mine deeper insights into TET3-mediated regulation of muscle insulin sensitivity. The correlation between PGC-1α and TET3 expression levels was investigated using muscle tissues and in vitro-derived myotubes. PGC-1α phosphorylation and degradation were analysed using in vitro assays.ResultsTET3 expression was elevated in skeletal muscles of humans with type 2 diabetes and in HFD-fed and ob/ob mice compared with healthy controls. mKD mice exhibited enhanced glucose tolerance, insulin sensitivity and resilience to HFD-induced insulin resistance. Pathway analysis of RNA-seq identified ‘Mitochondrial Function’ and ‘PPARα Pathway’ to be among the top biological processes regulated by TET3. We observed higher PGC-1α levels (~25%) in muscles of mKD mice vs WT mice, and lower PGC-1α protein levels (~25–60%) in HFD-fed or ob/ob mice compared with their control counterparts. In human and murine myotubes, increased PGC-1α levels following TET3 knockdown contributed to improved mitochondrial respiration and insulin sensitivity. TET3 formed a complex with PGC-1α and interfered with its phosphorylation, leading to its destabilisation.Conclusions/interpretationOur results demonstrate an essential role for TET3 in the regulation of skeletal muscle insulin sensitivity and suggest that TET3 may be used as a potential therapeutic target for the metabolic syndrome.Data availabilitySequences are available from the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) with accession number of GSE224042.Graphical

Dysregulation of mitochondrial dynamics mediated aortic perivascular adipose tissue-associated vascular reactivity impairment under excessive fructose intake

Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic reactivity. However, whether and how PVAT alters vascular function under fructose overconsumption remains largely unknown. In this study, male Sprague-Dawley rats (8 weeks old) were fed a 60% high fructose diet (HFD) for 12 weeks. Fasting blood sugar, insulin, and triglycerides were significantly increased by HFD intake. Plasma adiponectin was significantly enhanced in the HFD group. The expression of uncoupling protein 1 (UCP1) and mitochondrial mass were reduced in the aortic PVAT of the HFD group. Concurrently, the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM) were suppressed. Furthermore, decreased fusion proteins (OPA1, MFN1, and MFN2) were accompanied by increased fission proteins (FIS1 and phospho-DRP1). Notably, the upregulated α-smooth muscle actin (α-SMA) and osteocalcin in the PVAT were concurrent with the impaired reactivity of aortic contraction and relaxation. Coenzyme Q10 (Q, 10 mg/100 mL, 4 weeks) effectively reversed the aforementioned events induced by HFD. Together, these results suggested that the dysregulation of mitochondrial dynamics mediated HFD-triggered PVAT whitening to impair aortic reactivity. Fortunately, coenzyme Q10 treatment reversed HFD-induced PVAT whitening and aortic reactivity.

SUMO-specific protease 2 regulates lipid droplet size through ERRα-mediated CIDEA expression in adipocytes

Lipid droplets are not only lipid storage sites but also are closely related to lipid metabolism. Lipid droplet growth increases lipid storage capacity and suppresses lipolysis via lipase associated with the lipid droplet surface. The cell death-inducing DFF45-like effector (CIDE) family of proteins mediates lipid droplet fusion, which mainly contributes to lipid droplet growth. We previously demonstrated small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2) plays important roles in lipid metabolism and induction/maintenance of adipogenesis. In this study, we determined whether SENP2 regulates lipid droplet size in adipocytes. Overexpression of SENP2 increased lipid droplet size in differentiated 3T3-L1 adipocytes and facilitated CIDEA transcription. We found SENP2 increased CIDEA expression mainly through desumoylation of estrogen-related receptor α (ERRα), which acted in coordination with peroxisome proliferator-activated receptor γ-coactivator α. In addition, palmitate treatment increased SENP2 and CIDEA mRNA levels. Specific small interfering RNA-mediated knockdown of SENP2, as well as ERRα knockdown, eliminated palmitate-induced CIDEA expression. These results suggest SENP2 enhances CIDEA expression by modulating ERRα when SENP2 is upregulated, such as after palmitate treatment, to increase lipid droplet size in adipocytes.

Molecular control of endurance training adaptation in male mouse skeletal muscle

Skeletal muscle has an enormous plastic potential to adapt to various external and internal perturbations. Although morphological changes in endurance-trained muscles are well described, the molecular underpinnings of training adaptation are poorly understood. We therefore aimed to elucidate the molecular signature of muscles of trained male mice and unravel the training status-dependent responses to an acute bout of exercise. Our results reveal that, even though at baseline an unexpectedly low number of genes define the trained muscle, training status substantially affects the transcriptional response to an acute challenge, both quantitatively and qualitatively, in part associated with epigenetic modifications. Finally, transiently activated factors such as the peroxisome proliferator-activated receptor-γ coactivator 1α are indispensable for normal training adaptation. Together, these results provide a molecular framework of the temporal and training status-dependent exercise response that underpins muscle plasticity in training.

Structural and functional impairments of skeletal muscle in patients with postacute sequelae of SARS-CoV-2 infection.

Following acute coronavirus disease 2019 (COVID-19), a substantial proportion of patients showed symptoms and sequelae for several months, namely the postacute sequelae of COVID-19 (PASC) syndrome. Major phenomena are exercise intolerance, muscle weakness, and fatigue. We aimed to investigate the physiopathology of exercise intolerance in patients with PASC syndrome by structural and functional analyses of skeletal muscle. At least 3 mo after infection, nonhospitalized patients with PASC (n = 11, age: 54 ± 11 yr; PASC) and patients without long-term symptoms (n = 12, age: 49 ± 9 yr; CTRL) visited the laboratory on four nonconsecutive days. Spirometry, lung diffusion capacity, and quality of life were assessed at rest. A cardiopulmonary incremental exercise test was performed. Oxygen consumption (V̇o2) kinetics were determined by moderate-intensity exercises. Muscle oxidative capacity (k) was assessed by near-infrared spectroscopy. Histochemical analysis, O2 flux (JO2) by high-resolution respirometry, and quantification of key molecular markers of mitochondrial biogenesis and dynamics were performed in vastus lateralis biopsies. Pulmonary and cardiac functions were within normal range in all patients. V̇o2peak was lower in PASC than CTRL (24.7 ± 5.0 vs. 32.9 ± 7.4 mL·min-1·kg-1, respectively, P < 0.05). V̇o2 kinetics was slower in PASC than CTRL (41 ± 12 vs. 30 ± 9 s-1, P < 0.05). k was lower in PASC than CTRL (1.54 ± 0.49 vs. 2.07 ± 0.51 min-1, P < 0.05). Citrate synthase, peroxisome proliferator-activated receptor-γ coactivator (PGC)1α, and JO2 for mitochondrial complex II were significantly lower in PASC vs. CTRL (all P values <0.05). In our cohort of patients with PASC, we showed limited exercise tolerance mainly due to "peripheral" determinants. Substantial reductions were observed for biomarkers of mitochondrial function, content, and biogenesis. PASC syndrome, therefore, appears to negatively impact skeletal muscle function, although the disease is a heterogeneous condition.NEW & NOTEWORTHY Several months after mild acute SARS-CoV-2 infection, a substantial proportion of patients present persisting, and often debilitating, symptoms and sequelae. These patients show reduced quality of life due to exercise intolerance, muscle weakness, and fatigue. The present study supports the hypothesis that "peripheral" impairments at skeletal muscle level, namely, reduced mitochondrial function and markers of mitochondrial biogenesis, are major determinants of exercise intolerance and fatigue, "central" phenomena at respiratory, and cardiac level being less relevant.

CLCF1 signaling restrains thermogenesis and disrupts metabolic homeostasis by inhibiting mitochondrial biogenesis in brown adipocytes

Great progress has been made in identifying positive regulators that activate adipocyte thermogenesis, but negative regulatory signaling of thermogenesis remains poorly understood. Here, we found that cardiotrophin-like cytokine factor 1 (CLCF1) signaling led to loss of brown fat identity, which impaired thermogenic capacity. CLCF1 levels decreased during thermogenic stimulation but were considerably increased in obesity. Adipocyte-specific CLCF1 transgenic (CLCF1-ATG) mice showed impaired energy expenditure and severe cold intolerance. Elevated CLCF1 triggered whitening of brown adipose tissue by suppressing mitochondrial biogenesis. Mechanistically, CLCF1 bound and activated ciliary neurotrophic factor receptor (CNTFR) and augmented signal transducer and activator of transcription 3 (STAT3) signaling. STAT3 transcriptionally inhibited both peroxisome proliferator-activated receptor-γ coactivator (PGC) 1α and 1β, which thereafter restrained mitochondrial biogenesis in adipocytes. Inhibition of CNTFR or STAT3 could diminish the inhibitory effects of CLCF1 on mitochondrial biogenesis and thermogenesis. As a result, CLCF1-TG mice were predisposed to develop metabolic dysfunction even without external metabolic stress. Our findings revealed a brake signal on nonshivering thermogenesis and suggested that targeting this pathway could be used to restore brown fat activity and systemic metabolic homeostasis in obesity.

Activation of G-protein-coupled receptor 39 reduces neuropathic pain in a rat model.

Activated G-protein-coupled receptor 39 (GPR39) has been shown to attenuate inflammation by interacting with sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). However, whether GPR39 attenuates neuropathic pain remains unclear. In this study, we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats. Intrathecal injection of TC-G 1008, a specific agonist of GPR39, significantly alleviated mechanical allodynia in the rats with spared nerve injury, improved spinal cord mitochondrial biogenesis, and alleviated neuroinflammation. These changes were abolished by GPR39 small interfering RNA (siRNA), Ex-527 (SIRT1 inhibitor), and PGC-1α siRNA. Taken together, these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1α pathway in rats with spared nerve injury.

Effect of antioxidants on kidney damage repair in - diabetes-induced animal: a literature study

Diabetes mellitus is a disease characterized by hyperglycemia. Chronic hyperglycemia indiabetes mellitus can cause various complications, one of which is diabetic nephropathy,which affects the kidney. Chronic hyperglycemia causes an increase in free radicals and adecrease in antioxidant activity resulting in oxidative stress conditions. This study aims to determine kidney damage caused by oxidative stress and the role of antioxidants in reducingthis damage through literature studies. The literature used comes from Google search results such as PubMed, Google Scholar, ResearchGate, and ScienceDirect. From the search results, ten journals meeting the inclusion and exclusion criteria were selected for review and comparison so that a conclusion could be drawn. The results of this literature study have demonstrated that biochemical parameters, such as increased levels of creatinine, urea, malondialdehyde (MDA), and decreased antioxidant enzymes, as well as kidney histological parameters, such as changes in the shape of tubules, glomeruli, and increased kidney expression, are indicators of kidney damage caused by oxidative stress. The mechanism of antioxidants in reducing kidney damage is through DNA cutting, binding to phenolic OH groups, down-regulation of the oxidase expression of nitrogen oxides 4 nicotinamide adenine dinucleotide phosphate (Nox4 NADPH), antioxidant enzyme systems, activation of the activated protein kinase pathway - silent mating type information regulation 2 homolog 1- peroxisome proliferator-activated receptor-γ coactivator 1α (AMPK-SirT1- PGC-1 α), protein glycation reactions, and inhibition of protein 53 (P53) so that erythroid nuclear factor 2-related factor 2 (Nrf2) can activate antioxidant gene transcription.

Biochemical aspects of magnesium-enhanced bone regeneration

Current research is focused on practical implications of magnesium-based implants largely due to their biodegradability and ability to promote bone healing and formation. However, the mechanism underlying the osteogenesis regulation by magnesium is still unclear.We describe cellular and molecular mechanisms underlying the effect of magnesium ions (Mg2+) on bone growth following the device implantation. The presented data demonstrate magnesium-induced activation of canonical Wnt/β-catenin signaling pathway in human bone marrow stromal cells resulting in their differentiation into osteoblasts, osteogenic effect and recovery of bone defects. We describe the role of the molecular mechanisms responsible for osteopromotive properties of Mg2+ and associated with unique transient receptor potential melastatin 7 (TRPM7) cation channels mediating the Mg2+ influx. TRPM7-mediated Mg2+ influx is important for platelet-derived growth factor (PDGF)-induced proliferation, adhesion, and migration of human osteoblasts, as well as for promotion of Mg2+-associated bone regeneration.We discuss the effect of Mg2+ on intracellular signaling processes, expression of the vascular endothelial growth factor (VEGF), hypoxia-inducible factor-2α, and peroxisome proliferator-activated receptor-γ coactivator 1α. Mg2+ can promote bone regeneration by enhancing the production of type X collagen and VEGF by osteogenic cells in bone marrow.

Mutation of TP53 Confers Ferroptosis Resistance in Lung Cancer Through the FOXM1/MEF2C Axis

Ferroptosis is a highly regulated tumor suppressor process. Loss or mutation of TP53 can cause changes in sensitivity to ferroptosis. Mutations in TP53 may be associated with the malignant or indolent progression of ground glass nodules in early lung cancer, but whether ferroptosis may also be involved in determining this biological process has not yet been determined. Using invivo and invitro gain- and loss-of-function approaches, this study used clinical tissue for mutation analysis and pathological research to show that wild-type TP53 inhibited the expression of forkhead box M1 (FOXM1) by binding to peroxisome proliferator-activated receptor-γ coactivator 1α, maintaining the mitochondrial function and thus affecting the sensitivity to ferroptosis. This function was absent in mutant cells, resulting in overexpression of FOXM1 and ferroptosis resistance. Mechanistically, FOXM1 activated the transcription level of myocyte-specific enhancer factor 2C in the mitogen-activated protein kinase signaling pathway, leading to stress protection when exposed to ferroptosis inducers. This study provides new insights into the mechanism of association between TP53 mutation and ferroptosis tolerance, which can aid a deeper understanding of the role of TP53 in the malignant progression of lung cancer.

Inhibition of lipid droplet accumulation by Solanumnigrum by suppressing adipogenesis and inducing lipolysis, thermogenesis and autophagy in 3T3‑L1 cells.

It has been reported that Solanum nigrum exhibits anti-obesity effects in animal models induced by a high-fat diet. However, research on how Solanum nigrum exerts its anti-obesity effects is currently limited. Thus, the present study focused on identifying the mechanism of action associated with the anti-obesity activity of Solanum nigrum aerial part (SNAP), which significantly inhibited the accumulation of lipid droplets in differentiating 3T3-L1 cells. Intracellular lipid accumulation in 3T3-L1 cells was analyzed by Oil-Red O staining and glycerol content was analyzed using an ELISA kit. In addition, changes in protein expression within 3T3-L1 cells were analyzed using western blot analysis. It decreased the expression level of adipogenic proteins such as CCAAT/enhancer-binding protein α, Peroxisome proliferator-activated receptor γ, fatty acid binding protein 4, and adiponectin. In addition, SNAP increased the expression levels of lipolytic proteins, such as adipose triglyceride lipase and hormone-sensitive lipase, while decreasing perilipin-1. The treatment of fully differentiated 3T3-L1 cells increased the free glycerol levels. SNAP treatment resulted in increased AMP-activated protein kinase phosphorylation and the expression levels of thermogenic proteins (peroxisome proliferator-activated receptor-γ coactivator 1-α, PR domain containing 16 and uncoupling protein 1) and an autophagic protein (LC3-II). Overall, these results suggested that SNAP inhibited lipid droplet accumulation by suppressing adipogenesis and promoting lipolysis, thermogenesis and autophagy.

Role of PGC-1α mediated synaptic plasticity, mitochondrial function, and neuroinflammation in the antidepressant effect of Zi-Shui-Qing-Gan-Yin.

Depression is the most prevalent psychiatric disorder, which needs deeper mechanism research studies and effective therapy. Zi-Shui-Qing-Gan-Yin (ZSQGY) is a traditional Chinese medicine decoction that has been widely used in China in the treatment of depressive symptoms. The aim of the study was to examine the anti-depressive effects of ZSQGY and the possible mechanism of action in the monosodium glutamate (MSG)-induced depressive model and the corticosterone (CORT)-induced PC12 cell model. Liquid chromatography-mass spectrometry (LC-MS) was performed to determine the major compounds in the water extract of ZSQGY. The depressive behaviors were evaluated by the field swimming test (FST), the sucrose preference test (SPT), and the open field test (OFT). Golgi staining and transmission electron microscopy (TEM) were performed to display the alterations of synaptic ultrastructure. The mitochondrion function and inflammatory factors were also quantified. The changes in peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) expression were evaluated. The results of this study demonstrated that ZSQGY significantly improved depressive behaviors. ZSQGY also reversed the changes in synaptic plasticity, improved mitochondrion function, and reduced the levels of inflammatory factors. The neuroprotective effects were accompanied by the increased expression of PGC-1α. However, the beneficial changes were reversed after the inhibition of PGC-1α. These results indicated that ZSQGY effectively could improve depressive behaviors via the mechanisms that regulate synaptic structural plasticity, improve mitochondrion function, and alleviate neuroinflammation, which could, or partly, attribute to the regulation of PGC-1α.

Glucagon Promotes Gluconeogenesis through the GCGR/PKA/CREB/PGC-1α Pathway in Hepatocytes of the Japanese Flounder Paralichthys olivaceus.

In order to investigate the mechanism of glucagon regulation of gluconeogenesis, primary hepatocytes of the Japanese flounder (Paralichthys olivaceus) were incubated with synthesized glucagon, and methods based on inhibitors and gene overexpression were employed. The results indicated that glucagon promoted glucose production and increased the mRNA levels of glucagon receptor (gcgr), guanine nucleotide-binding protein Gs α subunit (gnas), adenylate cyclase 2 (adcy2), protein kinase A (pka), cAMP response element-binding protein 1 (creb1), peroxisome proliferator-activated receptor-γ coactivator 1α (pgc-1α), phosphoenolpyruvate carboxykinase 1 (pck1), and glucose-6-phosphatase (g6pc) in the hepatocytes. An inhibitor of GCGR decreased the mRNA expression of gcgr, gnas, adcy2, pka, creb1, pgc-1α, pck1, g6pc, the protein expression of phosphorylated CREB and PGC-1α, and glucose production. The overexpression of gcgr caused the opposite results. An inhibitor of PKA decreased the mRNA expression of pgc-1α, pck1, g6pc, the protein expression of phosphorylated-CREB, and glucose production in hepatocytes. A CREB-targeted inhibitor significantly decreased the stimulation by glucagon of the mRNA expression of creb1, pgc-1α, and gluconeogenic genes, and glucose production decreased accordingly. After incubating the hepatocytes with an inhibitor of PGC-1α, the glucagon-activated mRNA expression of pck1 and g6pc was significantly down-regulated. Together, these results demonstrate that glucagon promotes gluconeogenesis through the GCGR/PKA/CREB/PGC-1α pathway in the Japanese flounder.

Swimming in cold water upregulates genes involved in thermogenesis and the browning of white adipose tissues.

The purpose of this study was to investigate whether there is an interacting effect of six weeks of swimming in cold water on the gene expression of browning markers in adipose tissue in rodents. Twenty male Wistar rats were randomly divided into four groups: Control (C, 25 °C), Cold Exposure (CE, 4 °C), Swimming in tepid Water (STW, 30 °C), and Swimming in Cold Water (SCW, 15 °C). The swimming included 2-3 min intervals, 1 min rest, until exhaustion, three days a week for six weeks, with 3 to 6% of bodyweight overload. Rats from CE were exposed to cold for 2 h per day, five days per week. After the experimental protocol, interscapular brown (BAT) and inguinal subcutaneous white (WAT) fat tissues were excised, weighed, and processed for beiging and mitochondrial biogenesis markers gene expression. The experimental protocols resulted in an apparent increase in the number of brown adipocytes (per mm2) in the adipose deposits compared to the C group; substantial changes were observed in the SCW group. Compared to other groups, cold exposure alone increased significantly serum norepinephrine, and also β2-adrenergic receptor expression was upregulated in the adipocytes compared to the C group. The STW group increased the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1 alpha (PGC-1α), β2-adrenergic receptor, and CCAAT/enhancer-binding proteins-α(c/EBP-α) in WAT in comparison with the C group(p < 0.05). In both adipocytes, the SCW intervention significantly upregulated the expression of PGC-1α, PPAR-γ, and c/EBP-α genes in comparison with the C and CE groups. In addition, the expression of TFAM and UCP1 was upregulated substantially in the SCW group compared to other groups. Our data demonstrate that swim training and cold exposure present additive effects in the expression of genes involved in the beiging process and mitochondrial biogenesis markers in BAT and WAT. In addition, it seems that the upregulation of these genes is related to the activation of β2-adrenergic receptors.

Bone Marrow-Derived Mesenchymal Stem Cells and Pioglitazone or Exendin-4 Synergistically Improve Insulin Resistance via Multiple Modulatory Mechanisms in High-Fat Diet/Streptozotocin-Induced Diabetes in Rats.

Diabetes mellitus (DM) is a metabolic disease, characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. The current study was designed to assess the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) alone and in combination with pioglitazone (Pz) or exendin-4 (Ex) in high-fat diet/streptozotocin (HFD/STZ)-induced diabetes in rats. The rats were subjected to the HFD for three weeks before being injected with a single low dosage of STZ (35 mg/kg bw). The animals were assigned to different treatment groups after type II diabetes mellitus (T2DM) induction was confirmed. Severe insulin resistance was verified in untreated HFD/STZ T2DM rats, along with the exaggeration of oxidative stress, inflammation, apoptosis, and autophagy suppression in the adipose tissues. Monotherapy of HFD/T2DM rats with BM-MSCs and Pz or Ex alleviated diabetic complications by increasing insulin sensitivity, decreasing apoptosis and inflammation as evidenced by a decrease in serum tumor necrosis factor-alpha, caspase-3, and nuclear factor-kappa B (NF-κB) genes expression and Janus kinase (JNK) protein expression, and enhancing autophagy as revealed by upregulation in beclin and LC3, as well as peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α) genes expression in the adipose tissues. An augmented ameliorative efficacy was recorded in combined treatments. The biochemical and molecular results were confirmed by histological investigation of pancreatic tissues. Combining Pz or Ex with BM-MSCs is a synergistic therapeutic option that reduces insulin resistance and subsequent complications in T2DM via multiple molecular mechanisms.

Common Regulators of Lipid Metabolism and Bone Marrow Adiposity in Postmenopausal Women.

A variety of metabolic disorders are associated with a decrease in estradiol (E2) during natural or surgical menopause. Postmenopausal women are prone to excessive fat accumulation in skeletal muscle and adipose tissue due to the loss of E2 via abnormalities in lipid metabolism and serum lipid levels. In skeletal muscle and adipose tissue, genes related to energy metabolism and fatty acid oxidation, such as those encoding peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and estrogen-related receptor alpha (ERRα), are downregulated, leading to increased fat synthesis and lipid metabolite accumulation. The same genes regulate lipid metabolism abnormalities in the bone marrow. In this review, abnormalities in lipid metabolism caused by E2 deficiency were investigated, with a focus on genes able to simultaneously regulate not only skeletal muscle and adipose tissue but also bone metabolism (e.g., genes encoding PGC-1α and ERRα). In addition, the mechanisms through which mesenchymal stem cells lead to adipocyte differentiation in the bone marrow as well as metabolic processes related to bone marrow adiposity, bone loss, and osteoporosis were evaluated, focusing on the loss of E2 and lipid metabolic alterations. The work reviewed here suggests that genes underlying lipid metabolism and bone marrow adiposity are candidate therapeutic targets for bone loss and osteoporosis in postmenopausal women.