Leptin gene transfer regulates fibromuscular development and lipid deposition in muscles via SIRT1, FOXO3a and PGC-1α in mice in vivo

Wang, Yizhen; Huang, Yanna; Sun, Kaiyue; Qi, Jianhua; Xiang, Lan

doi:10.3892/ijmm.2011.711

Cited by 7 publications

(5 citation statements)

References 27 publications

(36 reference statements)

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“…However, the upregulated genes in IBxDU pigs associated to this pathway are members of the HSPs family, and thus, its activation might be a consequence of cellular stress, or activated protein catabolism. On the other hand, DE genes involved in this pathway in IB pigs play important roles in protein catabolism (FOXO3A, [64]), but also in lipid metabolism and adipogenesis ( NFATC1 , FOS , FOXO3A , [83, 88, 89]) and in osteogenesis and glucose uptake ( BGLAP , [90]). Thus, although the glucocorticoid receptor signaling pathway was enriched in both IB and IBxDU piglets, a different set of DE genes was involved in each genetic type and thus, different metabolic consequences might be expected.…”

Section: Discussionmentioning

confidence: 99%

Developmental Stage, Muscle and Genetic Type Modify Muscle Transcriptome in Pigs: Effects on Gene Expression and Regulatory Factors Involved in Growth and Metabolism

Ayuso

Fernández²,

Núñez³

et al. 2016

PLoS ONE

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Iberian pig production includes purebred (IB) and Duroc-crossbred (IBxDU) pigs, which show important differences in growth, fattening and tissue composition. This experiment was conducted to investigate the effects of genetic type and muscle (Longissimus dorsi (LD) vs Biceps femoris (BF)) on gene expression and transcriptional regulation at two developmental stages. Nine IB and 10 IBxDU piglets were slaughtered at birth, and seven IB and 10 IBxDU at four months of age (growing period). Carcass traits and LD intramuscular fat (IMF) content were measured. Muscle transcriptome was analyzed on LD samples with RNA-Seq technology. Carcasses were smaller in IB than in IBxDU neonates (p < 0.001), while growing IB pigs showed greater IMF content (p < 0.05). Gene expression was affected (p < 0.01 and Fold change > 1.5) by the developmental stage (5,812 genes), muscle type (135 genes), and genetic type (261 genes at birth and 113 at growth). Newborns transcriptome reflected a highly proliferative developmental stage, while older pigs showed upregulation of catabolic and muscle functioning processes. Regarding the genetic type effect, IBxDU newborns showed enrichment of gene pathways involved in muscle growth, in agreement with the higher prenatal growth observed in these pigs. However, IB growing pigs showed enrichment of pathways involved in protein deposition and cellular growth, supporting the compensatory gain experienced by IB pigs during this period. Moreover, newborn and growing IB pigs showed more active glucose and lipid metabolism than IBxDU pigs. Moreover, LD muscle seems to have more active muscular and cell growth, while BF points towards lipid metabolism and fat deposition. Several regulators controlling transcriptome changes in both genotypes were identified across muscles and ages (SIM1, PVALB, MEFs, TCF7L2 or FOXO1), being strong candidate genes to drive expression and thus, phenotypic differences between IB and IBxDU pigs. Many of the identified regulators were known to be involved in muscle and adipose tissues development, but others not previously associated with pig muscle growth were also identified, as PVALB, KLF1 or IRF2. The present study discloses potential molecular mechanisms underlying phenotypic differences observed between IB and IBxDU pigs and highlights candidate genes implicated in these molecular mechanisms.

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Section: Discussionmentioning

confidence: 99%

Developmental Stage, Muscle and Genetic Type Modify Muscle Transcriptome in Pigs: Effects on Gene Expression and Regulatory Factors Involved in Growth and Metabolism

Ayuso

Fernández²,

Núñez³

et al. 2016

PLoS ONE

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“…In our previous studies, we found that leptin and adiponectin gene transfer by HD could regulate energy metabolism by regulating AMPK/PGC-1α transcription [32,33]. To ascertain whether MLPL can also regulate them as leptin and adiponection, we investigated the expression and protein levels of SIRT1, FOXO3a, AMPK, and PGC-1α in the liver, fat and muscle tissue after the gene transfer.…”

Section: Discussionmentioning

confidence: 99%

Leu452His Mutation in Lipoprotein Lipase Gene Transfer Associated with Hypertriglyceridemia in Mice in vivo

et al. 2013

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Mutated mouse lipoprotein lipase (LPL) containing a leucine (L) to histidine (H) substitution at position 452 was transferred into mouse liver by hydrodynamics-based gene delivery (HD). Mutated-LPL (MLPL) gene transfer significantly increased the concentrations of plasma MLPL and triglyceride (TG) but significantly decreased the activity of plasma LPL. Moreover, the gene transfer caused adiposis hepatica and significantly increased TG content in mouse liver. To understand the effects of MLPL gene transfer on energy metabolism, we investigated the expression of key functional genes related to energy metabolism in the liver, epididymal fat, and leg muscles. The mRNA contents of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), fatty acid-binding protein (FABP), and uncoupling protein (UCP) were found to be significantly reduced. Furthermore, we investigated the mechanism by which MLPL gene transfer affected fat deposition in the liver, fat tissue, and muscle. The gene expression and protein levels of forkhead Box O3 (FOXO3), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) were found to be remarkably decreased in the liver, fat and muscle. These results suggest that the Leu452His mutation caused LPL dysfunction and gene transfer of MLPL in vivo produced resistance to the AMPK/PGC-1α signaling pathway in mice.

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“…The class III HDACs or sirtuins consist of seven members (Sirtuins 1–7) homologous to the yeast HDAC silent information regulator 2. Sirtuin 1 (SIRT1) is a regulator of proteins and genes involved with tumor suppressor p53 and nuclear factor-kappa B (NF-κB) and a member of the forkhead transcription factor (FOXO) family (4, 5). SIRT1 is required for estrogen-induced breast cancer growth, and its inactivation eliminates estrogen/estrogen receptor α -induced cell growth and tumor development, triggering apoptosis (4).…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase III as a potential therapeutic target for the treatment of lethal sepsis

Zhao

Liu

et al. 2014

Journal of Trauma and Acute Care Surgery

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Background We have recently demonstrated that inhibition of histone deacetylase (HDAC) class I, II and IV with non-specific HDAC inhibitors improves survival in a mouse model of lethal cecal ligation and puncture (CLP). However, the consequence of HDAC class III inhibition is unknown in this model. The aims of present study were to explore the effect of EX-527, a selective SIRT1 inhibitor, on survival in the lethal model of CLP-sepsis, and to assess the impact of the treatment on inflammatory cytokine production, coagulopathy and bone marrow atrophy during severe sepsis. Methods Experiment I: C57BL/6J mice were subjected to CLP, and 1 h later intraperitoneally injected with either EX-527 dissolved in dimethyl sulfoxide (DMSO), or DMSO only. Survival was monitored for 10 days. Experiment II: One hour after CLP animals were randomly treated with: (i) DMSO vehicle, and (ii) EX-527. Peritoneal fluid and blood samples were collected for measurement of cytokines, and blood was also used to evaluate coagulation status using Thrombelastography. In addition, long bones (femurs and tibias) were harvested from animals to determine morphological changes of bone marrow by H&E staining. Experiment III: Normal primary splenocytes were cultured, and treated with lipopolysaccharide in the presence or absence of EX-527 to assess cytokine production. Results EX-527 significantly improved survival, and attenuated levels of cytokines in blood and peritoneal fluid compared to the vehicle control. It also decreased TNF-α and IL-6 production by splenocytes in vitro. Selective inhibition of SIRT1 was associated with dramatic improvements in fibrin cross-linkage, platelet function and clot rigidity, but without a significant impact on the clot initiation parameters. Moreover, inhibition of SIRT1 decreased bone marrow atrophy significantly. Conclusions Selective inhibition of Class III histone deacetylase SIRT1 significantly improves survival, attenuates “cytokine storm” and sepsis-associated coagulopathy, and decreases bone marrow atrophy in a lethal mouse septic model.

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Leptin gene transfer regulates fibromuscular development and lipid deposition in muscles via SIRT1, FOXO3a and PGC-1α in mice in vivo

Cited by 7 publications

References 27 publications

Developmental Stage, Muscle and Genetic Type Modify Muscle Transcriptome in Pigs: Effects on Gene Expression and Regulatory Factors Involved in Growth and Metabolism

Developmental Stage, Muscle and Genetic Type Modify Muscle Transcriptome in Pigs: Effects on Gene Expression and Regulatory Factors Involved in Growth and Metabolism

Leu452His Mutation in Lipoprotein Lipase Gene Transfer Associated with Hypertriglyceridemia in Mice in vivo

Histone deacetylase III as a potential therapeutic target for the treatment of lethal sepsis

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