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

Abstract

Abstract. Leptin gene transfer in the liver by hydrodynamicbased gene delivery instead of peptide administration was used to investigate the effects of leptin on muscle mass accretion and lipid accumulation in muscles of wild-type mice. Food intake (P<0.01), body weight (P<0.01) and white adipose tissue (P<0.01) were significantly reduced in the leptin genetreated group compared with the control group. Moreover, plasma leptin concentration was significantly increased after administration of the mouse leptin gene at a dose of 15 µg per mouse for 1 day (P<0.01) or 1 week (P<0.05). Furthermore, the mRNA abundance of myosin heavy chain type I (MyHC-I), myosin heavy chain type II (MyHC-IIa, MyHC-IIx), adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) genes in gastrocnemius muscle and extensor digitorum longus after administration of leptin for 1 week were significantly increased compared with the control group. Finally, we investigated the mechanism by which leptin gene transfer affects fibromuscular and fat deposition in muscle. Gene expression and protein levels of SIRT1, and proliferator-activated receptor-γ coactivator-1α (PGC-1α) were remarkably increased in extensor digitorum longus. On the other hand, PGC-1α and FOXO3a gene expression was observed to have significantly increased in gastrocnemius muscle. However, only changes in the protein levels of PGC-1α were observed (P<0.05). These results suggest that leptin may affect the growth and development of muscle, and fat deposition in wild-type mice via SIRT1 and FOXO3a and their downstream targets, including PGC-1α.

Leptin Gene Transfer Improves Symptoms of Type 2 Diabetic Mice by Regulating Leptin Signaling Pathway and Insulin Resistance of Peripheral Tissues

“…2A) indicated the leptin gene had been successfully transferred, overexpressed in the liver, and secreted into the blood, consistent with previous studies. [26][27][28] Therefore, peripherally administered high-dose leptin could lower glucose levels in T2D mice.…”

“…1C) was observed, as in previous studies. [26][27][28] However, the weight-reducing effects of leptin were not observed in T2D mice. Moreover, the decrease in blood glucose (Fig.…”

“…Protein samples from the hypothalamus or epididymal adipose tissue were treated and analyzed via electrophoresis, as described in a previous study. 28 In the current experiment, 80 lg of each hypothalamus sample or 10 lg of each fat sample was loaded in each well and then run at 120 V for 40 min. Proteins were transferred onto polyvinylidene difluoride membranes and then blocked with 5% nonfat milk for 1 h. The first antibodies used in this study included anti-adiponectin, anti-NPY (Cell Signaling Technology, Boston, MA), and anti-GAPDH (Beijing ComWin Biotech Co. Ltd., Beijing, China).…”

Leptin Gene Transfer Improves Symptoms of Type 2 Diabetic Mice by Regulating Leptin Signaling Pathway and Insulin Resistance of Peripheral Tissues

“…2A) indicated the leptin gene had been successfully transferred, overexpressed in the liver, and secreted into the blood, consistent with previous studies. [26][27][28] Therefore, peripherally administered high-dose leptin could lower glucose levels in T2D mice.…”

“…1C) was observed, as in previous studies. [26][27][28] However, the weight-reducing effects of leptin were not observed in T2D mice. Moreover, the decrease in blood glucose (Fig.…”

“…Protein samples from the hypothalamus or epididymal adipose tissue were treated and analyzed via electrophoresis, as described in a previous study. 28 In the current experiment, 80 lg of each hypothalamus sample or 10 lg of each fat sample was loaded in each well and then run at 120 V for 40 min. Proteins were transferred onto polyvinylidene difluoride membranes and then blocked with 5% nonfat milk for 1 h. The first antibodies used in this study included anti-adiponectin, anti-NPY (Cell Signaling Technology, Boston, MA), and anti-GAPDH (Beijing ComWin Biotech Co. Ltd., Beijing, China).…”

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

“…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.…”

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

“…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.…”

Leptin Gene Transfer Improves Symptoms of Type 2 Diabetic Mice by Regulating Leptin Signaling Pathway and Insulin Resistance of Peripheral Tissues

“…2A) indicated the leptin gene had been successfully transferred, overexpressed in the liver, and secreted into the blood, consistent with previous studies. [26][27][28] Therefore, peripherally administered high-dose leptin could lower glucose levels in T2D mice.…”

“…1C) was observed, as in previous studies. [26][27][28] However, the weight-reducing effects of leptin were not observed in T2D mice. Moreover, the decrease in blood glucose (Fig.…”

“…Protein samples from the hypothalamus or epididymal adipose tissue were treated and analyzed via electrophoresis, as described in a previous study. 28 In the current experiment, 80 lg of each hypothalamus sample or 10 lg of each fat sample was loaded in each well and then run at 120 V for 40 min. Proteins were transferred onto polyvinylidene difluoride membranes and then blocked with 5% nonfat milk for 1 h. The first antibodies used in this study included anti-adiponectin, anti-NPY (Cell Signaling Technology, Boston, MA), and anti-GAPDH (Beijing ComWin Biotech Co. Ltd., Beijing, China).…”

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

“…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.…”

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

“…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.…”

Leptin Gene Transfer Improves Symptoms of Type 2 Diabetic Mice by Regulating Leptin Signaling Pathway and Insulin Resistance of Peripheral Tissues

“…2A) indicated the leptin gene had been successfully transferred, overexpressed in the liver, and secreted into the blood, consistent with previous studies. [26][27][28] Therefore, peripherally administered high-dose leptin could lower glucose levels in T2D mice.…”

“…1C) was observed, as in previous studies. [26][27][28] However, the weight-reducing effects of leptin were not observed in T2D mice. Moreover, the decrease in blood glucose (Fig.…”

“…Protein samples from the hypothalamus or epididymal adipose tissue were treated and analyzed via electrophoresis, as described in a previous study. 28 In the current experiment, 80 lg of each hypothalamus sample or 10 lg of each fat sample was loaded in each well and then run at 120 V for 40 min. Proteins were transferred onto polyvinylidene difluoride membranes and then blocked with 5% nonfat milk for 1 h. The first antibodies used in this study included anti-adiponectin, anti-NPY (Cell Signaling Technology, Boston, MA), and anti-GAPDH (Beijing ComWin Biotech Co. Ltd., Beijing, China).…”

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

“…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.…”

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

“…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.…”