Gintonin-enriched fraction protects against sarcopenic obesity by promoting energy expenditure and attenuating skeletal muscle atrophy in high-fat diet-fed mice

Magnesium lithospermate B (MLB) is a primary hydrophilic component of Danshen, the dried root of Salvia miltiorrhiza used in traditional medicine, and its beneficial effects on obesity-associated metabolic abnormalities were reported in our previous study. The present study investigated the anti-muscle atrophy potential of MLB in mice with high-fat diet (HFD)-induced obesity. In addition to metabolic abnormalities, the HFD mice had a net loss of skeletal muscle weight and muscle fibers and high levels of muscle-specific ubiquitin E3 ligases, namely the muscle atrophy F-box (MAFbx) and muscle RING finger protein 1 (MuRF-1). MLB supplementation alleviated those health concerns. Parallel changes were revealed in high circulating tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), skeletal TNF receptor I (TNFRI), nuclear factor-kappa light chain enhancer of activated B cells (NF-κB), p65 phosphorylation, and Forkhead box protein O1 (FoxO1) as well as low skeletal phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) phosphorylation. The study revealed that MLB prevented obesity-associated skeletal muscle atrophy, likely through the inhibition of MAFbx/MuRF-1-mediated muscular degradation. The activation of the PI3K-Akt-FoxO1 pathway and inhibition of the TNF-α/TNFRI/NF-κB pathway were assumed to be beneficial effects of MLB.

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Abstract 394: Posttranslational Modification Of Klf5 Mediates Metabolic Dysfunction And Vascular Disease In Metabolic Syndrome

Circulation ◽

10.1161/circ.116.suppl_16.ii_63-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Yumiko Oishi ◽

Ichiro Manabe ◽

Kazuyuki Tobe ◽

Takashi Kadowaki ◽

Ryozo Nagai

Keyword(s):

Skeletal Muscle ◽

Metabolic Syndrome ◽

Energy Expenditure ◽

Posttranslational Modifications ◽

High Fat Diet ◽

Metabolic Diseases ◽

C2c12 Myotubes ◽

Metabolic Dysfunction ◽

High Fat ◽

Increased Risk

We have previously shown that a zinc finger transcription factor, Krüppel-like factor 5 (KLF5), plays an important role in pathogenesis of cardiovascular diseases, such as atherosclerosis. KLF5 heterozygous knockout ( KLF5 +/ − ) mice exhibited much less neointima formation, cardiac hypertrophy and fibrosis. We also found that expression of KLF5 correlated with a higher incidence of restenosis following PCI and the SNP located within the KLF5 promoter was associated with an increased risk of hypertension in man. Interestingly, KLF5 is also expressed in metabolic tissues such as adipose tissue, skeletal muscle, and pancreatic β-cells. Thus, we hypothesized that KLF5 might play a role in metabolic diseases. To test this, KLF5 +/ − mice were fed with high-fat diet. Although KLF5 +/ − mice ate more food than wild-type littermates, they were resistant to high-fat diet-induced obesity and protected from dyslipidemia, glucose intolerance and hepatic steatosis, indicating that KLF5 + /− mice were less susceptible to metabolic syndrome. The systemic O 2 consumption and expression of genes involved in energy expenditure in skeletal muscle were increased in KLF5 + /− mice, demonstrating enhanced energy expenditure, which partly explains the phenotype. Knocking down KLF5 by siRNA increased expression levels of UCP2/3 and CPT-1b in C2C12 myotubes, suggesting that KLF5 may inhibit energy expenditure-related genes. Chromatin immunoprecipitation and coimmunoprecipitation assays showed that KLF5 interacted with corepressors, such as SMRT and NCoR, and strongly inhibited the UCP and CPT-1b promoters. We found that this inhibitory activity of KLF5 depended on its SUMOylation. When KLF5 was deSUMOylated, it activated the promoters. These data demonstrate that KLF5 acts as a molecular switch for energy expenditure and the posttranslational modifications of KLF5 including SUMOylation turns on/off the switch function of KLF5. Given that KLF5 also controls tissue remodeling in response to external stress, KLF5 may mediate metabolic dysfunction and atherosclerosis in metabolic syndrome. Our findings also suggest that the posttranscriptional modification of KLF5 is an attractive novel therapeutic target.

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Amyotrophy Induced by a High-Fat Diet Is Closely Related to Inflammation and Protein Degradation Determined by Quantitative Phosphoproteomic Analysis in Skeletal Muscle of C57BL/6 J Mice

Journal of Nutrition ◽

10.1093/jn/nxz236 ◽

2019 ◽

Vol 150 (2) ◽

pp. 294-302

Author(s):

Ya-nan Sun ◽

Jia-qiang Huang ◽

Zhong-zhou Chen ◽

Min Du ◽

Fa-zheng Ren ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Weight ◽

Protein Kinase ◽

Glucose Metabolism ◽

Protein Degradation ◽

Muscle Atrophy ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Serum Glucose ◽

High Fat

ABSTRACT Background Ectopic fat accumulation in skeletal muscle results in dysfunction and atrophy, but the underlying molecular mechanisms remain unclear. Objective The aim of this study was to investigate the effects of a high-fat diet (HFD) in modulating the structure and energy metabolism of skeletal muscle and the underlying mechanisms in mice. Methods Four-week-old male C57BL/6 J mice (n = 30) were allowed 1 wk for acclimatization. After 6 mice with low body weight were removed from the study, the remaining 24 mice were fed with a normal-fat diet (NFD; 10% energy from fat, n = 12) or an HFD (60% energy from fat, n = 12) for 24 wk. At the end of the experiment, serum glucose and lipid concentrations were measured, and skeletal muscle was collected for atrophy analysis, inflammation measurements, and phosphoproteomic analysis. Results Compared with the NFD, the HFD increased (P < 0.05) body weight (35.8%), serum glucose (64.5%), and lipid (27.3%) concentrations, along with elevated (P < 0.05) expressions of the atrophy-related proteins muscle ring finger 1 (MURF1; 27.6%) and muscle atrophy F-box (MAFBX; 44.5%) in skeletal muscle. Phosphoproteomic analysis illustrated 64 proteins with differential degrees of phosphorylation between the HFD and NFD groups. These proteins were mainly involved in modulating cytoskeleton [adenylyl cyclase-associated protein 2 (CAP2) and actin-α skeletal muscle (ACTA1)], inflammation [NF-κB-activating protein (NKAP) and serine/threonine-protein kinase RIO3 (RIOK3)], glucose metabolism [Cdc42-interacting protein 4 (TRIP10); protein kinase C, and casein kinase II substrate protein 3 (PACSIN3)], and protein degradation [heat shock protein 90 kDa (HSP90AA1)]. The HFD-induced inhibitions of the insulin signaling pathway and activations of inflammation in skeletal muscle were verified by Western blot analysis. Conclusions Quantitative phosphoproteomic analysis in C57BL/6 J mice fed an NFD or HFD for 24 wk revealed that the phosphorylation of inflammatory proteins and proteins associated with glucose metabolism at specific serine residues may play critical roles in the regulation of skeletal muscle atrophy induced by an HFD. This work provides information regarding underlying molecular mechanisms for inflammation-induced dysfunction and atrophy in skeletal muscle.

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α-Ionone attenuates high-fat diet-induced skeletal muscle wasting in mice via activation of cAMP signaling

Food & Function ◽

10.1039/c8fo01992d ◽

2019 ◽

Vol 10 (2) ◽

pp. 1167-1178 ◽

Cited By ~ 3

Author(s):

Tao Tong ◽

Minji Kim ◽

Taesun Park

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

High Fat Diet ◽

Muscle Wasting ◽

Camp Signaling ◽

High Fat ◽

Skeletal Muscle Wasting ◽

Naturally Occurring ◽

Flavoring Agent

α-Ionone, a naturally occurring flavoring agent, attenuates muscle atrophy in HFD-fed mice via activation of cAMP signaling.

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Shift in metabolic fuel in acylation-stimulating protein-deficient mice following a high-fat diet

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00689.2007 ◽

2008 ◽

Vol 294 (6) ◽

pp. E1051-E1059 ◽

Cited By ~ 23

Author(s):

Christian Roy ◽

Sabina Paglialunga ◽

Alexandre Fisette ◽

Patrick Schrauwen ◽

Esther Moonen-Kornips ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Energy Expenditure ◽

High Fat Diet ◽

Ex Vivo ◽

Direct Result ◽

Acid Oxidation ◽

High Fat ◽

Metabolic Potential ◽

Deficient Mice

ASP-deficient mice (C3 KO) have delayed postprandial TG clearance, are hyperphagic, and display increased energy expenditure. Markers of carbohydrate and fatty acid metabolism in the skeletal muscle and heart were examined to evaluate the mechanism. On a high-fat diet, compared with wild-type mice, C3 KO mice have increased energy expenditure, decreased RQ, lower ex vivo glucose oxidation (−39%, P = 0.018), and higher ex vivo fatty acid oxidation (+68%, P = 0.019). They have lower muscle glycogen content (−25%, P < 0.05) and lower activities for the glycolytic enzymes glycogen phosphorylase (−31%, P = 0.005), hexokinase (−43%, P = 0.007), phosphofructokinase (−51%, P < 0.0001), and GAPDH (−15%, P = 0.04). Analysis of mitochondrial enzyme activities revealed that hydroxyacyl-coenzyme A dehydrogenase was higher (+25%, P = 0.004) in C3 KO mice. Furthermore, Western blot analysis of muscle revealed significantly higher fatty acid transporter CD36 (+40%, P = 0.006) and cytochrome c (a marker of mitochondrial content; +69%, P = 0.034) levels in C3 KO mice, whereas the activity of AMP kinase was lower (−48%, P = 0.003). Overall, these results demonstrate a shift in the metabolic potential of skeletal muscle toward increased fatty acid utilization. Whether this is 1) a consequence of decreased adipose tissue storage with repartitioning toward muscle or 2) a direct result of the absence of ASP interaction with the receptor C5L2 in muscle remains to be determined. However, these in vivo data suggest that ASP inhibition could be a potentially viable approach in correcting muscle metabolic dysfunction in obesity.

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Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

10.1101/720540 ◽

2019 ◽

Author(s):

Erin J. Stephenson ◽

JeAnna R. Redd ◽

Detrick Snyder ◽

Quynh T. Tran ◽

Binbin Lu ◽

...

Keyword(s):

Skeletal Muscle ◽

Energy Expenditure ◽

High Fat Diet ◽

High Fat ◽

Constitutive Activation ◽

Mechanistic Target Of Rapamycin ◽

Systemic Insulin Resistance ◽

Mtorc1 Signaling ◽

Futile Cycling ◽

Mtorc1 Activation

AbstractThe mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and age-associated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet-and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal muscle-specific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca2+ through SERCA2. Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan. These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.

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Anti-Obesity and Anti-Diabetic Effects of Acacia Polyphenol in Obese Diabetic KKAy Mice Fed High-Fat Diet

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nep241 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 52

Author(s):

Nobutomo Ikarashi ◽

Takahiro Toda ◽

Takehiro Okaniwa ◽

Kiyomi Ito ◽

Wataru Ochiai ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Weight ◽

Adipose Tissue ◽

Energy Expenditure ◽

White Adipose Tissue ◽

High Fat Diet ◽

Acid Synthesis ◽

Diet Group ◽

High Fat ◽

Kkay Mice

Acacia polyphenol (AP) extracted from the bark of the black wattle tree (Acacia meansii) is rich in unique catechin-like flavan-3-ols, such as robinetinidol and fisetinidol. The present study investigated the anti-obesity/anti-diabetic effects of AP using obese diabetic KKAy mice. KKAy mice received either normal diet, high-fat diet or high-fat diet with additional AP for 7 weeks. After the end of administration, body weight, plasma glucose and insulin were measured. Furthermore, mRNA and protein expression of obesity/diabetic suppression-related genes were measured in skeletal muscle, liver and white adipose tissue. As a result, compared to the high-fat diet group, increases in body weight, plasma glucose and insulin were significantly suppressed for AP groups. Furthermore, compared to the high-fat diet group, mRNA expression of energy expenditure-related genes (PPARα, PPARδ, CPT1, ACO and UCP3) was significantly higher for AP groups in skeletal muscle. Protein expressions of CPT1, ACO and UCP3 for AP groups were also significantly higher when compared to the high-fat diet group. Moreover, AP lowered the expression of fat acid synthesis-related genes (SREBP-1c, ACC and FAS) in the liver. AP also increased mRNA expression of adiponectin and decreased expression of TNF-αin white adipose tissue. In conclusion, the anti-obesity actions of AP are considered attributable to increased expression of energy expenditure-related genes in skeletal muscle, and decreased fatty acid synthesis and fat intake in the liver. These results suggest that AP is expected to be a useful plant extract for alleviating metabolic syndrome.

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Anti-Sarcopenic Obesity Effects of Lonicera caerulea Extract in High-Fat Diet-Fed Mice

Antioxidants ◽

10.3390/antiox10101633 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1633

Author(s):

You-Suk Lee ◽

Eun-Jung Park ◽

Sung-Min Kim ◽

Jong-Yeon Kim ◽

Hae-Jeung Lee

Keyword(s):

Body Weight ◽

Muscle Strength ◽

Mrna Expression ◽

Muscle Mass ◽

Muscle Atrophy ◽

High Fat Diet ◽

Sarcopenic Obesity ◽

High Fat ◽

Lonicera Caerulea ◽

Diet Control

Sarcopenic obesity is a combination of sarcopenia and obesity. Although several herbal extracts showed improvement on sarcopenia and obesity, respectively, there are few studies on sarcopenic obesity. Lonicera caerulea (honeysuckle berry, HB) can ameliorate metabolic disorders including obesity. However, its effects on sarcopenic obesity have not been reported yet. Thus, the aim of this study was to investigate whether HB extract might have any beneficial effects on sarcopenic obesity in high-fat diet-induced mice. Forty-eight mice were classified into six groups and treated for eight weeks: (1) NC, normal diet control; (2) HC, high-fat diet control; (3) PC, high-fat diet with orlistat; (4) HB100, high-fat diet with HB extract at 100 mg/kg; (5) HB200, high-fat diet with HB extract at 200 mg/kg; and (6) HB400, high-fat diet with HB extract at 400 mg/kg. Body weight, fat accumulation, muscle mass, muscle strength, and mRNA expression of muscle atrophy were monitored. Compared with the HC group, HB administration showed anti-obesity properties. It reduced body weight gain and modulated serum biochemical parameters and tissue antioxidant enzymes. HB also increased muscle strength and muscle mass of hind legs. In addition, it decreased mRNA expression levels of Atrogin1 and MuRF1 as markers of muscle atrophy but increased PGC1α and SIRT1 as markers of muscle growth. These results suggest that HB might be effective in preventing sarcopenia associated with obesity.

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