The Role of Fasting Interventions on Skeletal Muscle in High Fat Diet Fed Mice

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient ( cd44−/−) mice and wild-type littermates ( cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44−/− mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44−/− mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44−/− mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44−/− compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44−/− mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44−/− mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

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Abstract 17649: Inhibition of Src Homology 2 Domain-containing Phosphatase 1 (SHP-1) Increases Insulin Sensitivity in High-fat Diet-induced Insulin Resistant C57black6 Mice

Circulation ◽

10.1161/circ.130.suppl_2.17649 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Janine Krüger ◽

Markus Dagnell ◽

Philipp Stawowy ◽

Evren Caglayan ◽

Arne Östman ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Body Weight ◽

Glucose Tolerance ◽

High Fat Diet ◽

Metabolic Diseases ◽

High Fat ◽

Insulin Resistant ◽

Cardiovascular Morbidity And Mortality

Background: Insulin resistance plays a crucial role in the development of type 2 diabetes, and exerts great impact on vascular inflammation and remodeling. At the molecular level a post-insulin receptor (IR) defect in insulin signaling has been suggested to contribute to insulin resistance. IR signaling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). The precise role of PTPs in insulin resistance, however, has not been explored. Results: Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat) to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD mice were treated with PTP-inhibitors for additional 6 weeks. Mice under HFD exhibited a significant increase in body weight as well as decreased respiratory quotient and adiponectin levels, and were characterized by impaired insulin- and glucose tolerance. Organ-based gene expression analyses in insulin-resistant mice demonstrated upregulation of SHP-1, PTP1B, LAR, and DEP-1 in insulin-sensitive organs. SHP-1 was further explored in vitro. Insulin stimulation in murine liver cells induced site-selective hyper-phosphorylation at IR tyrosine-sites Y1158, and Y1361 after inhibition of SHP-1. Furthermore, SHP-1 impairment time-dependently enhanced insulin-induced Akt- and Erk-phosphorylation, and resulted in elevated glucose uptake in skeletal muscle cells. Administration of a SHP-1 inhibitor (Sodium Stibogluconate) and a brought pan-PTP inhibitor (BMOV) in HFD mice led to improvement of both insulin- and glucose tolerance. In accordance, PTP-activity was significantly impaired in epididymal fat, skeletal muscle, and liver under BMOV treatment, being confirmed by reduced ex vivo dephosphorylation of a radioactive labelled peptide (AEEEIYGEFEAKKKK). Finally, BMOV- and SHP-1 treatment also resulted in reduced body weight. Conclusions: IR-antagonizing PTPs were organ-specifically regulated in insulin resistance. The results indicate a central role of PTPs and, in particular, of SHP-1 as endogenous antagonists of the IR. Taken together targeting PTPs led to beneficial effects in insulin resistance, and may thus improve metabolic diseases as well as cardiovascular morbidity and mortality.

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Altered nutrient response of mTORC1 as a result of changes in REDD1 expression: effect of obesity vs. REDD1 deficiency

Journal of Applied Physiology ◽

10.1152/japplphysiol.01350.2013 ◽

2014 ◽

Vol 117 (3) ◽

pp. 246-256 ◽

Cited By ~ 28

Author(s):

David L. Williamson ◽

Zhuyun Li ◽

Rubin M. Tuder ◽

Elena Feinstein ◽

Scot R. Kimball ◽

...

Keyword(s):

Skeletal Muscle ◽

High Fat Diet ◽

Wild Type ◽

High Fat ◽

Low Fat ◽

Mouse Muscle ◽

Nutrient Response ◽

Diet Induced Obesity ◽

Mtorc1 Signaling

Although aberrant mTORC1 signaling has been well established in models of obesity, little is known about its repressor, REDD1. Therefore, the initial goal of this study was to determine the role of REDD1 on mTORC1 in obese skeletal muscle. REDD1 expression (protein and message) and mTORC1 signaling (S6K1, 4E-BP1, raptor-mTOR association, Rheb GTP) were examined in lean vs. ob/ob and REDD1 wild-type (WT) vs. knockout (KO) mice, under conditions of altered nutrient intake [fasted and fed or diet-induced obesity (10% vs. 60% fat diet)]. Despite higher ( P < 0.05) S6K1 and 4E-BP1 phosphorylation, two models of obesity ( ob/ob and diet-induced) displayed elevated ( P < 0.05) skeletal muscle REDD1 expression compared with lean or low-fat-fed mouse muscle under fasted conditions. The ob/ob mice displayed elevated REDD1 expression ( P < 0.05) that coincided with aberrant mTORC1 signaling (hyperactive S6K1, low raptor-mTOR binding, elevated Rheb GTP; P < 0.05) under fasted conditions, compared with the lean, which persisted in a dysregulated fashion under fed conditions. REDD1 KO mice gained limited body mass on a high-fat diet, although S6K1 and 4E-BP1 phosphorylation remained elevated ( P < 0.05) in both the low-fat and high-fat-fed KO vs. WT mice. Similarly, the REDD1 KO mouse muscle displayed blunted mTORC1 signaling responses (S6K1 and 4E-BP1, raptor-mTOR binding) and circulating insulin under fed conditions vs. the robust responses ( P < 0.05) in the WT fed mouse muscle. These studies suggest that REDD1 in skeletal muscle may serve to limit hyperactive mTORC1, which promotes aberrant mTORC1 signaling responses during altered nutrient states.

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Intramuscular Injection of miR-1 Reduces Insulin Resistance in Obese Mice

Frontiers in Physiology ◽

10.3389/fphys.2021.676265 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alice C. Rodrigues ◽

Alexandre R. Spagnol ◽

Flávia de Toledo Frias ◽

Mariana de Mendonça ◽

Hygor N. Araújo ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Oxygen Consumption ◽

Insulin Sensitivity ◽

Mitochondrial Respiration ◽

High Fat Diet ◽

C2c12 Cells ◽

High Fat ◽

Spare Capacity

The role of microRNAs in metabolic diseases has been recognized and modulation of them could be a promising strategy to treat obesity and obesity-related diseases. The major purpose of this study was to test the hypothesis that intramuscular miR-1 precursor replacement therapy could improve metabolic parameters of mice fed a high-fat diet. To this end, we first injected miR-1 precursor intramuscularly in high-fat diet-fed mice and evaluated glucose tolerance, insulin sensitivity, and adiposity. miR-1-treated mice did not lose weight but had improved insulin sensitivity measured by insulin tolerance test. Next, using an in vitro model of insulin resistance by treating C2C12 cells with palmitic acid (PA), we overexpressed miR-1 and measured p-Akt content and the transcription levels of a protein related to fatty acid oxidation. We found that miR-1 could not restore insulin sensitivity in C2C12 cells, as indicated by p-Akt levels and that miR-1 increased expression of Pgc1a and Cpt1b in PA-treated cells, suggesting a possible role of miR-1 in mitochondrial respiration. Finally, we analyzed mitochondrial oxygen consumption in primary skeletal muscle cells treated with PA and transfected with or without miR-1 mimic. PA-treated cells showed reduced basal respiration, oxygen consumption rate-linked ATP production, maximal and spare capacity, and miR-1 overexpression could prevent impairments in mitochondrial respiration. Our data suggest a role of miR-1 in systemic insulin sensitivity and a new function of miR-1 in regulating mitochondrial respiration in skeletal muscle.

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The role of carnitine in the animal exposed to cold

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y68-012 ◽

1968 ◽

Vol 46 (1) ◽

pp. 71-75 ◽

Cited By ~ 4

Author(s):

G. Delisle ◽

M. W. Radomski

Keyword(s):

Skeletal Muscle ◽

Oxygen Consumption ◽

High Fat Diet ◽

Free Carnitine ◽

Enzymatic Assay ◽

High Fat

Changes in the concentrations of carnitine and its derivatives in the liver, heart, and skeletal muscle of rats exposed continuously to 4 °C for periods ranging up to 7 weeks were studied by using a specific enzymatic assay for carnitine. In heart and muscle the concentrations of free carnitine and fatty acylcarnitine were not elevated in cold-acclimatized animals, but that of acetylarnitine increased twofold. In the liver of cold-acclimatized rats, significant increases in all three of the carnitine fractions were observed. The concentration of fatty acylcarnitine in tissues from control animals was greatly elevated by starvation or a high-fat diet but, in contrast, the level was not increased in cold-exposed animals subjected to the same nutritional variants. Normal rats maintained at 22 °C and injected with daily doses of dl-carnitine for 14 days cooled more rapidly and survived for shorter times when exposed to −20 °C than animals injected with saline. Carnitine injections did not alter the oxygen consumption of normal or cold-exposed rats.

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Skeletal muscle protein degradation induced by high‐fat diet is decreased by macadamia oil supplementation: Role of E3 ubiquitin enzyme ligase MuRF‐1 and atrogin‐1

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.lb706 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Sandro M Hirabara ◽

Luis G O Sousa ◽

Carlos F Rodrigues ◽

Amanda R Martins ◽

Jose C Rosa Neto ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Degradation ◽

High Fat Diet ◽

Muscle Protein ◽

Skeletal Muscle Protein ◽

High Fat ◽

Muscle Protein Degradation

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The Role of Skeletal Muscle Tribbles 3 (TRB3) on Endoplasmic Reticulum (ER) stress‐ and high fat diet‐induced insulin resistance

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.1154.5 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Ho‐Jin Koh ◽

Taro Toyoda ◽

Michelle M Jung ◽

Min‐Young Lee ◽

Michael F Hirshman ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Endoplasmic Reticulum ◽

Er Stress ◽

High Fat Diet ◽

High Fat

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Role of skeletal muscle autophagy in high-fat-diet–induced obesity and exercise

Nutrition Reviews ◽

10.1093/nutrit/nuz044 ◽

2019 ◽

Vol 78 (1) ◽

pp. 56-64

Author(s):

Adrienne R Herrenbruck ◽

Lance M Bollinger

Keyword(s):

Skeletal Muscle ◽

High Fat Diet ◽

Control Mechanism ◽

Degradation Pathway ◽

The Body ◽

High Fat ◽

Diet Induced Obesity ◽

Quality Control Mechanism ◽

The Impact

Abstract Autophagy is a complex degradation pathway responsible for clearing damaged and dysfunctional organelles. High-fat-diet–induced obesity has been shown to alter autophagy throughout the body in a tissue-specific manner. The impact of obesity on skeletal muscle autophagy has yet to be elucidated. This review examines the impact of high-fat-diet–induced obesity and exercise on skeletal muscle autophagy. Better understanding this major quality control mechanism may help develop novel therapies to combat high-fat-diet–induced obesity comorbidities.

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