scholarly journals Rosiglitazone Enhances Glucose Tolerance by Mechanisms Other than Reduction of Fatty Acid Accumulation within Skeletal Muscle

Endocrinology ◽  
2004 ◽  
Vol 145 (12) ◽  
pp. 5665-5670 ◽  
Author(s):  
Sarah J. Lessard ◽  
Sonia L. Lo Giudice ◽  
Winnie Lau ◽  
Julianne J. Reid ◽  
Nigel Turner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Tolerance ◽  
Dry Mass ◽  
Zucker Rats ◽  
Control Group ◽  
Fatty Acid Accumulation ◽  
Acid Accumulation ◽  
Obese Zucker Rats ◽  
Rosiglitazone Treatment

Abstract We hypothesized that improved glucose tolerance with rosiglitazone treatment would coincide with decreased levels of im triacylglycerol (IMTG), diacylglycerol, and ceramide. Obese Zucker rats were randomly divided into two experimental groups: control (n = 9) and rosiglitazone (n = 9), with lean Zucker rats (n = 9) acting as a control group for obese controls. Rats received either vehicle or 3 mg/kg rosiglitazone for 6 wk. Glucose tolerance was impaired (P < 0.01) in obese compared with lean rats, but was normalized after rosiglitazone treatment. IMTG content was higher in obese compared with lean rats (70.5 ± 5.1 vs. 27.5 ± 2.0 μmol/g dry mass; P < 0.05) and increased an additional 30% (P < 0.05) with rosiglitazone treatment. Intramuscular fatty acid composition shifted toward a higher proportion of monounsaturates (P < 0.05) in obese rosiglitazone-treated rats due to an increase in palmitoleate (16:1; P < 0.05). Rosiglitazone treatment increased (P < 0.05) skeletal muscle diacylglycerol and ceramide levels by 65% and 100%, respectively, compared with obese rats, but elevated muscle diacylglycerol was not associated with changes in the total or membrane contents of the diacylglycerol-sensitive protein kinase C isoforms θ, δ, α, and β. In summary, we observed a disassociation among skeletal muscle IMTG, diacylglycerol and ceramide content, and glucose tolerance with rosiglitazone treatment in obese Zucker rats. Our data suggest, therefore, that rosiglitazone enhances glucose tolerance by mechanisms other than reduction of fatty acid accumulation within skeletal muscle.

Inverse relationship between PGC-1α protein expression and triacylglycerol accumulation in rodent skeletal muscle

2006 ◽  
Vol 100 (2) ◽  
pp. 377-383 ◽  
Author(s):  
Carley R. Benton ◽  
Xiao-Xia Han ◽  
Maria Febbraio ◽  
Terry E. Graham ◽  
Arend Bonen
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Protein Expression ◽  
Zucker Rats ◽  
Triacylglycerol Synthesis ◽  
Fatty Acid Accumulation ◽  
Acid Accumulation ◽  
Intramuscular Lipid ◽  
Obese Zucker Rats

PGC-1α is a key regulator of tissue metabolism, including skeletal muscle. Because it has been shown that PGC-1α alters the capacity for lipid metabolism, it is possible that PGC-1α expression is regulated by the intramuscular lipid milieu. Therefore, we have examined the relationship between PGC-1α protein expression and the intramuscular fatty acid accumulation in hindlimb muscles of animals in which the capacity for fatty acid accumulation in muscle is increased (Zucker obese rat) or reduced [FAT/CD36 null (KO) mice]. Rates of palmitate incorporation into triacylglycerols were determined in perfused red (RG) and white gastrocnemius (WG) muscles of lean and obese Zucker rats and in perfused RG and WG muscles of FAT/CD36 KO and wild-type (WT) mice. In obese Zucker rats, the rate of palmitate incorporation into triacylglycerol depots in RG and WG muscles were 28 and 24% greater than in lean rats ( P < 0.05). In FAT/CD36 KO mice, the rates of palmitate incorporation into triacylglycerol depots were lower in RG (−50%) and WG muscle (−24%) compared with the respective muscles in WT mice ( P < 0.05). In the obese animals, PGC-1α protein content was reduced in both RG (−13%) and WG muscles (−15%) ( P < 0.05). In FAT/CD36 KO mice, PGC-1α protein content was upregulated in both RG (+32%, P < 0.05) and WG muscles (+50%, P < 0.05). In conclusion, from studies in these two animal models, it appears that PGC-1α protein expression is inversely related to components of intramuscular lipid metabolism, because 1) PGC-1α protein expression is downregulated when triacylglycerol synthesis rates, an index of intramuscular lipid metabolism, are increased, and 2) PGC-1α protein expression is upregulated when triacylglycerol synthesis rates are reduced. Therefore, we speculate that the intramuscular lipid sensing may be involved in regulating the protein expression of PGC-1α in skeletal muscle.

scholarly journals AVE0991, a Nonpeptide Angiotensin 1-7 Receptor Agonist, Improves Glucose Metabolism in the Skeletal Muscle of Obese Zucker Rats: Possible Involvement of Prooxidant/Antioxidant Mechanisms

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Viktoria Dobrocsyova ◽  
Miroslava Slamkova ◽  
Katarina Krskova ◽  
Lucia Balazova ◽  
Maciej Suski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Tolerance ◽  
Insulin Signaling ◽  
Receptor Agonist ◽  
Colorimetric Assay ◽  
Whole Body ◽  
Zucker Rats ◽  
Ros Generation ◽  
Morbidly Obese ◽  
Obese Zucker Rats

Angiotensin 1-7 (Ang 1-7) enhances insulin signaling and glucose transport activity in the skeletal muscle. The aim of our study was to evaluate the effect of AVE0991, a nonpeptide Mas receptor agonist, on the metabolic parameters, expression of RAS components and markers of oxidative stress, and insulin signaling in the skeletal morbidly obese rats. 33-week-old male obese Zucker rats were treated with vehicle and AVE0991 (0.5 mg/kg BW/day) via osmotic minipumps for two weeks. Gene expressions were determined by qPCR and/or Western blot analysis in musculus quadriceps. The enzymatic activities were detected flourometrically (aminopeptidase A) or by colorimetric assay kit (protein tyrosine phosphatase 1B). Administration of AVE0991 enhanced insulin signaling cascade in the skeletal muscle, reflected by improved whole-body glucose tolerance. It has been shown that reactive oxygen species (ROS) have insulin-mimetic action in muscle. The expression of renin receptor, transcription factor PLZF, and prooxidant genes was upregulated by AVE0991 accompanied by elevated expression of genes coding enzymes with antioxidant action. Our results show that AVE0991 administration activates genes involved in both ROS generation and clearance establishing a new prooxidant/antioxidant balance on a higher level, which might contribute to the improved insulin signaling pathway and glucose tolerance of obese Zucker rats.

Chronic rosiglitazone treatment restores AMPKα2 activity in insulin-resistant rat skeletal muscle

2006 ◽  
Vol 290 (2) ◽  
pp. E251-E257 ◽  
Author(s):  
Sarah J. Lessard ◽  
Zhi-Ping Chen ◽  
Matthew J. Watt ◽  
Michael Hashem ◽  
Julianne J. Reid ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Zucker Rats ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ampk Signaling ◽  
Palmitate Oxidation ◽  
Insulin Resistant ◽  
Obese Zucker Rats

Rosiglitazone (RSG) is an insulin-sensitizing thiazolidinedione (TZD) that exerts peroxisome proliferator-activated receptor-γ (PPARγ)-dependent and -independent effects. We tested the hypothesis that part of the insulin-sensitizing effect of RSG is mediated through the action of AMP-activated protein kinase (AMPK). First, we determined the effect of acute (30–60 min) incubation of L6 myotubes with RSG on AMPK regulation and palmitate oxidation. Compared with control (DMSO), 200 μM RSG increased ( P < 0.05) AMPKα1 activity and phosphorylation of AMPK (Thr172). In addition, acetyl-CoA carboxylase (Ser218) phosphorylation and palmitate oxidation were increased ( P < 0.05) in these cells. To investigate the effects of chronic RSG treatment on AMPK regulation in skeletal muscle in vivo, obese Zucker rats were randomly allocated into two experimental groups: control and RSG. Lean Zucker rats were treated with vehicle and acted as a control group for obese Zucker rats. Rats were dosed daily for 6 wk with either vehicle (0.5% carboxymethylcellulose, 100 μl/100 g body mass), or 3 mg/kg RSG. AMPKα1 activity was similar in muscle from lean and obese animals and was unaffected by RSG treatment. AMPKα2 activity was ∼25% lower in obese vs. lean animals ( P < 0.05) but was normalized to control values after RSG treatment. ACC phosphorylation was decreased with obesity ( P < 0.05) but restored to the level of lean controls with RSG treatment. Our data demonstrate that RSG restores AMPK signaling in skeletal muscle of insulin-resistant obese Zucker rats.

scholarly journals Chronic renin inhibition with aliskiren improves glucose tolerance, insulin sensitivity, and skeletal muscle glucose transport activity in obese Zucker rats

2012 ◽  
Vol 302 (1) ◽  
pp. R137-R142 ◽  
Author(s):  
Elizabeth M. Marchionne ◽  
Maggie K. Diamond-Stanic ◽  
Mujalin Prasonnarong ◽  
Erik J. Henriksen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Transport ◽  
Insulin Action ◽  
Whole Body ◽  
Zucker Rats ◽  
Obese Zucker Rats ◽  
Renin Inhibition

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker ( fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser473 phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

Insect Meal as Alternative Protein Source Exerts Pronounced Lipid-Lowering Effects in Hyperlipidemic Obese Zucker Rats

2019 ◽  
Vol 149 (4) ◽  
pp. 566-577 ◽  
Author(s):  
Denise K Gessner ◽  
Anne Schwarz ◽  
Sandra Meyer ◽  
Gaiping Wen ◽  
Erika Most ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Cholesterol Biosynthesis ◽  
Control Diet ◽  
Plasma Concentrations ◽  
Protein Source ◽  
Lipid Lowering ◽  
Zucker Rats ◽  
Control Group ◽  
Obese Zucker Rats

ABSTRACT Background Specific dietary proteins exert strong health-related effects compared with casein. Objective Herein, the hypothesis was tested using screening and conventional biochemical and molecular biological techniques that protein-rich insect meal compared with casein influences metabolic health in hyperlipidemic rats. Methods A 4-wk feeding trial with male, 8-wk-old homozygous obese Zucker rats (n = 36) and male, 8-wk-old heterozygous lean Zucker rats (n = 12) was performed. Obese rats were randomly divided into 3 obese groups (OC, OI50, and OI100) of 12 rats each and lean rats served as a lean control group (LC). LC and OC were fed a control diet with 20% casein as protein source, whereas in OI50 and OI100 50% and 100% of the casein, respectively, was replaced isonitrogenously by insect meal from Tenebrio molitor L. All data were analyzed by 1-factor ANOVA, except transcriptomic data which were analyzed by groupwise comparisons with the OC group. Results Transcript profiling revealed a coordinated inhibition by −17% to −521% and −37% to −859% of genes involved in fatty acid, triacylglycerol (TG), and cholesterol biosynthesis in the livers of OI100 and OI50, respectively, compared with OC (P < 0.05). Enzyme activities of fatty acid synthase, glucose-6 phosphate dehydrogenase, and 3-hydroxy-3-methylglutaryl-coenzyme-A reductase in the liver were 100–150% greater in OC compared with LC, but reduced by 50–60% in OI100 compared with OC (P < 0.05), to the same level as in LC. Liver and plasma concentrations of TG and cholesterol were 250–1000%, 30–800%, and 40–600% higher in OC, OI50, and OI100, respectively, than in LC (P < 0.05), but 40–60% and 20–60% lower in OI100 and OI50, respectively, than in group OC (P < 0.05). Plasma and liver concentrations of homocysteine were 20–30% lower in group OI100 than in group OC (P < 0.05). Conclusion Insect meal exerts pronounced lipid-lowering effects in hyperlipidemic rats and, thus, might be useful for hyperlipidemic individuals.

scholarly journals Insulin-Regulated Aminopeptidase Inhibition Ameliorates Metabolism in Obese Zucker Rats

2020 ◽  
Vol 7 ◽  
Author(s):  
Katarina Krskova ◽  
Lucia Balazova ◽  
Viktoria Dobrocsyova ◽  
Rafal Olszanecki ◽  
Maciej Suski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Area Under The Curve ◽  
Signal Transduction Pathway ◽  
Whole Body ◽  
Zucker Rats ◽  
Epididymal Adipose Tissue ◽  
Markers Of Inflammation ◽  
Obese Zucker Rats

The aim of our study was to determine the influence of inhibition of insulin-regulated aminopeptidase/oxytocinase (IRAP) on glucose tolerance and metabolism of skeletal muscle and visceral adipose tissue in obese Zucker rats. Obese Zucker rats administered with IRAP inhibitor–HFI-419 at a dose of 29 μg/100 g BW/day by osmotic minipumps implanted subcutaneously for 2 weeks. Two-hour intraperitoneal glucose tolerance test (ipGTT) was performed in fasting rats. Plasma oxytocin levels were measured by enzyme immunoassay after plasma extraction. In the musculus quadriceps and epididymal adipose tissue, the expression of factors affecting tissue oxidative status and metabolism was determined by real-time qPCR and/or Western blot analysys. The plasma and tissue enzymatic activities were determined by colorimetric or fluorometric method. Circulated oxytocin levels in obese animals strongly tended to increase after HFI-419 administration. This was accompanied by significantly improved glucose utilization during ipGTT and decreased area under the curve (AUC) for glucose. In skeletal muscle IRAP inhibitor treatment up-regulated enzymes of antioxidant defense system – superoxide dismutase 1 and 2 and improved insulin signal transduction pathway. HFI-419 increased skeletal muscle aminopeptidase A expression and activity and normalized its plasma levels in obese animals. In epididymal adipose tissue, gene expression of markers of inflammation and adipocyte hypertrophy was down-regulated in obese rats after HFI-419 treatment. Our results demonstrate that IRAP inhibition improves whole-body glucose tolerance in insulin-resistant Zucker fatty rats and that this metabolic effect of HFI-419 involves ameliorated redox balance in skeletal muscle.

scholarly journals Regulation of fatty acid transport by fatty acid translocase/CD36

2004 ◽  
Vol 63 (2) ◽  
pp. 245-249 ◽  
Author(s):  
Arend Bonen ◽  
Shannon E. Campbell ◽  
Carley R. Benton ◽  
Adrian Chabowski ◽  
Susan L. M. Coort ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Fatty Acid ◽  
Mitochondrial Membrane ◽  
Zucker Rats ◽  
Fatty Acid Transport ◽  
Cd36 Expression ◽  
Uptake Rates ◽  
Streptozotocin Induced Diabetes ◽  
Obese Zucker Rats

Fatty acid (FA) translocase (FAT)/CD36 is a key protein involved in regulating the uptake of FA across the plasma membrane in heart and skeletal muscle. A null mutation of FAT/CD36 reduces FA uptake rates and metabolism, while its overexpression increases FA uptake rates and metabolism. FA uptake into the myocyte may be regulated (a) by altering the expression of FAT/CD36, thereby increasing the plasmalemmal content of this protein (i.e. streptozotocin-induced diabetes, chronic muscle stimulation), or (b) by relocating this protein to the plasma membrane, without altering its expression (i.e. obese Zucker rats). By repressing FAT/CD36 expression, and thereby lowering the plasmalemmal FAT/CD36 (i.e. leptin-treated animals), the rate of FA transport is reduced. Within minutes of beginning muscle contraction or being exposed to insulin FA transport is increased. This increase is a result of the contraction- and insulin-induced translocation of FAT/CD36 from an intracellular depot to the cell surface. Neither PPARα nor PPARγ activation alter FAT/CD36 expression in muscle, despite the fact that PPARα activation increases FAT/CD36 by 80% in liver. A novel observation is that FAT/CD36 also appears to be involved in mitochondrial FA oxidation, as this protein is located on the mitochondrial membrane and seems to be required to participate in moving FA across the mitochondrial membrane. Clearly, FAT/CD36 has an important role in FA homeostasis in skeletal muscle and the heart.

scholarly journals Glucose metabolism in perfused skeletal muscle. Demonstration of insulin resistance in the obese Zucker rat

1979 ◽  
Vol 178 (3) ◽  
pp. 733-741 ◽  
Author(s):  
F W Kemmer ◽  
M Berger ◽  
L Herberg ◽  
F A Gries ◽  
A Wirdeier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Muscle Cell ◽  
Inhibitory Effect ◽  
Zucker Rats ◽  
Control Group ◽  
Lactate Oxidation ◽  
Obese Zucker Rats

1. The effect of insulin (0.5, 10 and 50 munits/ml of perfusate) on glucose uptake and disposal in skeletal muscle was studied in the isolated perfused hindquarter of obese (fa/fa) and lean (Fa/Fa) Zucker rats and Osborne-Mendel rats. 2. A concentration of 0.5 munit of insulin/ml induced a significant increase in glucose uptake (approx. 2.5 mumol/min per 30 g of muscle) in lean Zucker rats and in Osborne-Mendel rats, and 10 munits of insulin/ml caused a further increase to approx. 6 mumol/min per 30 g of muscle; but 50 munits of insulin/ml had no additional stimulatory effect. In contrast, in obese Zucker rats only 10 and 50 munits of insulin/ml had a stimulatory effect on glucose uptake, the magnitude of which was decreased by 50-70% when compared with either lean control group. Since under no experimental condition tested was an accumulation of free glucose in muscle-cell water observed, the data suggest an impairment of insulin-stimulated glucose transport across the muscle-cell membrane in obese Zucker rats. 3. The intracellular disposal of glucose in skeletal muscle of obese Zucker rats was also insulin-insensitive: even at insulin concentrations that clearly stimulated glucose uptake, no effect of insulin on lactate oxidation (nor an inhibitory effect on alanine release) was observed; [14C]glucose incorporation into skeletal-muscle lipids was stimulated by 50 munits of insulin/ml, but the rate was still only 10% of that observed in lean Zucker rats. 4. The data indicate that the skeletal muscle of obese Zucker rats is insulin-resistant with respect to both glucose-transport mechanisms and intracellular pathways of glucose metabolism, such as lactate oxidation. The excessive degree of insulin-insensitivity in skeletal muscle of obese Zucker rats may represent a causal factor in the development of the glucose intolerance in this species.

Chronic selective glycogen synthase kinase-3 inhibition enhances glucose disposal and muscle insulin action in prediabetic obese Zucker rats

2006 ◽  
Vol 291 (2) ◽  
pp. E207-E213 ◽  
Author(s):  
Betsy B. Dokken ◽  
Erik J. Henriksen
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Transport ◽  
Glycogen Synthase ◽  
Whole Body ◽  
Zucker Rats ◽  
Oral Glucose ◽  
Insulin Resistant ◽  
Obese Zucker Rats

Increasing evidence supports a negative role of glycogen synthase kinase-3 (GSK-3) in regulation of skeletal muscle glucose transport. We assessed the effects of chronic treatment of insulin-resistant, prediabetic obese Zucker ( fa/ fa) rats with a highly selective GSK-3 inhibitor (CT118637) on glucose tolerance, whole body insulin sensitivity, plasma lipids, skeletal muscle insulin signaling, and in vitro skeletal muscle glucose transport activity. Obese Zucker rats were treated with either vehicle or CT118637 (30 mg/kg body wt) twice per day for 10 days. Fasting plasma insulin and free fatty acid levels were reduced by 14 and 23% ( P < 0.05), respectively, in GSK-3 inhibitor-treated animals compared with vehicle-treated controls. The glucose response during an oral glucose tolerance test was reduced by 18% ( P < 0.05), and whole body insulin sensitivity was increased by 28% ( P < 0.05). In vivo insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (50%) and IRS-1-associated phosphatidylinositol-3′ kinase (79%) relative to fasting plasma insulin levels were significantly elevated ( P < 0.05) in plantaris muscles of GSK-3 inhibitor-treated animals. Whereas basal glucose transport in isolated soleus and epitrochlearis muscles was unaffected by chronic GSK-3 treatments, insulin stimulation of glucose transport above basal was significantly enhanced (32–60%, P < 0.05). In summary, chronic treatment of insulin-resistant, prediabetic obese Zucker rats with a specific GSK-3 inhibitor enhances oral glucose tolerance and whole body insulin sensitivity and is associated with an amelioration of dyslipidemia and an improvement in IRS-1-dependent insulin signaling in skeletal muscle. These results provide further evidence that selective targeting of GSK-3 in muscle may be an effective intervention for the treatment of obesity-associated insulin resistance.

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