Exercise does not improve insulin resistance and mitochondrial characteristics together

2021 ◽  
Author(s):  
Amanda J Genders ◽  
Jujiao Kuang ◽  
Evelyn C Marin ◽  
Nicholas J Saner ◽  
Javier Botella ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Exercise Training ◽  
Protein Expression ◽  
Respiratory Function ◽  
Citrate Synthase ◽  
Whole Body ◽  
Chow Diet ◽  
Mitochondrial Content ◽  
Insulin Tolerance ◽  
Mitochondrial Respiratory

The aim of this study was to investigate the relationship between mitochondrial content and respiratory function and whole-body insulin resistance in high fat diet (HFD) fed rats. Male Wistar rats were given either a chow diet or a HFD for 12 weeks. After four weeks of the dietary intervention, half of the rats in each group began eight weeks of interval training. In vivo glucose and insulin tolerance were assessed. Mitochondrial respiratory function was assessed in permeabilised soleus and white gastrocnemius (WG) muscles. Mitochondrial content was determined by measurement of citrate synthase (CS) activity and protein expression of components of the electron transport system (ETS). We found HFD rats had impaired glucose and insulin tolerance but increased mitochondrial respiratory function and increased protein expression of components of the ETS. This was accompanied by an increase in CS activity in WG. Exercise training improved glucose and insulin tolerance in the HFD rats. Mitochondrial respiratory function was increased with exercise training in the chow fed animals in soleus muscle. This exercise effect was absent in the HFD animals. In conclusion, exercise training improved insulin resistance in HFD rats, but without changes in mitochondrial respiratory function and content. The lack of an association between mitochondrial characteristics and whole-body insulin resistance was reinforced by the absence of strong correlations between these measures. Our results suggest that improvements in mitochondrial respiratory function and content are not responsible for improvements of whole-body insulin resistance in HFD rats.

scholarly journals Changes in insulin resistance do not occur in parallel with changes in mitochondrial content and function in male rats

2020 ◽  
Author(s):  
Amanda J Genders ◽  
Jujiao Kuang ◽  
Evelyn C Marin ◽  
Nicholas J Saner ◽  
Javier Botella ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Exercise Training ◽  
Mitochondrial Respiration ◽  
High Fat Diet ◽  
Respiratory Function ◽  
High Fat ◽  
Mitochondrial Content ◽  
Insulin Tolerance ◽  
And Function ◽  
Mitochondrial Respiratory

AbstractAims/hypothesisTo investigate if there is a causal relationship between changes in insulin resistance and mitochondrial respiratory function and content in rats fed a high fat diet (HFD) with or without concurrent exercise training. We hypothesised that provision of a high fat diet (HFD) would increase insulin resistance and decrease mitochondrial characteristics (content and function), and that exercise training would improve both mitochondrial characteristics and insulin resistance in rats fed a HFD.MethodsMale Wistar rats were given either a chow diet or a high fat diet (HFD) for 12 weeks. After 4 weeks of the dietary intervention, half of the rats in each group began eight weeks of interval training. In vivo glucose and insulin tolerance was assessed, as was ex vivo glucose uptake in epitrochlearis muscle. Mitochondrial respiratory function was assessed in permeabilised soleus and white gastrocnemius (WG) muscles. Mitochondrial content was determined by measurement of citrate synthase (CS) activity and protein expression of components of the electron transport system (ETS).ResultsHFD rats had impaired glucose and insulin tolerance. HFD did not change CS activity in the soleus; however, it did increase CS activity in WG (Chow 5.9 ± 0.5, HFD 7.2 ± 0.7 mol h-1 kg protein-1). Protein expression of components of the ETS and mitochondrial respiratory function (WG Chow 65.2 ± 8.4, HFD 88.6 ± 8.7 pmol O2 s-1 mg-1) were also increased by HFD. Exercise training improved glucose and insulin tolerance in the HFD rats. Exercise training did not alter CS activity in either muscle. Mitochondrial respiratory function was increased with exercise training in the chow fed animals in soleus muscle, but not in WG. This exercise effect was absent in the HFD animals. Mitochondrial characteristics did not consistently correlate with insulin or glucose tolerance.Conclusions/interpretationHFD induced insulin resistance, but it did not negatively affect any of the measured mitochondrial characteristics. Exercise training improved insulin resistance, but without changes in mitochondrial respiration and content. The lack of an association between mitochondrial characteristics and insulin resistance was reinforced by the absence of strong correlations between these measures. Our results suggest that defects in mitochondrial respiration and content are not responsible for insulin resistance in HFD rats.

scholarly journals Exercise training improves vascular mitochondrial function

2016 ◽  
Vol 310 (7) ◽  
pp. H821-H829 ◽  
Author(s):  
Song-Young Park ◽  
Matthew J. Rossman ◽  
Jayson R. Gifford ◽  
Leena P. Bharath ◽  
Johann Bauersachs ◽  
...  
Keyword(s):  
Exercise Training ◽  
Vascular Function ◽  
Respiratory Function ◽  
Complex I ◽  
Citrate Synthase ◽  
Reactive Oxygen Species Generation ◽  
Redox Balance ◽  
Respiratory Capacity ◽  
The Impact ◽  
Mitochondrial Respiratory

Exercise training is recognized to improve cardiac and skeletal muscle mitochondrial respiratory capacity; however, the impact of chronic exercise on vascular mitochondrial respiratory function is unknown. We hypothesized that exercise training concomitantly increases both vascular mitochondrial respiratory capacity and vascular function. Arteries from both sedentary (SED) and swim-trained (EX, 5 wk) mice were compared in terms of mitochondrial respiratory function, mitochondrial content, markers of mitochondrial biogenesis, redox balance, nitric oxide (NO) signaling, and vessel function. Mitochondrial complex I and complex I + II state 3 respiration and the respiratory control ratio (complex I + II state 3 respiration/complex I state 2 respiration) were greater in vessels from EX relative to SED mice, despite similar levels of arterial citrate synthase activity and mitochondrial DNA content. Furthermore, compared with the SED mice, arteries from EX mice displayed elevated transcript levels of peroxisome proliferative activated receptor-γ coactivator-1α and the downstream targets cytochrome c oxidase subunit IV isoform 1, isocitrate dehydrogenase ( Idh) 2, and Idh3a, increased manganese superoxide dismutase protein expression, increased endothelial NO synthase phosphorylation (Ser1177), and suppressed reactive oxygen species generation (all P < 0.05). Although there were no differences in EX and SED mice concerning endothelium-dependent and endothelium-independent vasorelaxation, phenylephrine-induced vasocontraction was blunted in vessels from EX compared with SED mice, and this effect was normalized by NOS inhibition. These training-induced increases in vascular mitochondrial respiratory capacity and evidence of improved redox balance, which may, at least in part, be attributable to elevated NO bioavailability, have the potential to protect against age- and disease-related challenges to arterial function.

scholarly journals FABP4-Cre Mediated Expression of Constitutively Active ChREBP Protects Against Obesity, Fatty Liver, and Insulin Resistance

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4020-4032 ◽  
Author(s):  
Alli M. Nuotio-Antar ◽  
Naravat Poungvarin ◽  
Ming Li ◽  
Michael Schupp ◽  
Mahmoud Mohammad ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Fatty Liver ◽  
Binding Protein ◽  
Western Diet ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Chow Diet ◽  
Fatty Acid Binding ◽  
Constitutively Active

Carbohydrate response element binding protein (ChREBP) regulates cellular glucose and lipid homeostasis. Although ChREBP is highly expressed in many key metabolic tissues, the role of ChREBP in most of those tissues and the consequent effects on whole-body glucose and lipid metabolism are not well understood. Therefore, we generated a transgenic mouse that overexpresses a constitutively active ChREBP isoform under the control of the fatty acid binding protein 4-Cre-driven promoter (FaChOX). Weight gain was blunted in male, but not female, FaChOX mice when placed on either a normal chow diet or an obesogenic Western diet. Respiratory exchange ratios were increased in Western diet-fed FaChOX mice, indicating a shift in whole-body substrate use favoring carbohydrate metabolism. Western diet-fed FaChOX mice showed improved insulin sensitivity and glucose tolerance in comparison with controls. Hepatic triglyceride content was reduced in Western diet-fed FaChOX mice in comparison with controls, suggesting protection from fatty liver. Epididymal adipose tissue exhibited differential expression of genes involved in differentiation, browning, metabolism, lipid homeostasis, and inflammation between Western diet-fed FaChOX mice and controls. Our findings support a role for ChREBP in modulating adipocyte differentiation and adipose tissue metabolism and inflammation as well as consequent risks for obesity and insulin resistance.

scholarly journals ADAR1 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice

2020 ◽  
Author(s):  
Xiaobing Cui ◽  
Jia Fei ◽  
Sisi Chen ◽  
Gaylen L. Edwards ◽  
Shi-You Chen
Keyword(s):  
Insulin Resistance ◽  
Food Intake ◽  
High Fat Diet ◽  
Peptide Yy ◽  
Tolerance Test ◽  
Chow Diet ◽  
High Fat ◽  
Blood Biochemical ◽  
Insulin Tolerance ◽  
Normal Chow

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases, and many other chronic diseases. The objective of this study was to determine the role of adenosine deaminase acting on RNA 1 (ADAR1) in the development of obesity and insulin resistance. Wild-type (WT) and heterozygous ADAR1-deficient (Adar1+/-) mice were fed normal chow or high-fat diet (HFD) for 12 weeks. Adar1+/- mice fed with HFD exhibited a lean phenotype with reduced fat mass compared with WT controls, although no difference was found under chow diet conditions. Blood biochemical analysis and insulin tolerance test showed that Adar1+/- improved HFD-induced dyslipidemia and insulin resistance. Metabolic studies showed that food intake was decreased in Adar1+/- mice compared with the WT mice under HFD conditions. Paired feeding studies further demonstrated that Adar1+/- protected mice from HFD-induced obesity through decreased food intake. Furthermore, Adar1+/- restored the increased ghrelin expression in stomach and the decreased serum peptide YY levels under HFD conditions. These data indicate that ADAR1 may contribute to diet-induce obesity, at least partially, through modulating the ghrelin and peptide YY expression and secretion.

PGC-1α mediates exercise-induced skeletal muscle VEGF expression in mice

2009 ◽  
Vol 297 (1) ◽  
pp. E92-E103 ◽  
Author(s):  
Lotte Leick ◽  
Ylva Hellsten ◽  
Joachim Fentz ◽  
Stine S. Lyngby ◽  
Jørgen F. P. Wojtaszewski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Protein Expression ◽  
Protein Content ◽  
Acute Exercise ◽  
Whole Body ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Exercise Induced ◽  
Vegf Protein

The aim of the present study was to test the hypothesis that PGC-1α is required for exercise-induced VEGF expression in both young and old mice and that AMPK activation leads to increased VEGF expression through a PGC-1α-dependent mechanism. Whole body PGC-1α knockout (KO) and littermate wild-type (WT) mice were submitted to either 1) 5 wk of exercise training, 2) lifelong (from 2 to 13 mo of age) exercise training in activity wheel, 3) a single exercise bout, or 4) 4 wk of daily subcutaneous AICAR or saline injections. In skeletal muscle of PGC-1α KO mice, VEGF protein expression was ∼60–80% lower and the capillary-to-fiber ratio ∼20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1α KO mice, but acute exercise and AICAR treatment increased the VEGF mRNA content in WT mice only. Exercise training of young mice increased skeletal muscle VEGF protein expression ∼50% in WT mice but with no effect in PGC-1α KO mice. Furthermore, a training-induced prevention of an age-associated decline in VEGF protein content was observed in WT but not in PGC-1α KO muscles. In addition, repeated AICAR treatments increased skeletal muscle VEGF protein expression ∼15% in WT but not in PGC-1α KO mice. This study shows that PGC-1α is essential for exercise-induced upregulation of skeletal muscle VEGF expression and for a training-induced prevention of an age-associated decline in VEGF protein content. Furthermore, the findings suggest an AMPK-mediated regulation of VEGF expression through PGC-1α.

scholarly journals Exercise Training Improves Whole Body Insulin Resistance via Adiponectin Receptor 1

2016 ◽  
Vol 37 (01) ◽  
pp. e5-e5
Author(s):  
J.-K. Cho ◽  
S.-U. Kim ◽  
H.-R. Hong ◽  
J.-H. Yoon ◽  
H.-S. Kang
Keyword(s):  
Insulin Resistance ◽  
Exercise Training ◽  
Adiponectin Receptor ◽  
Whole Body ◽  
Adiponectin Receptor 1

scholarly journals SUN-LB52 The Protective Effects of Hepatocyte GH Receptor (GHR) Signaling Against Steatosis and Liver Injury Is Sexually Dimorphic and Autonomous of IGF1

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Andre Sarmento-Cabral ◽  
Mercedes del Rio-Moreno ◽  
Mari C Vazquez-Borrego ◽  
Mariyah Mahmood ◽  
Elena Gutierrez-Casado ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Injury ◽  
Fatty Liver ◽  
Negative Feedback ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Whole Body ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Systemic Insulin Resistance

Abstract GH dysregulation contributes to the development of non-alcoholic fatty liver disease (NAFLD), however debate remains as to the relative contribution of the direct vs indirect effects of GH, via IGF1. Mouse models with congenital, liver-specific knockout of the GHR, JAK2 or STAT5, as adults exhibit steatosis, glucose intolerance, insulin resistance and white adipose tissue (WAT) lipolysis. It is believed that fatty liver is due to the dramatic reduction in circulating IGF1 altering systemic metabolism, due to loss of the insulin-like effects of IGF1 and the loss of IGF1 negative feedback to the pituitary leading to a rise in GH that promotes systemic insulin resistance and WAT lipolysis shifting the flux of fatty acids to the liver. In addition, low IGF1/high GH alters the development of other metabolically relevant tissues, which could indirectly contribute to the liver phenotype observed with congenital loss of hepatic GH signaling. To directly test the actions of GH on adult hepatocyte function, we developed a mouse model of adult-onset, hepatocyte-specific knockdown of the GHR (aHepGHRkd; 12 week-old, GHRfl/fl mice treated with AAV8-TBGp-Cre). aHepGHRkd enhanced hepatic de novo lipogenesis (DNL), rapidly leading to steatosis in males, but not females. In males, enhanced DNL and steatosis was sustained with age and associated with hepatocyte ballooning, inflammation and mild fibrosis. These changes occurred independent of severe systemic insulin resistance and WAT lipolysis, although the aHepGHRkd mice exhibit low IGF1/high GH similar to that of congenital models. To directly test the role of hepatocyte GHR signaling, independent of changes in IGF1, aHepGHRkd mice were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes (AAV8-TBGp-rIGF1). Mice were fed standard chow diet and tissues collected 8m post-AAV. IGF1 replacement elevated plasma IGF1 in aHepGHRkd mice, resulting in a reduction in plasma GH and pituitary expression of Gh, Ghrhr and Ghsr, indicating negative feedback of IGF1 was restored. In male aHepGHRkd mice, IGF1 replacement reduced insulin and whole body lipid utilization and increased WAT, however it did not reduce steatosis or alter hepatic fatty acid composition indicative of DNL and had minimal effects on liver injury markers. RNAseq analysis of liver extracts showed IGF1 replacement also had no major impact on the differentially expressed genes observed after aHepGHRkd. These results demonstrate that steatosis, DNL and liver injury observed in male aHepGHRkd mice are autonomous of IGF1. Despite the fact that hepatic GHR protein levels were not detectable in both female and male aHepGHRkd mice, females maintained moderate levels of IGF1 and were protected from steatosis. The mechanism by which female mice are protected remains to be elucidated, however is consistent with clinical data indicating pre-menopausal women are resistance to NAFLD.

scholarly journals A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition

2017 ◽  
Vol 312 (6) ◽  
pp. G666-G680 ◽  
Author(s):  
Anuradha Krishnan ◽  
Tasduq Sheikh Abdullah ◽  
Taofic Mounajjed ◽  
Stella Hartono ◽  
Andrea McConico ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Rate ◽  
Nonalcoholic Steatohepatitis ◽  
Lipid Composition ◽  
Fast Food ◽  
Citrate Synthase ◽  
Whole Body ◽  
Hepatic Inflammation ◽  
Histological Features ◽  
Hepatic Lipid

The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13–276 pmol·s−1·ml−1 per unit citrate synthase) than SC mice (17–394 pmol·s−1·ml−1 per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of NASH. NEW & NOTEWORTHY This study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include 1) hepatic lipid composition changes in a multiphasic fashion as NASH evolves; 2) insulin resistance precedes hepatic inflammation and fibrosis, answering a longstanding chicken-and-egg question regarding the relationship of insulin resistance to liver histology in NASH; and 3) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent.

scholarly journals Angiotensin receptor-mediated oxidative stress is associated with impaired cardiac redox signaling and mitochondrial function in insulin-resistant rats

2013 ◽  
Vol 305 (4) ◽  
pp. H599-H607 ◽  
Author(s):  
José Pablo Vázquez-Medina ◽  
Irina Popovich ◽  
Max A. Thorwald ◽  
Jose A. Viscarra ◽  
Ruben Rodriguez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Protein Expression ◽  
Mitochondrial Function ◽  
Citrate Synthase ◽  
Cellular Metabolism ◽  
Redox Signaling ◽  
Angiotensin Receptor ◽  
Long Evans

Activation of angiotensin receptor type 1 (AT1) contributes to NADPH oxidase (Nox)-derived oxidative stress during metabolic syndrome. However, the specific role of AT1 in modulating redox signaling, mitochondrial function, and oxidative stress in the heart remains more elusive. To test the hypothesis that AT1 activation increases oxidative stress while impairing redox signaling and mitochondrial function in the heart during diet-induced insulin resistance in obese animals, Otsuka Long Evans Tokushima Fatty (OLETF) rats ( n = 8/group) were treated with the AT1 blocker (ARB) olmesartan for 6 wk. Cardiac Nox2 protein expression increased 40% in OLETF compared with age-matched, lean, strain-control Long Evans Tokushima Otsuka (LETO) rats, while mRNA and protein expression of the H2O2-producing Nox4 increased 40–100%. ARB treatment prevented the increase in Nox2 without altering Nox4. ARB treatment also normalized the increased levels of protein and lipid oxidation (nitrotyrosine, 4-hydroxynonenal) and increased the redox-sensitive transcription factor Nrf2 by 30% and the activity of antioxidant enzymes (SOD, catalase, GPx) by 50–70%. Citrate synthase (CS) and succinate dehydrogenase (SDH) activities decreased 60–70%, whereas cardiac succinate levels decreased 35% in OLETF compared with LETO, suggesting that mitochondrial function in the heart is impaired during obesity-induced insulin resistance. ARB treatment normalized CS and SDH activities, as well as succinate levels, while increasing AMPK and normalizing Akt, suggesting that AT1 activation also impairs cellular metabolism in the diabetic heart. These data suggest that the cardiovascular complications associated with metabolic syndrome may result from AT1 receptor-mediated Nox2 activation leading to impaired redox signaling, mitochondrial activity, and dysregulation of cellular metabolism in the heart.

scholarly journals Are Alterations in Skeletal Muscle Mitochondria a Cause or Consequence of Insulin Resistance?

2020 ◽  
Vol 21 (18) ◽  
pp. 6948 ◽  
Author(s):  
Amanda J. Genders ◽  
Graham P. Holloway ◽  
David J. Bishop
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Substrate Oxidation ◽  
Whole Body ◽  
Mitochondrial Content ◽  
Major Site ◽  
Conflicting Information ◽  
Skeletal Muscle Insulin Resistance ◽  
Skeletal Muscle Mitochondria

As a major site of glucose uptake following a meal, skeletal muscle has an important role in whole-body glucose metabolism. Evidence in humans and animal models of insulin resistance and type 2 diabetes suggests that alterations in mitochondrial characteristics accompany the development of skeletal muscle insulin resistance. However, it is unclear whether changes in mitochondrial content, respiratory function, or substrate oxidation are central to the development of insulin resistance or occur in response to insulin resistance. Thus, this review will aim to evaluate the apparent conflicting information placing mitochondria as a key organelle in the development of insulin resistance in skeletal muscle.

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