Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Cardiovasc Diabetol ; 22(1): 17, 2023 01 27.
Article in English | MEDLINE | ID: mdl-36707786

ABSTRACT

BACKGROUND: Type 2 Diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and associated with poor outcome after myocardial infarction (MI). In T2DM, cardiac metabolic flexibility, i.e. the switch between carbohydrates and lipids as energy source, is disturbed. The RabGTPase-activating protein TBC1D4 represents a crucial regulator of insulin-stimulated glucose uptake in skeletal muscle by controlling glucose transporter GLUT4 translocation. A human loss-of-function mutation in TBC1D4 is associated with impaired glycemic control and elevated T2DM risk. The study's aim was to investigate TBC1D4 function in cardiac substrate metabolism and adaptation to MI. METHODS: Cardiac glucose metabolism of male Tbc1d4-deficient (D4KO) and wild type (WT) mice was characterized using in vivo [18F]-FDG PET imaging after glucose injection and ex vivo basal/insulin-stimulated [3H]-2-deoxyglucose uptake in left ventricular (LV) papillary muscle. Mice were subjected to cardiac ischemia/reperfusion (I/R). Heart structure and function were analyzed until 3 weeks post-MI using echocardiography, morphometric and ultrastructural analysis of heart sections, complemented by whole heart transcriptome and protein measurements. RESULTS: Tbc1d4-knockout abolished insulin-stimulated glucose uptake in ex vivo LV papillary muscle and in vivo cardiac glucose uptake after glucose injection, accompanied by a marked reduction of GLUT4. Basal cardiac glucose uptake and GLUT1 abundance were not changed compared to WT controls. D4KO mice showed mild impairments in glycemia but normal cardiac function. However, after I/R D4KO mice showed progressively increased LV endsystolic volume and substantially increased infarction area compared to WT controls. Cardiac transcriptome analysis revealed upregulation of the unfolded protein response via ATF4/eIF2α in D4KO mice at baseline. Transmission electron microscopy revealed largely increased extracellular matrix (ECM) area, in line with decreased cardiac expression of matrix metalloproteinases of D4KO mice. CONCLUSIONS: TBC1D4 is essential for insulin-stimulated cardiac glucose uptake and metabolic flexibility. Tbc1d4-deficiency results in elevated cardiac endoplasmic reticulum (ER)-stress response, increased deposition of ECM and aggravated cardiac damage following MI. Hence, impaired TBC1D4 signaling contributes to poor outcome after MI.


Subject(s)
Diabetes Mellitus, Type 2 , Myocardial Infarction , Male , Mice , Humans , Animals , GTPase-Activating Proteins/genetics , GTPase-Activating Proteins/metabolism , Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Insulin/pharmacology , Muscle, Skeletal/metabolism , Myocardial Infarction/metabolism , Reperfusion , Glucose Transporter Type 4/genetics , Glucose Transporter Type 4/metabolism
2.
Mol Metab ; 6(11): 1443-1453, 2017 11.
Article in English | MEDLINE | ID: mdl-29107291

ABSTRACT

OBJECTIVE: Ribosomal protein S6 Kinase-1 (S6K1) has been linked to resistance exercise-mediated improvements in glycemia. We hypothesized that S6K1 may also play a role in regulating glycemic control in response to endurance exercise training. METHODS: S6k1-knockout (S6K1KO) and WT mice on a 60 cal% high-fat diet were trained for 4 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. RESULTS: WT mice showed improved glucose tolerance after training. In contrast, S6K1KO mice displayed equally high glucose tolerance already in the sedentary state with no further improvement after training. Similarly, training decreased mitochondrial ROS production in skeletal muscle of WT mice, whereas ROS levels were already low in the sedentary S6K1KO mice with no further decrease after training. Nevertheless, trained S6K1KO mice displayed an increased running capacity compared to trained WT mice, as well as substantially reduced triglyceride contents in liver and skeletal muscle. The improvements in glucose handling and running endurance in S6K1KO mice were associated with markedly increased ketogenesis and a higher respiratory exchange ratio. CONCLUSIONS: In high-fat fed mice, loss of S6K1 mimics endurance exercise training by reducing mitochondrial ROS production and upregulating oxidative utilization of ketone bodies. Pharmacological targeting of S6K1 may improve the outcome of exercise-based interventions in obesity and diabetes.


Subject(s)
Glucose/metabolism , Muscle, Skeletal/physiology , Oxidative Stress/physiology , Physical Endurance/physiology , Ribosomal Protein S6 Kinases, 90-kDa/deficiency , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Animals , Blood Glucose/metabolism , Diet, High-Fat , Dietary Fats/metabolism , Endurance Training , Exercise Tolerance/physiology , Glucose Tolerance Test , Insulin/metabolism , Insulin Resistance/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Skeletal/enzymology , Muscle, Skeletal/metabolism , Obesity/metabolism , Oxidation-Reduction , Oxidative Stress/genetics , Ribosomal Protein S6 Kinases, 90-kDa/genetics , Running
3.
Int J Obes (Lond) ; 40(8): 1242-9, 2016 08.
Article in English | MEDLINE | ID: mdl-27089993

ABSTRACT

BACKGROUND: Variants in the gene TBC1D1 have been previously associated with obesity-related traits in several species, including humans, mice, rabbits and chicken. While in humans variants in TBC1D1 were linked to obesity, disruption of the Tbc1d1 gene reduced body weight in mice. TBC1D1 has been identified as a regulator of insulin-dependent glucose transport in skeletal muscle, however, its role in energy homeostasis in the obese state remains unclear. The impact of TBC1D1 deficiency on energy homeostasis, glucose and lipid metabolism in an established mouse model of obesity was examined. METHODS: Obese leptin (ob/ob)- and Tbc1d1-double-deficient mice (D1KO-ob/ob) were generated by crossing obese B6.V.Lep(ob/ob)-mice with lean Tbc1d1-deficient mice on a C57BL/6J background. Male mice on either standard (SD) or high-fat diet (HFD) were analyzed for body weight, body composition, food intake, voluntary physical activity and energy expenditure by indirect calorimetry. Glucose and insulin tolerance as well as glucose transport and fatty acid oxidation in skeletal muscle were analyzed. RESULTS: In obese mice, Tbc1d1 deficiency resulted in reduced body weight on both SD and HFD. However, food intake was unchanged on SD or even increased in HFD-fed Tbc1d1-deficient mice without alterations in voluntary physical activity. Despite substantially reduced insulin-stimulated glucose transport and increased fatty acid oxidation in intact isolated skeletal muscle, obese Tbc1d1-deficient mice showed no gross changes in glycemia and glucose tolerance compared with obese controls. Indirect calorimetry revealed that obese Tbc1d1-deficient mice had a decreased respiratory quotient together with increased daily energy expenditure. CONCLUSIONS: In obese leptin-deficient mice, lack of TBC1D1 has no impact on feeding behavior or energy intake but results in increased energy expenditure, altered energy substrate preference with increased fatty acid oxidation and suppression of obesity. TBC1D1 may have an evolutionary conserved role in regulating energy homeostasis in vertebrates.


Subject(s)
Energy Metabolism , GTPase-Activating Proteins/deficiency , Gene Deletion , Leptin/deficiency , Obesity/genetics , Obesity/prevention & control , Animals , Biological Transport , Calorimetry, Indirect , Diet, High-Fat , Disease Models, Animal , Fatty Acids/metabolism , GTPase-Activating Proteins/genetics , Glucose/metabolism , Homeostasis , Insulin/metabolism , Insulin Resistance , Lipid Metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Mice, Obese , Muscle, Skeletal/metabolism
4.
Am J Physiol Endocrinol Metab ; 304(5): E495-506, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23277187

ABSTRACT

Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) mitochondria increases lifespan considerably in high-fat diet-fed UCP1 Tg mice compared with wild types (WT). To clarify the underlying mechanisms, we investigated substrate metabolism as well as oxidative stress damage and antioxidant defense in SM of low-fat- and high-fat-fed mice. Tg mice showed an increased protein expression of phosphorylated AMP-activated protein kinase, markers of lipid turnover (p-ACC, FAT/CD36), and an increased SM ex vivo fatty acid oxidation. Surprisingly, UCP1 Tg mice showed elevated lipid peroxidative protein modifications with no changes in glycoxidation or direct protein oxidation. This was paralleled by an induction of catalase and superoxide dismutase activity, an increased redox signaling (MAPK signaling pathway), and increased expression of stress-protective heat shock protein 25. We conclude that increased skeletal muscle mitochondrial uncoupling in vivo does not reduce the oxidative stress status in the muscle cell. Moreover, it increases lipid metabolism and reactive lipid-derived carbonyls. This stress induction in turn increases the endogenous antioxidant defense system and redox signaling. Altogether, our data argue for an adaptive role of reactive species as essential signaling molecules for health and longevity.


Subject(s)
Antioxidants/metabolism , Longevity/physiology , Muscle, Skeletal/metabolism , Muscle, Skeletal/physiology , Aconitate Hydratase/metabolism , Animals , Biomarkers , Body Composition/drug effects , Body Composition/genetics , Body Composition/physiology , Catalase/blood , Dietary Fats/adverse effects , Fatty Acids/metabolism , Insulin Resistance/physiology , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mitogen-Activated Protein Kinases/metabolism , Muscle Proteins/biosynthesis , Muscle Proteins/genetics , Oxidation-Reduction , Oxidative Stress/drug effects , Oxidative Stress/physiology , Real-Time Polymerase Chain Reaction , Superoxide Dismutase/metabolism , Triglycerides/blood
5.
Diabetes Obes Metab ; 14 Suppl 3: 57-67, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22928565

ABSTRACT

ß-Cell dysfunction is a critical component in the development of type 2 diabetes. Whilst both genetic and environmental factors contribute to the development of the disease, relatively little is known about the molecular network that is responsible for diet-induced functional changes in pancreatic ß-cells. Recent genome-wide association studies for diabetes-related traits have generated a large number of candidate genes that constitute possible links between dietary factors and the genetic susceptibility for ß-cell failure. Here, we summarize recent approaches for identifying nutritionally regulated transcripts in islets on a genome-wide scale. Polygenic mouse models for type 2 diabetes have been instrumental for investigating the mechanism of diet-induced ß-cell dysfunction. Enhanced oxidative metabolism, triggered by a combination of dietary carbohydrates and fat, appears to play a critical role in the pathophysiology of diet-induced impairment of islets. More systematic studies of gene-diet interactions in ß-cells of rodent models in combination with genetic profiling might reveal the regulatory circuits fundamental for the understanding of diet-induced impairments of ß-cell function in humans.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Diet , Insulin-Secreting Cells/metabolism , Insulin/metabolism , Polymorphism, Single Nucleotide , Animals , Diabetes Mellitus, Type 2/diet therapy , Diabetes Mellitus, Type 2/genetics , Epigenesis, Genetic , Gene Expression Profiling , Genetic Predisposition to Disease , Genome-Wide Association Study , Glucose Tolerance Test , Humans , Insulin/genetics , Mice , Mice, Inbred C57BL , Mice, Obese , Multifactorial Inheritance
SELECTION OF CITATIONS
SEARCH DETAIL
...