• diacylglycerol kinase
• glucose tolerance
• muscle development
• muscle regeneration
• satellite cell
• type II diabetes

• combined training, cold
• muscle
• positron emission computed tomography
• type 2 diabetes

• Humans
• Diabetes Mellitus, Type 2/physiopathology
• Diabetes Mellitus, Type 2/therapy
• Male
• Middle Aged
• Muscle, Skeletal/metabolism
• Muscle, Skeletal/physiopathology
• Thermogenesis
• Positron Emission Tomography Computed Tomography
• Fluorodeoxyglucose F18/administration & dosage
• Female
• Overweight/physiopathology
• Overweight/therapy
• Overweight/metabolism
• Resistance Training/methods
• Treatment Outcome
• Energy Metabolism
• Radiopharmaceuticals/administration & dosage
• Time Factors
• Adult
• Exercise Therapy/methods
• Aged

• 303571/2018-7 Conselho Nacional de Desenvolvimento Científico e Tecnológico
• 001 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
• 2016/08751-3 Fundação de Amparo à Pesquisa do Estado de São Paulo

• Exercise
• Glucose metabolism
• Lipid metabolism
• Lipid species
• Obesity

• Animals
• Diacylglycerol Kinase/metabolism
• Diacylglycerol Kinase/genetics
• Obesity/metabolism
• Obesity/genetics
• Mice
• Mice, Transgenic
• Diet, High-Fat/adverse effects
• Male
• Glucose/metabolism
• Physical Conditioning, Animal/physiology
• Muscle, Skeletal/metabolism
• Humans
• Glucose Intolerance/metabolism
• Glucose Intolerance/genetics
• Glucose Intolerance/prevention & control
• Mice, Inbred C57BL
• Insulin Resistance/genetics

• diacylglycerol kinase
• myotube
• myristic acid
• type II diabetes
• β-tubulin

Recent literature shows that exercise is not simply a way to generate a calorie deficit as an add-on to restrictive diets but exerts powerful additional biological effects via its impact on mitochondrial function, the release of chemical messengers induced by muscular activity, and its ability to reverse epigenetic alterations. This review aims to summarize the current literature dealing with the hypothesis that some of these effects of exercise unexplained by an energy deficit are related to the balance of substrates used as fuel by the exercising muscle. This balance of substrates can be measured with reliable techniques, which provide information about metabolic disturbances associated with sedentarity and obesity, as well as adaptations of fuel metabolism in trained individuals. The exercise intensity that elicits maximal oxidation of lipids, termed LIPOXmax, FATOXmax, or FATmax, provides a marker of the mitochondrial ability to oxidize fatty acids and predicts how much fat will be oxidized over 45–60 min of low- to moderate-intensity training performed at the corresponding intensity. LIPOXmax is a reproducible parameter that can be modified by many physiological and lifestyle influences (exercise, diet, gender, age, hormones such as catecholamines, and the growth hormone-Insulin-like growth factor I axis). Individuals told to select an exercise intensity to maintain for 45 min or more spontaneously select a level close to this intensity. There is increasing evidence that training targeted at this level is efficient for reducing fat mass, sparing muscle mass, increasing the ability to oxidize lipids during exercise, lowering blood pressure and low-grade inflammation, improving insulin secretion and insulin sensitivity, reducing blood glucose and HbA_1c in type 2 diabetes, and decreasing the circulating cholesterol level. Training protocols based on this concept are easy to implement and accept in very sedentary patients and have shown an unexpected efficacy over the long term. They also represent a useful add-on to bariatric surgery in order to maintain and improve its weight-lowering effect. Additional studies are required to confirm and more precisely analyze the determinants of LIPOXmax and the long-term effects of training at this level on body composition, metabolism, and health.

• BVRA
• HO-1
• PPARα
• bilirubin
• biliverdin reductase
• inflammation
• metabolic disease
• nitrate
• nutraceuticals
• vitamin D
• vitamin E

• ERRγ
• PPARδ
• aged mice
• skeletal muscle function
• γ-Oryzanol

• Aging
• Animals
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria, Muscle
• Muscle Strength
• Muscle, Skeletal/drug effects
• Muscle, Skeletal/physiology
• Organelle Biogenesis
• PPAR delta/metabolism
• Phenylpropionates/pharmacology
• Physical Conditioning, Animal
• Physical Endurance
• Receptors, Estrogen/metabolism
• ERRalpha Estrogen-Related Receptor

• Citrate synthase
• Cytochrome c oxidase
• Mitochondrial dysfunction
• PGC1α
• Tfam
• Type 2 Diabetes

• endurance exercise
• high-density lipoprotein (HDL)
• lipid metabolism
• lipoprotein
• low-density lipoprotein (LDL)
• plasma fatty acids

This study examines how the high-fat diet (HFD) affects mitochondrial dynamics and biogenesis, and also whether combining it with low-intensity endurance exercise adds to these effects. Six 8-week-old male Sprague–Dawley (SD) rats were put on control (CON; standard chow diet), HF (HFD intake), and HFEx (HFD + low-intensity treadmill exercise) for 6 weeks. As a result, no change in body weight was observed among the groups. However, epididymal fat mass increased significantly in the two groups that had been given HFD. Blood free fatty acid (FFA) also increased significantly in the HF group. While HFD increased insulin resistance (IR), this was improved significantly in the HFEx group. HFD also significantly increased mitochondrial biogenesis-related factors (PPARδ, PGC-1α, and mtTFA) and mitochondrial electron transport chain proteins; however, no additional effect from exercise was observed. Mitochondrial dynamic-related factors were also affected: Mfn2 increased significantly in the HFEx group, while Drp1 and Fis-1 increased significantly in both the HF and HFEx groups. The number of mitochondria in the subsarcolemmal region, and their size in the subsarcolemmal and intermyofibrillar regions, also increased significantly in the HFEx group. Taken overall, these results show that HFD in combination with low-intensity endurance exercise has no additive effect on mitochondrial biogenesis, although it does have such an effect on mitochondrial dynamics by improving IR.

• exercise
• high-fat diet
• mitochondrial biogenesis
• mitochondrial dynamics
• mitochondrial function

Accumulating evidence mainly from observational studies supports the notion that lifestyle factors such as regular physical activity can modulate potential risk factors of dementia. Regarding a potential mechanism for this interaction, results from intervention studies show that exercising can induce neuroplastic changes in the human brain. However, a detailed look at the study results reveals a wide interindividual variability in the observed effects. This heterogeneity may originate from the fact that there are “responders” and “non-responders” with respect to the impact of physical exercise on physiological outcome parameters (i.e., VO₂ peak) and the brain. From this, it follows that recommendations for physical exercise programs should not follow a “one size fits all” approach. Instead, we propose that the exercises should be tailored to an individual in order to maximize the potential neuroplastic and preventive effects of regular exercise. These adaptations should take the individual performance levels into account and impact both the quality (i.e., type) and the quantity of exercises (i.e., intensity, duration, and volume).

• dementia
• exercise
• neuroplasticity
• personalized medicine
• responder

• diabetes mellitus
• mitochondria dysfunction

• Adipose Tissue/metabolism
• Brain/metabolism
• DNA, Mitochondrial
• Diabetes Mellitus, Type 2/metabolism
• Endothelium, Vascular/metabolism
• Epigenesis, Genetic
• Exercise
• Humans
• Insulin-Secreting Cells/metabolism
• Liver/metabolism
• Mitochondria/metabolism
• Mitochondria, Heart/metabolism
• Mitochondria, Liver/metabolism
• Mitochondria, Muscle/metabolism
• Muscle, Skeletal/metabolism
• Myocardium/metabolism
• Peripheral Nervous System/metabolism
• Transcriptome

• R01 HL128485 NHLBI NIH HHS
• R56 HL128485 NHLBI NIH HHS

• Cyclin D1
• Diacylglycerol kinase
• Myogenic differentiation
• Protein kinase C
• Skeletal muscle

• differentially expressed genes
• gluconeogenesis
• systematic analysis
• type II diabetes

Diabetes mellitus is one of the most common metabolic diseases spread all over the world, which results in hyperglycemia caused by the breakdown of insulin secretion or insulin action or both. Diabetes has been reported to disrupt the functions and dynamics of mitochondria, which play a fundamental role in regulating metabolic pathways and are crucial to maintain appropriate energy balance. Similar to mitochondria, the functions and the abilities of stem cells are attenuated under diabetic condition in several tissues. In recent years, several studies have suggested that the regulation of mitochondria functions and dynamics is critical for the precise differentiation of stem cells. Importantly, physical exercise is very useful for preventing the diabetic alteration by improving the functions of both mitochondria and stem cells. In the present review, we provide an overview of the diabetic alterations of mitochondria and stem cells and the preventive effects of physical exercise on diabetes, focused on skeletal muscle and the nervous system. We propose physical exercise as a countermeasure for the dysfunction of mitochondria and stem cells in several target tissues under diabetes complication and to improve the physiological function of patients with diabetes, resulting in their quality of life being maintained.

• diabetes
• exercise
• mitochondria
• neural stem cells
• satellite cells

• insulin resistance
• metabolic syndrome
• uncoupling protein

• Case-Control Studies
• Cohort Studies
• Female
• Homeostasis/physiology
• Humans
• Insulin/blood
• Insulin Resistance/physiology
• Logistic Models
• Male
• Metabolic Syndrome/blood
• Metabolic Syndrome/epidemiology
• Metabolic Syndrome/physiopathology
• Middle Aged
• Mitochondrial Uncoupling Proteins/blood
• Prevalence
• Propensity Score
• Taiwan/epidemiology

• Dairy fat
• Diabetes
• Diacylglycerol kinase
• Hyperglycaemia
• Myristic acid

• Animals
• Blood Glucose/analysis
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/drug therapy
• Diacylglycerol Kinase/metabolism
• Hyperglycemia/blood
• Hyperglycemia/drug therapy
• Hypoglycemic Agents/pharmacology
• Hypoglycemic Agents/therapeutic use
• Male
• Mice
• Myristic Acid/pharmacology
• Myristic Acid/therapeutic use
• Treatment Outcome

• Exercise
• Fibre type
• Obesity
• Skeletal muscle

This study examined the association between objectively measured physical activity patterns and risk factors of metabolic syndrome (MetS) in Saudi men.

The study was cross-sectional, and 84 healthy men from the Saudi population (age 37.6 ± 8.8 years, body mass index [BMI] 28.4 ± 5.4 kg/m²) were recruited. Measurements of physical activity were made using triaxial accelerometers over 7 consecutive days of leisure time physical activity. Waist circumference and blood pressure were measured, and fasting blood samples taken to measure glucose, high density lipoprotein cholesterol (HDL), and triglycerides (TG).

A total 21.4 % of participants had three or more risk factors for MetS, with low HDL levels the most frequent factor. Light physical activity (LPA) and BMI explained 13 % of the variation in TG. Moderate to vigorous physical activity (MVPA) with a minimum 10-min per session (10-min MVPA), LPA, and BMI explained 16 % of the variation in HDL. Sedentary behavior was not significantly associated with risk factors of MetS, although odds ratios indicated that decreased sedentarism does have a protective effect against MetS.

LPA and 10-min MVPA were associated with elevated HDL levels among Saudi men. Future studies should confirm whether time spent physically active independent of intensity is an important factor in improving HDL levels.

• C2C12
• antioxidant
• exercise
• mice
• stress kinases

Exercise can increase peroxisome proliferator-activated receptor-δ (PPARδ) expression in skeletal muscle. PPARδ regulates muscle metabolism and reprograms muscle fibre types to enhance running endurance. This study utilized metabolomic profiling to examine the effects of GW501516, a PPARδ agonist, on running endurance in mice. While training alone increased the exhaustive running performance, GW501516 treatment enhanced running endurance and the proportion of succinate dehydrogenase (SDH)-positive muscle fibres in both trained and untrained mice. Furthermore, increased levels of intermediate metabolites and key enzymes in fatty acid oxidation pathways were observed following training and/or treatment. Training alone increased serum inositol, glucogenic amino acids, and branch chain amino acids. However, GW501516 increased serum galactose and β-hydroxybutyrate, independent of training. Additionally, GW501516 alone raised serum unsaturated fatty acid levels, especially polyunsaturated fatty acids, but levels increased even more when combined with training. These findings suggest that mechanisms behind enhanced running capacity are not identical for GW501516 and training. Training increases energy availability by promoting catabolism of proteins, and gluconeogenesis, whereas GW501516 enhances specific consumption of fatty acids and reducing glucose utilization.

• PPARδ
• heart failure
• metabolism
• skeletal muscle

• HUVECs
• PPARβ
• insulin signalling
• reactive oxygen species

• endurance
• exercise
• insulin-like growth factor
• myostatin
• nuclear receptors
• resistance
• skeletal muscle

Type 2 diabetes is characterized by a decreased ability of insulin to facilitate glucose uptake into insulin sensitive tissue, i.e., skeletal muscle. The mechanism behind this is at the moment unresolved. It has been suggested that increased amount of lipids inside the skeletal muscle (intramuscular triglyceride, diacylglycerol and ceramides) will impair insulin action in skeletal muscle, but data are not consistent in the human literature. It has also been hypothesized that the impaired insulin sensitivity is due to a dysfunction in the mitochondria resulting in an impaired ability to oxidize lipids, but the majority of the literature is not supporting this hypothesis. Recently it has been suggested that the production of reactive oxygen species play an essential role in skeletal muscle insulin sensitivity. It is well accepted that physical activity (endurance, strength and high intensity training) improves insulin sensitivity in healthy humans and in patients with type 2 diabetes. Whether patients with type 2 diabetes have the same beneficial effects (same improvement) as control subjects, when it comes to regular physical activity in regard to mitochondrial function, is not established in the literature. This review will focus only on the effect of physical activity on skeletal muscle (mitochondrial function) in patients with type 2 diabetes.

• Mitochondria
• Exercise
• Type 2 diabetes

• Cholesterol/biosynthesis
• Fatty Acids/biosynthesis
• Fatty Acids/metabolism
• Glucose/metabolism
• Humans
• Insulin/blood
• Middle Aged
• Mitochondria/drug effects
• Mitochondria/metabolism
• Muscle Fibers, Skeletal/cytology
• Muscle Fibers, Skeletal/drug effects
• Muscle Fibers, Skeletal/metabolism
• Oleic Acid/metabolism
• Oxidation-Reduction/drug effects
• PPAR delta/agonists
• PPAR delta/metabolism
• Substrate Specificity
• Thiazoles/pharmacology
• Transcriptome/drug effects

• HIV
• exercise
• insulin resistance
• left ventricular dysfunction
• metabolic syndrome

Performing exercise in a glycogen depleted state increases skeletal muscle lipid utilization and the transcription of genes regulating mitochondrial β-oxidation. Potential candidates for glycogen-mediated metabolic adaptation are the peroxisome proliferator activated receptor (PPAR) coactivator-1α (PGC-1α) and the transcription factor/nuclear receptor PPAR-∂. It was therefore the aim of the present study to examine whether acute exercise with or without glycogen manipulation affects PGC-1α and PPAR-∂ function in rodent skeletal muscle. Twenty female Wistar rats were randomly assigned to 5 experimental groups (n = 4): control [CON]; normal glycogen control [NG-C]; normal glycogen exercise [NG-E]; low glycogen control [LG-C]; and low glycogen exercise [LG-E]). Gastrocnemius (GTN) muscles were collected immediately following exercise and analyzed for glycogen content, PPAR-∂ activity via chromatin immunoprecipitation (ChIP) assays, AMPK α1/α2 kinase activity, and the localization of AMPK and PGC-1α. Exercise reduced muscle glycogen by 47 and 75% relative to CON in the NG-E and LG-E groups, respectively. Exercise that started with low glycogen (LG-E) finished with higher AMPK-α2 activity (147%, p<0.05), nuclear AMPK-α2 and PGC-1α, but no difference in AMPK-α1 activity compared to CON. In addition, PPAR-∂ binding to the CPT1 promoter was significantly increased only in the LG-E group. Finally, cell reporter studies in contracting C2C12 myotubes indicated that PPAR-∂ activity following contraction is sensitive to glucose availability, providing mechanistic insight into the association between PPAR-∂ and glycogen content/substrate availability. The present study is the first to examine PPAR-∂ activity in skeletal muscle in response to an acute bout of endurance exercise. Our data would suggest that a factor associated with muscle contraction and/or glycogen depletion activates PPAR-∂ and initiates AMPK translocation in skeletal muscle in response to exercise.

• AMP-Activated Protein Kinases/metabolism
• Animals
• Cell Line
• Enzyme Activation
• Female
• Glucose/metabolism
• Glycogen/metabolism
• Muscle, Skeletal/metabolism
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Peroxisome Proliferator-Activated Receptors/metabolism
• Physical Conditioning, Animal
• Rats
• Transcription Factors/metabolism

• 097726 Wellcome Trust

• Exercise
• Mitochondria
• Obesity
• Physical activity
• Skeletal muscle
• Weight loss

• Aging/genetics
• Aging/metabolism
• Diabetes Mellitus, Type 1/genetics
• Diabetes Mellitus, Type 1/metabolism
• Diabetes Mellitus, Type 2/genetics
• Diabetes Mellitus, Type 2/metabolism
• Exercise
• Humans
• Insulin Resistance/physiology
• Mitochondria, Muscle/genetics
• Mitochondria, Muscle/metabolism
• Muscle, Skeletal/metabolism
• Obesity/genetics
• Obesity/metabolism
• Weight Loss

• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters/blood
• Adenylate Kinase/blood
• Adenylate Kinase/metabolism
• Biopsy
• Blotting, Western
• CD36 Antigens/blood
• Cholesterol/blood
• Cohort Studies
• Energy Metabolism/physiology
• Exercise/physiology
• Female
• Heat-Shock Proteins/blood
• Humans
• Lipids/blood
• Lipoprotein Lipase/blood
• Lipoproteins/blood
• Male
• Middle Aged
• Muscle, Skeletal/enzymology
• Muscle, Skeletal/metabolism
• Obesity/blood
• Obesity/enzymology
• Obesity/metabolism
• PPAR alpha/blood
• PPAR delta/metabolism
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Proton-Translocating ATPases/blood
• Receptors, LDL/blood
• Statistics, Nonparametric
• Transcription Factors/blood

• Adaptation, Physiological/physiology
• Animals
• Exercise/physiology
• Glycogen/metabolism
• Glycogen/physiology
• Humans
• Muscle, Skeletal/physiology
• Physical Conditioning, Animal
• Proteome
• Signal Transduction/physiology

• Aged
• Blood Glucose/genetics
• Blood Glucose/metabolism
• China
• Diabetes Mellitus, Type 2/genetics
• Female
• Genetic Association Studies
• Glycated Hemoglobin/genetics
• Humans
• Insulin/blood
• Male
• Middle Aged
• PPAR delta/genetics
• Polymorphism, Single Nucleotide
• Vitamin D/genetics
• Vitamin D/metabolism

The nuclear receptor, NR1C2 or peroxisome proliferator-activated receptor (PPAR)-δ, is ubiquitously expressed and important for placental development, fatty acid metabolism, wound healing, inflammation, and tumour development. PPARδ has been hypothesized to function as both a ligand activated transcription factor and a repressor of transcription in the absence of agonist. In this paper, treatment of mice conditionally expressing human PPARδ with GW501516 resulted in a marked loss in body weight that was not evident in nontransgenic animals or animals expressing a dominant negative derivative of PPARδ. Expression of either functional or dominant negative hPPARδ blocked bezafibrate-induced PPARα-dependent hepatomegaly and blocked the effect of bezafibrate on the transcription of PPARα target genes. These data demonstrate, for the first time, that PPARδ could inhibit the activation of PPARα in vivo and provide novel models for the investigation of the role of PPARδ in pathophysiology.

• Diabetes Mellitus, Type 2/etiology
• Diabetes Mellitus, Type 2/metabolism
• Exercise
• Exercise Therapy/methods
• Humans
• Insulin Resistance/physiology
• Muscle, Skeletal/metabolism
• Obesity/complications
• Obesity/metabolism
• Obesity/therapy
• Oxidation-Reduction

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that act as lipid sensors and adapt the metabolic rates of various tissues to the concentration of dietary lipids. PPARs are pharmacological targets for the treatment of metabolic disorders. PPARα and PPARγ are activated by hypolipidemic and insulin-sensitizer compounds, such as fibrates and thiazolidinediones. The roles of PPARβ/δ in metabolic regulations remained unclear until recently. Treatment of obese monkeys and rodents by specific PPARβ/δ agonists promoted normalization of metabolic parameters and reduction of adiposity. Recent evidences strongly suggested that some of these beneficial actions are related to activation of fatty acid catabolism in skeletal muscle and also that PPARβ/δ is involved in the adaptive responses of skeletal muscle to environmental changes, such as long-term fasting or physical exercise, by controlling the number of oxidative myofibers. These observations indicated that PPARβ/δ agonists might have therapeutic usefulness in metabolic syndrome by increasing fatty acid consumption in skeletal muscle and reducing obesity.

During pregnancy crucial anatomic, physiologic, and metabolic changes challenge the mother and the fetus. The placenta is a remarkable organ that allows the mother and the fetus to adapt to the new metabolic, immunologic, and angiogenic environment imposed by gestation. One of the physiologic systems that appears to have evolved to sustain this metabolic regulation is mediated by peroxisome proliferator-activated receptors (PPARs). In clinical pregnancy-specific disorders, including preeclampsia, gestational diabetes, and intrauterine growth restriction, aberrant regulation of components of the PPAR system parallels dysregulation of metabolism, inflammation and angiogenesis. This review summarizes current knowledge on the role of PPARs in regulating human trophoblast invasion, early placental development, and also in the physiology of clinical pregnancy and its complications. As increasingly indicated in the literature, pregnancy disorders, such as preeclampsia and gestational diabetes, represent potential targets for treatment with PPAR ligands. With the advent of more specific PPAR agonists that exhibit efficacy in ameliorating metabolic, inflammatory, and angiogenic disturbances, further studies of their application in pregnancy-related diseases are warranted.