Exercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M.

The discovery of exercise-regulated circulatory factors has fueled interest in organ crosstalk, especially between skeletal muscle and adipose tissue, and the role in mediating beneficial effects of exercise. We studied the adipose tissue transcriptome in men and women with normal glucose tolerance or type 2 diabetes following an acute exercise bout, revealing substantial exercise- and time-dependent changes, with sustained increase in inflammatory genes in type 2 diabetes. We identify oncostatin-M as one of the most upregulated adipose-tissue-secreted factors post-exercise.

Distinctive exercise-induced inflammatory response and exerkine induction in skeletal muscle of people with type 2 diabetes.

Mechanistic insights into the molecular events by which exercise enhances the skeletal muscle phenotype are lacking, particularly in the context of type 2 diabetes. Here, we unravel a fundamental role for exercise-responsive cytokines () on skeletal muscle development and growth in individuals with normal glucose tolerance or type 2 diabetes. Acute exercise triggered an inflammatory response in skeletal muscle, concomitant with an infiltration of immune cells.

Exercise timing influences multi-tissue metabolome and skeletal muscle proteome profiles in type 2 diabetic patients - A randomized crossover trial.

Aims/hypothesis: Metabolic effects of exercise may partly depend on the time-of-day when exercise is performed. We tested the hypothesis that exercise timing affects the adaptations in multi-tissue metabolome and skeletal muscle proteome profiles in men with type 2 diabetes.

Methods: Men fitting the inclusion (type 2 diabetes, age 45-68 years and body mass index 23-33 kg/m) and exclusion criteria (insulin treatment, smoking, concurrent systemic disease, and regular exercise training) were included in a randomized crossover trial (n = 15).

Afternoon exercise is more efficacious than morning exercise at improving blood glucose levels in individuals with type 2 diabetes: a randomised crossover trial.

Aims/hypothesis: Exercise is recommended for the treatment and prevention of type 2 diabetes. However, the most effective time of day to achieve beneficial effects on health remains unknown. We aimed to determine whether exercise training at two distinct times of day would have differing effects on 24 h blood glucose levels in men with type 2 diabetes.

IL6 and LIF mRNA expression in skeletal muscle is regulated by AMPK and the transcription factors NFYC, ZBTB14, and SP1.

Adenosine monophosphate-activated protein kinase (AMPK) controls glucose and lipid metabolism and modulates inflammatory responses to maintain metabolic and inflammatory homeostasis during low cellular energy levels. The AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) interferes with inflammatory pathways in skeletal muscle, but the mechanisms are undefined. We hypothesized that AMPK activation reduces cytokine mRNA levels by blocking transcription through one or several transcription factors.

FAK tyrosine phosphorylation is regulated by AMPK and controls metabolism in human skeletal muscle.

Aims/hypothesis: Insulin-mediated signals and AMP-activated protein kinase (AMPK)-mediated signals are activated in response to physiological conditions that represent energy abundance and shortage, respectively. Focal adhesion kinase (FAK) is implicated in insulin signalling and cancer progression in various non-muscle cell types and plays a regulatory role during skeletal muscle differentiation. The role of FAK in skeletal muscle in relation to insulin stimulation or AMPK activation is unknown.

Direct effects of exercise on kynurenine metabolism in people with normal glucose tolerance or type 2 diabetes.

Background: Systemic kynurenine levels are associated with resistance to stress-induced depression and are modulated by exercise. Tryptophan is a precursor for serotonin and kynurenine synthesis. Kynurenine is transformed into the neuroprotective catabolite kynurenic acid by kynurenine aminotransferases (KATs).

Looking Ahead Perspective: Where Will the Future of Exercise Biology Take Us?

The health-promoting benefits of exercise have been recognized for centuries, yet the molecular and cellular mechanisms for the acute and chronic adaptive response to a variety of physical activities remain incompletely described. This Perspective will take a forward view to highlight emerging questions and frontiers in the ever-changing landscape of exercise biology. The biology of exercise is complex, highly variable, and involves a myriad of adaptive responses in multiple organ systems.

Changes in gene expression in responders and nonresponders to a low-intensity walking intervention.

Objective: Daily physical activity remains an effective strategy to prevent obesity and type 2 diabetes. However, the metabolic response to exercise training is variable, and the precise clinical and molecular determinants that mark the metabolic improvements remain unknown. We tested the hypothesis that clinical improvements in glucose control after low-intensity exercise in individuals with impaired glucose tolerance (IGT) are coupled to alterations in skeletal muscle gene expression.

A new twist on brown fat metabolism.

The transcriptional coactivator PGC-1alpha promotes mitochondrial biogenesis and thermogenic programs in brown adipose tissue. Pan et al. (2009) identify the transcription factor twist-1 as a negative feedback regulator of PGC-1alpha.

Kinetics of GLUT4 trafficking in rat and human skeletal muscle.

Objective: In skeletal muscle, insulin stimulates glucose transport activity three- to fourfold, and a large part of this stimulation is associated with a net translocation of GLUT4 from an intracellular compartment to the cell surface. We examined the extent to which insulin or the AMP-activated protein kinase activator AICAR can lead to a stimulation of the exocytosis limb of the GLUT4 translocation pathway and thereby account for the net increase in glucose transport activity.

Research Design And Methods: Using a biotinylated photoaffinity label, we tagged endogenous GLUT4 and studied the kinetics of exocytosis of the tagged protein in rat and human skeletal muscle in response to insulin or AICAR.

Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance.

Type 2 (non-insulin-dependent) diabetes mellitus is a progressive metabolic disorder arising from genetic and environmental factors that impair beta cell function and insulin action in peripheral tissues. We identified reduced diacylglycerol kinase delta (DGKdelta) expression and DGK activity in skeletal muscle from type 2 diabetic patients. In diabetic animals, reduced DGKdelta protein and DGK kinase activity were restored upon correction of glycemia.

Insulin signaling and glucose transport in skeletal muscle from first-degree relatives of type 2 diabetic patients.

Aberrant insulin signaling and glucose metabolism in skeletal muscle from type 2 diabetic patients may arise from genetic defects and an altered metabolic milieu. We determined insulin action on signal transduction and glucose transport in isolated vastus lateralis skeletal muscle from normal glucose-tolerant first-degree relatives of type 2 diabetic patients (n = 8, 41 +/- 3 years, BMI 25.1 +/- 0.

Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6.

The primary gene mutated in Charcot-Marie-Tooth type 2A is mitofusin-2 (Mfn2). Mfn2 encodes a mitochondrial protein that participates in the maintenance of the mitochondrial network and that regulates mitochondrial metabolism and intracellular signaling. The potential for regulation of human Mfn2 gene expression in vivo is largely unknown.

Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects.

AS160 is a newly described substrate for the protein kinase Akt that links insulin signaling and GLUT4 trafficking. In this study, we determined the expression of and in vivo insulin action on AS160 in human skeletal muscle. In addition, we compared the effect of physiological hyperinsulinemia on AS160 phosphorylation in 10 lean-to-moderately obese type 2 diabetic and 9 healthy subjects.

Direct activation of glucose transport in primary human myotubes after activation of peroxisome proliferator-activated receptor delta.

Activators of peroxisome proliferator-activated receptor (PPAR)gamma have been studied intensively for their insulin-sensitizing properties and antidiabetic effects. Recently, a specific PPARdelta activator (GW501516) was reported to attenuate plasma glucose and insulin levels when administered to genetically obese ob/ob mice. This study was performed to determine whether specific activation of PPARdelta has direct effects on insulin action in skeletal muscle.

Sending the signal: molecular mechanisms regulating glucose uptake.

The molecular signaling mechanisms by which insulin leads to increased glucose transport and metabolism and gene expression are not completely elucidated. We have characterized the nature of insulin signaling defects in skeletal muscle from Type 2 diabetic patients. Insulin receptor substrate (IRS-1) phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and glucose transport activity are impaired as a consequence of functional defects, whereas insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase (MAPK) phosphorylation, and glycogen synthase activity are normal.

Insulin action on expression of novel adipose genes in healthy and type 2 diabetic subjects.

Objective: Adipose tissue secretes several molecules that may participate in metabolic cross-talk to other insulin-sensitive tissues. Thus, adipose tissue is a key endocrine organ that regulates insulin sensitivity in other peripheral insulin target tissues. We have studied the expression and acute insulin regulation of novel genes expressed in adipose tissue that are implicated in the control of whole body insulin sensitivity.

5-amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes.

AMP-activated protein kinase (AMPK) activation by AICAR (5-amino-imidazole carboxamide riboside) is correlated with increased glucose transport in rodent skeletal muscle via an insulin-independent pathway. We determined in vitro effects of insulin and/or AICAR exposure on glucose transport and cell-surface GLUT4 content in skeletal muscle from nondiabetic men and men with type 2 diabetes. AICAR increased glucose transport in a dose-dependent manner in healthy subjects.

Impaired insulin action on phosphatidylinositol 3-kinase activity and glucose transport in skeletal muscle of pancreatic cancer patients.

Introduction: Glucose intolerance or overt diabetes occurs in 80% of patients with pancreatic cancer (PC). This associated metabolic disorder includes peripheral insulin resistance, which may be caused by factors produced by the PC. The mechanism underlying PC-associated insulin resistance has not been clearly defined.

Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity.

In many cells and specially in muscle, mitochondria form elongated filaments or a branched reticulum. We show that Mfn2 (mitofusin 2), a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells, is induced during myogenesis and contributes to the maintenance and operation of the mitochondrial network. Repression of Mfn2 caused morphological and functional fragmentation of the mitochondrial network into independent clusters.

Reduction of risk factors following lifestyle modification programme in subjects with type 2 (non-insulin dependent) diabetes mellitus.

Exercise and improved diet is known to be beneficial in the management of type 2 (non-insulin dependent) diabetes mellitus. In practice, however, it is difficult for patients to implement these changes unaided. We hypothesized that a lifestyle modification programme involving residential visits would result in beneficial effects on glycaemic control and lipid profile.