Exercise stimulates the release of proteins with autocrine, paracrine, or endocrine functions produced in skeletal muscle, termed myokines. Based on the current state of knowledge, the major physiological function of myokines is to protect the functionality and to enhance the exercise capacity of skeletal muscle. Myokines control adaptive processes in skeletal muscle by acting as paracrine regulators of fuel oxidation, hypertrophy, angiogenesis, inflammatory processes, and regulation of the extracellular matrix. Endocrine functions attributed to myokines are involved in body weight regulation, low-grade inflammation, insulin sensitivity, suppression of tumor growth, and improvement of cognitive function. Muscle-derived regulatory RNAs and metabolites, as well as the design of modified myokines, are promising novel directions for treatment of chronic diseases.

Immortal hepatocyte cell lines are widely used to elucidate insulin-dependent signalling pathways and regulation of hepatic metabolism, although the often tumorigenic origin might not represent the metabolic state of healthy hepatocytes. We aimed to investigate if murine cell line AML12 and human cell line THLE-2, which are derived from healthy liver cells, are comparable to hepatoma cell line HepG2 for studying acute insulin signalling and expression of gluconeogenic enzymes and hepatokines. Insulin responsiveness of AML12 and THLE-2 cells was impaired when cells were cultured in the recommended growth medium, but comparable with HepG2 cells by using insulin-deficient medium. THLE-2 cells showed low abundance of insulin receptor, while protein levels in HepG2 and AML12 were comparable. AML12 and THLE-2 cells showed only low or non-detectable transcript levels of G6PC and PCK1 . Expression of ANGPTL4 was regulated similarly in HepG2 and AML12 cells upon peroxisome proliferator-activated receptor δ activation but only HepG2 cells resemble the in vivo regulation of hepatic ANGPTL4 by cAMP. Composition of the culture medium and protein expression levels of key signalling proteins should be considered when AML12 and THLE-2 are used to study insulin signalling. With regard to gluconeogenesis and hepatokine expression, HepG2 cells appear to be closer to the in vivo situation despite the tumorigenic origin.

BACKGROUND: Insulin resistance of the brain can unfavorably affect long-term weight maintenance and body fat distribution. Little is known if and how brain insulin sensitivity can be restored in humans. We aimed to evaluate the effects of an exercise intervention on insulin sensitivity of the brain and how this relates to exercise-induced changes in whole-body metabolism and behavior. METHODS: In this clinical trial, sedentary participants who were overweight and obese underwent an 8-week supervised aerobic training intervention. Brain insulin sensitivity was assessed in 21 participants (14 women, 7 men; age range 21–59 years; BMI range 27.5–45.5 kg/m ² ) using functional MRI, combined with intranasal administration of insulin, before and after the intervention. RESULTS: The exercise program resulted in enhanced brain insulin action to the level of a person of healthy weight, demonstrated by increased insulin-induced striatal activity and strengthened hippocampal functional connectivity. Improved brain insulin action correlated with increased mitochondrial respiration in skeletal muscle, reductions in visceral fat and hunger, as well as improved cognition. Mediation analyses suggest that improved brain insulin responsiveness helps mediate the peripheral exercise effects leading to healthier body fat distribution and reduced perception of hunger. CONCLUSION: Our study demonstrates that an 8-week exercise intervention in sedentary individuals can restore insulin action in the brain. Hence, the ameliorating benefits of exercise toward brain insulin resistance may provide an objective therapeutic target in humans in the challenge to reduce diabetes risk factors. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03151590). FUNDING: BMBF/DZD 01GI0925.

A substantial number of people at risk of developing type 2 diabetes could not improve insulin sensitivity by physical training intervention. We studied the mechanisms of this impaired exercise response in 20 middle-aged individuals at high risk of developing type 2 diabetes who performed 8 weeks of controlled cycling and walking training at 80% individual Vo2 peak. Participants identified as nonresponders in insulin sensitivity (based on the Matsuda index) did not differ in preintervention parameters compared with high responders. The failure to increase insulin sensitivity after training correlates with impaired upregulation of mitochondrial fuel oxidation genes in skeletal muscle, and with the suppression of the upstream regulators PGC1α and AMPKα2. The muscle transcriptomes of the nonresponders are further characterized by the activation of transforming growth factor (TGF)-β and TGF-β target genes, which is associated with increases in inflammatory and macrophage markers. TGF-β1 as inhibitor of mitochondrial regulators and insulin signaling is validated in human skeletal muscle cells. Activated TGF-β1 signaling downregulates the abundance of PGC1α, AMPKα2, the mitochondrial transcription factor TFAM, and mitochondrial enzymes. Thus, the data suggest that increased TGF-β activity in skeletal muscle can attenuate the improvement of mitochondrial fuel oxidation after training and contribute to the failure to increase insulin sensitivity.