Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance

Dagdeviren, Sezin; Jung, Dae Young; Lee, Eunjung; Friedline, Randall H.; Noh, Hye Lim; Kim, Jong Hun; Patel, Payal R.; Tsitsilianos, Nicholas; Tsitsilianos, Andrew V.; Tran, Duy A.; Tsougranis, George H.; Kearns, Caitlyn C.; Uong, Cecilia P.; Kwon, Jung Yeon; Müller, Werner; Lee, Ki Won; Kim, Jason K.

doi:10.1128/mcb.00181-16

Cited by 60 publications

(45 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On the other hand, in support of our findings, others found no effect of acute exercise on plasma IL-10 levels in patients with T2D (Korb et al, 2018). Since this myokine has been shown to have a positive effect on skeletal muscle metabolism (Hong et al, 2009;Dagdeviren et al, 2016), perhaps its mechanism of action in response to exercise is autocrine and unrelated to circulating concentrations. This hypothesis would support our findings, as well as those of others, regarding the lack of response to an acute bout of exercise in circulating IL-10.…”

Section: Il-10supporting

confidence: 87%

Plasma Myokine Concentrations After Acute Exercise in Non-obese and Obese Sedentary Women

et al. 2020

View full text Add to dashboard Cite

Exercise and physical activity levels influence myokine release from skeletal muscle and contribute to circulating concentrations. Indeed, many myokines, including interleukin (IL)-6, IL-15, secreted protein acidic rich in cysteine (SPARC), and fibroblast growth factor (FGF) 21 are higher in the circulation after an exercise bout. Since these peptides modulate muscle metabolism and can also be targeted toward other tissues to induce adaptations to energy demand, they are of great interest regarding metabolic diseases. Therefore, we set out to compare, in six women with obesity (BMI ≥30 kg/m 2 ) and five healthy women (BMI 22-29.9 kg/m 2 ), the effect of an acute bout of moderate-intensity, continuous cycling exercise (60 min, 60% VO 2 peak) on the release of myokines (IL-6, IL-8, IL-10, IL-13, IL-15, SPARC, and FGF21) in plasma for a 24-h time course. We found that plasma IL-8 and SPARC levels were reduced in the group of women with obesity, whereas plasma IL-13 concentrations were elevated in comparison to nonobese women both before and after the exercise bout. We also found that plasma FGF21 concentration during the 24 h following the bout of exercise was regulated differently in the non-obese in comparison to obese women. Plasma concentrations of FGF21, IL-6, IL-8, IL-15, and IL-18 were regulated by acute exercise. Our results confirm the results of others concerning exercise regulation of circulating myokines while providing insight into the time course of myokine release in circulation after an acute exercise bout and the differences in circulating myokines after exercise in women with or without obesity.

show abstract

Section: Il-10supporting

confidence: 87%

Plasma Myokine Concentrations After Acute Exercise in Non-obese and Obese Sedentary Women

et al. 2020

View full text Add to dashboard Cite

show abstract

“…These results are consistent with previous findings that alternatively activated M2polarized macrophages confer protection against dietinduced insulin resistance (3,(10)(11)(12). Moreover, the current results are also consistent with our previous findings that transgenic mice with muscle-specific overexpression of IL-10 were protected from obesitymediated insulin resistance in skeletal muscle (19). Thus, the anti-inflammatory effects of GRP78-deficient macrophages in skeletal muscle may be responsible for the muscle-specific improvement in insulin sensitivity in HFD-fed Lyz-GRP78 2/2 mice.…”

Section: Discussionsupporting

confidence: 94%

“…Protein lysates from BMDM and skeletal muscle (gastrocnemius) samples were prepared for Western blot analysis (19). After blotting, proteins on the membrane were detected with primary Abs against GRP94 (1:1000; Cell Signaling Technology, Danvers, MA, USA), ATF‐6A (1:1000; Santa Cruz Biotechnology, Dallas, TX, USA), ATF‐4 (1:1000; Santa Cruz Biotechnology), phospho‐Akt (Ser 473 ; 1:1000; Cell Signaling Technology), Akt (1:1000; Cell Signaling Technology), GLUT4 (1:1000; Cell Signaling Technology), phospho‐insulin receptor substrate (IRS)‐1 (Tyr 608 ; 1:1000; EMD Millipore, Billerica, MA, USA), and IRS‐1 (1:125; EMD Millipore).…”

Section: Methodsmentioning

confidence: 99%

Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet‐induced obesity

et al. 2018

Self Cite

View full text Add to dashboard Cite

Obesity-mediated inflammation is a major cause of insulin resistance, and macrophages play an important role in this process. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum chaperone that modulates unfolded protein response (UPR), and mice with GRP78 heterozygosity were resistant to diet-induced obesity. Here, we show that mice with macrophage-selective ablation of GRP78 (Lyz- GRP78) are protected from skeletal muscle insulin resistance without changes in obesity compared with wild-type mice after 9 wk of high-fat diet. GRP78-deficient macrophages demonstrated adapted UPR with up-regulation of activating transcription factor (ATF)-4 and M2-polarization markers. Diet-induced adipose tissue inflammation was reduced, and bone marrow-derived macrophages from Lyz- GRP78 mice demonstrated a selective increase in IL-6 expression. Serum IL-13 levels were elevated by >4-fold in Lyz- GRP78 mice, and IL-6 stimulated the myocyte expression of IL-13 and IL-13 receptor. Lastly, recombinant IL-13 acutely increased glucose metabolism in Lyz- GRP78 mice. Taken together, our data indicate that GRP78 deficiency activates UPR by increasing ATF-4, and promotes M2-polarization of macrophages with a selective increase in IL-6 secretion. Macrophage-derived IL-6 stimulates the myocyte expression of IL-13 and regulates muscle glucose metabolism in a paracrine manner. Thus, our findings identify a novel crosstalk between macrophages and skeletal muscle in the modulation of obesity-mediated insulin resistance.-Kim, J. H., Lee, E., Friedline, R. H., Suk, S., Jung, D. Y., Dagdeviren, S., Hu, X., Inashima, K., Noh, H. L., Kwon, J. Y., Nambu, A., Huh, J. R., Han, M. S., Davis, R. J., Lee, A. S., Lee, K. W., Kim, J. K. Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity.

show abstract

“…In healthy adults, there is a significant positive association between circulating IL‐10 levels and whole‐body insulin sensitivity (Straczkowski, Kowalska, Nikolajuk, Krukowska, & Gorska, ), and low IL‐10 production capacity is associated with high plasma glucose, high HbA 1c levels, type 2 diabetes, and dyslipidaemia (van Exel et al, ). Genetic alterations in IL‐10 (IL‐10KO), IL‐10 receptor KO (IL‐10RKO), and IL‐10 transgenic (IL‐10Tg) mice have been generated (Cintra et al, ; Dagdeviren et al, ; Hong et al, ; Kowalski et al, ) along with studies by which IL‐10 is administered as a treatment regime (Kim et al, ). Many, but not all, of these models have identified a protective role of IL‐10 against metabolic disease; however, from our analysis, we cannot identify any study involving IL‐10 modulation that has been conducted in female mice, and therefore, the question remains as to whether or not it is of importance in female metabolic processes.…”

Section: Sex Differences In Anti‐inflammatory‐related Mediatorsmentioning

confidence: 99%

Metabolic control and sex: A focus on inflammatory‐linked mediators

Henstridge

Abildgaard

Lindegaard

et al. 2019

British J Pharmacology

View full text Add to dashboard Cite

Men and women have many differing biological and physiological characteristics.Thus, it is no surprise that the control of metabolic processes and the mechanisms underlying metabolic-related diseases have sex-specific components. There is a clear metabolic sexual dimorphism in that up until midlife, men have a far greater likelihood of acquiring cardio-metabolic disease than women. Following menopause, however, this difference is reduced, suggestive of a protective role of the female sex hormones.Inflammatory processes have been implicated in the pathogenesis of cardio-metabolic disease with human studies correlating metabolic disease acquisition or risk with levels of various inflammatory markers. Rodent studies employing genetic modifications or novel pharmacological approaches have provided mechanistic insight into the role of these inflammatory mediators. Sex differences impact inflammatory processes and the subsequent biological response. As a consequence, this may affect how inflammation alters metabolic processes between the sexes. Recently, some of our work in the field of inflammatory genes and metabolic control identified a sexual dimorphism in a preclinical model and caused us to question the frequency and scale of such findings in the literature. This review concentrates on inflammatory-related signalling in relation to obesity, insulin resistance, and type 2 diabetes and highlights the differences observed between males and females. Differences in the activation and signalling of various inflammatory genes and proteins present another reason why studying both male and female patients or animals is important in the context of understanding and finding therapeutics for metabolic-related disease.

show abstract

Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance

Cited by 60 publications

References 42 publications

Plasma Myokine Concentrations After Acute Exercise in Non-obese and Obese Sedentary Women

Plasma Myokine Concentrations After Acute Exercise in Non-obese and Obese Sedentary Women

Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet‐induced obesity

Metabolic control and sex: A focus on inflammatory‐linked mediators

Contact Info

Product

Resources

About