Effects of myonectin on porcine intramuscular adipocyte differentiation and exogenous free fatty acid utilization.

As an important factor secreted by skeletal muscle, myonectin can regulate lipid metabolism and energy metabolism, but its role in the utilization of peripheral free fatty acids (FFAs) by porcine intramuscular fat cells remains to be further investigated. In this study, porcine intramuscular adipocytes were treated with recombinant myonectin and palmitic acid (PA), either alone or in combination, and then were examined for their uptake of exogenous FFAs, intracellular lipid synthesis and catabolism, and mitochondrial oxidation of fatty acids. The results showed that myonectin decreased the area of lipid droplets in intramuscular adipocytes (p < 0.05) and significantly increased (p < 0.05) the expression levels of hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL). Moreover, myonectin can up-regulate the expression of p38 mitogen-activated protein kinase (p38 MAPK). Myonectin significantly promoted the uptake of peripheral FFAs (p < 0.01), improved (p < 0.05) the expression of fatty transport protein 1 (FATP1) and fatty acid binding protein 4 (FABP4) in intramuscular adipocytes. Myonectin also significantly increased (p < 0.05) the expression levels of fatty acid oxidation markers: transcription factor (TFAM), uncoupling protein-2 (UCP2) and oxidative respiratory chain marker protein complex I (NADH-CoQ) in mitochondria of intramuscular adipocytes. In summary, myonectin promoted the absorption, transport, and oxidative metabolism of exogenous FFAs in mitochondria, thereby inhibiting lipid deposition in porcine intramuscular adipocytes.

Increased serum myonectin and irisin levels with myonectin and FNDC5 expressions in polycystic ovary syndrome: a case control study.

The aim of this study is to assess the FNDC5 and myonectin expressions and serum levels of myonectin and irisin in women with PCOS. 90 participants were included in this case-control study. 45 of these participants were with PCOS, and 45 of them were healthy volunteers matched for age and body mass index (BMI). Serum irisin and myonectin levels were measured with commercially available enzyme-linked immune sorbent assay (ELISA) kits. Expression of the myonectin and FNDC5 genes were determined by RT-PCR analysis. It was found out that FSI, HOMA-IR, LH, LH/FSH, TT, serum irisin and serum myonectin levels, myonectin mRNA expression, and FNDC5 mRNA expression were higher in the PCOS group, whereas HDL-C level was lower in the PCOS group (p < .05). When the groups were compared, it was detected that IR and HA were significantly higher in the PCOS group (p < .05). Serum irisin and myonectin levels, and myonectin and FNDC5 mRNA expressions were increased in women with PCOS. These molecules can be target molecules in PCOS pathophysiology and treatment.IMPACT STATEMENTWhat is already known on this subject? Although the aetiology of PCOS is not fully understood, it is thought that insulin resistance may play a critical role. In recent studies, the relationship of cytokines secreted from skeletal muscle with insulin resistance has been shown. The effects of irisin and myonectin, which are members of the myokine family, on lipid and glucose metabolism are known.What do the results of this study add? Although there are many studies in the literature regarding serum irisin levels in women with PCOS, their results are confusing. There is a study in the literature investigating the relationship between myonectin and PCOS. In our study, we evaluated myonectin and FNDC mRNA expressions in addition to serum irisin and myonectin levels. As a result, we found that markers and their mRNA expressions were lower in patients with PCOS compared to controls.What are the implications of these findings for clinical practice and/or further research? We think that the results of our study will shed light on future studies. Due to their effects on adipose tissue, these markers may play a role in the aetiology of long-term complications of PCOS. Moreover, they can become pharmacological targets in preventing these complications.

Comparative effects of high-intensity interval training and moderate-intensity continuous training on soleus muscle fibronectin type III domain-containing protein 5, myonectin and glucose transporter type 4 gene expressions: a study on the diabetic rat model.

BACKGROUND: The increase in fibronectin type-III domain-containing protein 5 (FNDC5), myonectin, and glucose transporter 4 (GLUT4) leads to a decrease in diabetes; meanwhile, exercise training can affect these factors. The result regarding the comparison between the effect of high-intensity interval training (HIIT) and that of moderate-intensity continuous training (MICT) is confusing. Thus, the present study investigated the comparative effects of HIIT and MICT on soleus muscle FNDC5, myonectin, and GLUT4 gene expressions in the diabetic rat model. METHODS AND RESULTS: Seventy-two male Wistar rats (weight 200 g ± 20) were randomly and equally assigned to six groups: control-healthy, MICT-healthy, HIIT-healthy, control-diabetes, MICT-diabetes, and HIIT-diabetes. At the first level, Streptozotocin (STZ) was utilized to induce diabetes in rats (at a dose of 55 mg/kg). After that, the training groups performed HIIT and MICT programs on the rodent treadmill for 6 weeks (five-session/week). Twenty-four hours after the last intervention, soleus muscle was removed, and sent to a research facility for future examinations. HIIT and MICT increased the muscle FNDC5, myonectin, and GLUT4 gene expression compared to the control group (P < 0.05). The type of training had no significant effect on the FNDC5 (P > 0.05), while the MICT program induced a greater increase in the myonec ztin and GLUT4 compared to the HIIT program (P < 0.05). Meanwhile, a positive relationship between all variables was observed. CONCLUSIONS: Exercise training has a beneficial effect on diabetes conditions via the effect of FNDC5, myonectin, and GLUT4. Due to the correlation between myonectin and GLUT4 shown in the present study, physical activity may alter myonectin through its effect on GLUT requiring further investigation by subsequent studies.

Association of decreased myonectin levels with metabolic and hormonal disturbance in polycystic ovary syndrome.

Myonectin is a myokine involving in glucose and lipid metabolisms. Polycystic ovary syndrome (PCOS) is a metabolic and reproductive disorder associated with insulin resistance. Our aims were to discover whether myonectin levels were altered in PCOS women comparing to controls and to determine the link of myonectin with hormonal-metabolic parameters in PCOS women. The current research was designed as a case-control study. Seventy-two subjects with PCOS and 72 age- and body mass index (BMI)-matched subjects as controls were enrolled into the study. Circulating myonectin levels were measured by ELISA. Myonectin levels were significantly lower in PCOS subjects compared to controls (6.77 ± 1.96 vs. 9.14 ± 2.87 ng/ml, p< .001). Myonectin exhibited an inverse association with BMI, insulin resistance, free androgen index (FAI) and triglycerides whereas it showed a positive association with high-density lipoprotein cholesterol (HDL-C) in women with PCOS. Logistic regression analysis revealed that decreased myonectin levels were parallel with increased probability of having PCOS risk. Decreased myonectin levels were associated with metabolic and hormonal disturbances in PCOS women, suggesting that myonectin may play a role in pathophysiology of PCOS.

Effects of an energy drink on myonectin in the liver, kidney and skeletal muscle of exercised rats.

Myonectin is a hormone that is produced mainly by skeletal muscle. We investigated the effects of exercise and energy drink (ED) administration on myonectin expression in skeletal muscle, liver and kidney tissue in rats; myonectin is produced by all three tissues. We used 28 male albino rats in four groups: untreated control (C), exercise (E), energy drink (ED) and exercise + energy drink (E + ED). The E and E + ED groups were exercised using a treadmill for 4 weeks. We also administered 3.5 ml/kg/day ED during week 1, 7 ml/kg/day during week 2 and 10 ml/kg/day during weeks 3 and 4 in the E and E + ED groups. We used ELISA to measure the levels of myonectin in skeletal muscle, liver and kidney tissues. We used immunohistochemical staining to investigate the localization and intensity of myonectin in these tissues. The amount of myonectin in skeletal muscle tissue was increased significantly in all experimental groups compared to group C. The amount of myonectin in the ED group was significantly greater than group E. No significant difference was observed in liver tissue; however, the amount of myonectin in the liver of group C was the greatest among all groups. The amount of myonectin in kidney tissue exhibited no significant difference among groups. Consumption of ED during exercise increased the amount of myonectin in kidney and skeletal muscle tissues and decreased it in liver tissue. We suggest that consumption of ED might adapt metabolism to incresed exercise by controling synthesis of myonectin in liver, kidney and skeletal muscle.

Myokines Produced by Cultured Bovine Satellite Cells Harvested from 3- and 11-Month-Old Angus Steers.

The myokines interleukin 6 (IL-6), interleukin 15 (IL-15), myonectin (CTRP15), fibronectin type III domain containing protein 5/irisin (FNDC5), and brain-derived neurotrophic factor (BDNF) are associated with skeletal muscle cell proliferation, differentiation, and muscle hypertrophy in biomedical model species. This study evaluated whether these myokines are produced by cultured bovine satellite cells (BSCs) harvested from 3- and 11-month-old commercial black Angus steers and if the expression and secretion of these targets change across 0, 12, 24, and 48 h in vitro. IL-6, IL-15, FNDC5, and BDNF expression were greater (p ≤ 0.05) in the differentiated vs. undifferentiated BSCs at 0, 12, 24, and 48 h. CTRP15 expression was greater (p ≤ 0.03) in the undifferentiated vs. differentiated BSCs at 24 and 48 h. IL-6 and CTRP15 protein from culture media were greater (p ≤ 0.04) in undifferentiated vs. differentiated BSCs at 0, 12, 24, and 48 h. BDNF protein was greater in the media of differentiated vs. undifferentiated BSCs at 0, 12, 24, and 48 h. IL-6, 1L-15, FNDC5, and BDNF are expressed in association with BSC differentiation, and CTRP15 appears to be expressed in association with BSC proliferation. This study also confirms IL-6, IL-15, CTRP15, and BDNF proteins present in media collected from primary cultures of BSCs.

Lack of association between serum myonectin levels and sarcopenia in older Asian adults.

Myonectin is a muscle-secreted factor that helps maintain homeostasis in the body by regulating several functions, including lipid metabolism. Previous studies suggested that myonectin may play a role in muscle health in an autocrine manner, but its impact on human skeletal muscle is still unclear. We aimed to investigate the relationship of serum myonectin levels with sarcopenia and related muscle parameters. We conducted a cross-sectional study of 142 older adults whose muscle mass, grip strength, gait speed, chair stands, and short physical performance battery (SPPB) were evaluated in the geriatric clinic of a tertiary medical center. Sarcopenia was defined based on Asian-specific cutoff values, and circulating myonectin levels were measured using an enzyme immunoassay. Before and after adjusting for age, sex, and body mass index, the serum myonectin level was not significantly different when the patients were stratified by status of sarcopenia, muscle mass, muscle strength, and physical performance. Furthermore, whether given as a continuous variable or divided into quartile groups, the serum myonectin level had no association with the skeletal muscle mass, grip strength, gait speed, chair stand test, or SPPB score. Our findings did not confirm the potential role of myonectin in muscle metabolism observed in experimental research. Thus, serum myonectin levels cannot predict the risk of sarcopenia in older Asian adults.

A comparison of CrossFit and concurrent training on myonectin, insulin resistance and physical performance in healthy young women.

OBJECTIVE: To compare the effect of CrossFit and concurrent aerobic + resistance training (CT) on circulating myonectin levels, insulin resistance index, and physical performance in young women. MATERIALS AND METHODS: Thirty healthy women were randomly assigned to CrossFit (n = 16) and CT (n = 14) groups, exercising three sessions per week for eight weeks. Serum myonectin levels, insulin resistance index, body composition, and performance variables were evaluated before and after the intervention period. RESULTS: Neither the CrossFit nor the CT group improved in myonectin levels and insulin resistance index. While, fat percentage, muscle mass, upper-limb strength, VO2max, HR at rest, lower body mean power output, and upper body peak power output improved more after CrossFit than the CT. CONCLUSION: It seems that CrossFit exercises by targeting multiple fitness components in one exercise session may allow participants to perform more activity in less time.

Review of Novel Potential Insulin Resistance Biomarkers in PCOS Patients-The Debate Is Still Open.

Research on proteins and peptides that play roles in metabolic regulation, which may be considered potential insulin resistance markers in some medical conditions, such as diabetes mellitus, obesity and polycystic ovarian syndrome (PCOS), has recently gained in interest. PCOS is a common endocrine disorder associated with hyperandrogenemia and failure of ovulation, which is often accompanied by metabolic abnormalities, including obesity, dyslipidemia, hyperinsulinemia, and insulin resistance. In this review, we focus on less commonly known peptides/proteins and investigate their role as potential biomarkers for insulin resistance in females affected by PCOS. We summarize studies comparing the serum fasting concentration of particular agents in PCOS individuals and healthy controls. Based on our analysis, we propose that, in the majority of studies, the levels of nesfastin-1, myonectin, omentin, neudesin were decreased in PCOS patients, while the levels of the other considered agents (e.g., preptin, gremlin-1, neuregulin-4, xenopsin-related peptide, xenin-25, and galectin-3) were increased. However, there also exist studies presenting contrary results; in particular, most data existing for lipocalin-2 are inconsistent. Therefore, further research is required to confirm those hypotheses, as well as to elucidate the involvement of these factors in PCOS-related metabolic complications.

Correlation of serum myonectin concentrations with the presence and severity of obstructive sleep apnoea syndrome.

OBJECTIVE: Myonectin, a newly discovered myokine, enhances fatty acid uptake in cultured adipocytes and hepatocytes and suppresses circulating concentrations of free fatty acids in mice. This study is performed to evaluate the association between serum myonectin concentrations with the presence and severity of OSAS. METHODS: This study was performed in a population of 191 patients with OSAS and 105 control subjects. Serum myonectin concentrations were measured using enzyme-linked immunosorbent assay method. RESULTS: Lower serum myonectin concentrations were found in OSAS patients than in the controls. Serum myonectin concentrations were associated with a reduced risk of OSAS (OR: 0.988, 95% CI: 0.984-0.993, P < 0.001). Severe OSAS patients had significantly lower myonectin concentrations compared with mild and moderate OSAS patients (P < 0.001 and P = 0.001, respectively). There are lower serum myonectin concentrations in moderate patients compared with mild patients (P = 0.024). Pearson correlation analysis revealed that serum myonectin concentrations were negatively correlated with the severity of OSAS (r = -0.344, P < 0.001). Simple linear regression analysis showed that serum myonectin concentrations in OSAS patients were negatively correlated with body mass index, fasting plasma glucose, homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol, low-density lipoprotein cholesterol (LDL-C) and apnoea hypopnea index. Multiple stepwise regression analysis shows that body mass index (ß = -0.289, P = 0.03), HOMA-IR (ß = -0.19, P = 0.003), total cholesterol (ß = -0.155, P = 0.016), LDL-C (ß = -0.176, P = 0.006) and apnoea hypopnea index (ß = -0.263, P < 0.001) remained to be associated with serum myonectin. CONCLUSION: Serum myonectin concentrations are inversely correlated with the presence and severity of OSAS.

Correlation analysis of myonectin levels with metabolic and hormonal disorders in patients with polycystic ovary syndrome.

BACKGROUND: This study aimed to investigate the relationship between myonectin levels and metabolic and hormonal disorders in patients with polycystic ovary syndrome (PCOS). METHODS: One hundred PCOS patients who sought medical advice from September 2017 to March 2019 in our hospital were selected as the PCOS group, while 100 healthy women matched for age and body mass index (BMI) with the PCOS patients were selected as the control group. General clinical information, myonectin levels, and metabolism and sex hormone-related indicators of the two groups were compared, and the correlation between myonectin, metabolism, and sex hormones was analyzed. RESULTS: There were no significant differences in age, BMI, blood pressure, or other general clinical information between the two groups (P>0.05). Compared with the control group, the levels of myonectin, sex hormone-binding globulin (SHBG), and high-density lipoprotein cholesterol (HDL-C) in the PCOS group were significantly decreased (P<0.05), while the levels of fasting blood glucose (FBG), homeostasis model assessment of insulin resistance (HOMA-IR), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), luteinizing hormone (LH), and testosterone were significantly increased (P<0.05). Pearson correlation analysis showed that the level of myonectin was negatively correlated with BMI, FBG, HOMA-IR, TG, and testosterone but was positively correlated with SHBG and HDL-C. Multivariate linear regression analysis showed that the level of myonectin was negatively correlated with BMI, HOMA-IR, and TG but positively correlated with SHBG and HDL-C. CONCLUSIONS: There is a correlation between the level of myonectin and multiple metabolic and hormone indices in PCOS patients indicating that myonectin may be an effective index to predict metabolic and hormone disorders in PCOS patients.

Serum myonectin is increased after laparoscopic sleeve gastrectomy.

OBJECTIVE: Myonectin, a newly discovered myokine, enhances fatty acid uptake in cultured adipocytes and hepatocytes and suppresses circulating levels of free fatty acids in mice. Recent studies showed that serum myonectin concentration is negatively correlated with obesity. This study was undertaken to evaluate the change of serum myonectin in obese patients after laparoscopic sleeve gastrectomy. METHODS: This study was performed in a population of 42 obese and 58 control subjects from April of 2018 to December of 2019. All obese subjects underwent laparoscopic sleeve gastrectomy. Anthropometric measurements, lipid profiles, HbA1c and serum myonectin were assessed at baseline and six months after laparoscopic sleeve gastrectomy. RESULTS: Serum myonectin concentrations were significantly lower in the obese patients than in the controls. Serum myonectin concentrations were increased at six months after laparoscopic sleeve gastrectomy. Simple linear regression analysis indicated that serum myonectin was negatively correlated with weight, waist circumference, hip circumference, body mass index, fasting plasma glucose, homeostasis model assessment of insulin resistance and HbA1c. Only body mass index was still inversely correlated with serum myonectin after multiple linear regression analysis. CONCLUSION: Serum myonectin is correlated with obesity and increased after laparoscopic sleeve gastrectomy.

Decreased serum myonectin concentrations in diabetic nephropathy patients.

Myonectin is a newly discovered myokine correlated with diabetes. Diabetic nephropathy (DN), which is diagnosed according to albuminuria, is one of the most common microvascular complications of diabetes. Albuminuria predisposes to future cardiovascular diseases and mortality. The aim of this study is to assess the association between serum myonectin concentrations with DN. A total of 188 patients with type 2 diabetes (T2DM) and 66 control subjects were enrolled in this investigation. T2DM patients were divided into three groups: normoalbuminuria (n = 84), microalbuminuria (n = 70), and macroalbuminuria (n = 34) according to urine albumin-to-creatinine ratio (ACR). T2DM patients showed lower serum myonectin concentrations compared with the controls. Serum myonectin concentrations were significantly decreased in macroalbuminuria group than in normoalbuminuria and microalbuminuria groups. In addition, microalbuminuria group had decreased serum myonectin concentrations compared with normoalbuminuria group. Logistic regression analysis demonstrated a correlation between serum myonectin and a decreased risk of T2DM and DN. Simply linear regression analysis indicated serum myonectin was negatively correlated body mass index (BMI), total cholesterol, low-density lipoprotein cholesterol, blood urea nitrogen, creatinine, uric acid, and ACR, and positively correlated with glomerular filtration rate, insulin treatment. BMI, ACR, and insulin treatment were still correlated with the serum myonectin after a multiple linear regression analysis. Our investigation indicates serum myonectin is decreased in DN patients and correlated with renal function.

Myokines in skeletal muscle physiology and metabolism: Recent advances and future perspectives.

Myokines are molecules produced and secreted by skeletal muscle to act in an auto-, para- and endocrine manner to alter physiological function of target tissues. The growing number of effects of myokines on metabolism of distant tissues provides a compelling case for crosstalk between skeletal muscle and other tissues and organs to regulate metabolic homoeostasis. In this review, we summarize and discuss the current knowledge regarding the impact on metabolism of several canonical and recently identified myokines. We focus specifically on myostatin, ß-aminoisobutyric acid, interleukin-15, meteorin-like and myonectin, and discuss how these myokines are induced and regulated as well as their overall function. We also review how these myokines may serve as potential prognostic biomarkers that reflect whole-body metabolism and how they may be attractive therapeutic targets for treating muscle and metabolic diseases.

Myonectin inhibits the differentiation of osteoblasts and osteoclasts in mouse cells.

Myonectin is a myokine, which is involved in the pathophysiology of diabetes and obesity, and various myokines are involved in the interactions between skeletal muscle and bone. However, roles of myonectin in bone have still remained unknown. We therefore examined the effects of myonectin on mouse osteoblast and osteoclast differentiation in vitro. Myonectin significantly suppressed the mRNA levels of osteogenic genes and alkaline phosphatase (ALP) activity in mouse osteoblasts. As for osteoclasts, myonectin significantly suppressed osteoclast formation as well as the mRNA levels of osteoclast-related genes enhanced by receptor activator nuclear factor κB ligand (RANKL) from mouse monocytic RAW264.7 cells. Moreover, myonectin significantly suppressed osteoclast formation from mouse bone marrow cells in the presence of macrophage-colony stimulating factor and RANKL. On the other hand, myonectin significantly suppressed RANKL-induced oxygen consumption rate and peroxisome proliferator-activated receptor γ coactivator-1ß mRNA levels in RAW264.7 cells, although myonectin did not affect these mitochondrial biogenesis parameters in mouse osteoblasts. In conclusion, the present study demonstrated that myonectin suppresses the differentiation and ALP activity in mouse osteoblasts. Moreover, myonectin suppressed osteoclast differentiation from mouse bone marrow and RAW264.7 cells partly through an inhibition of mitochondrial biogenesis.

Erythroferrone is not required for the glucoregulatory and hematologic effects of chronic erythropoietin treatment in mice.

Erythropoietin (EPO) acts on erythroid progenitor cells to promote their survival and differentiation to mature erythrocytes. Along with this canonical role, EPO is also reported to modulate energy metabolism, resulting in improved glucose tolerance and insulin sensitivity. EPO also stimulates the production of the hormone erythroferrone (ERFE) which acts to suppress hepcidin production, thus increasing dietary iron absorption and mobilizing stored iron for use in erythropoiesis. ERFE (initially termed myonectin) was also reported have an effect on systemic lipid metabolism by promoting the clearance of nonesterifed fatty acids (NEFA) from circulation. As increased levels of circulating NEFA blunt insulin sensitivity and impair glucose tolerance, ERFE-induced clearance of NEFA after EPO administration would have a beneficial effect on glucose metabolism. The aim of this study was to determine if the known metabolic effect of EPO treatment on glucose homeostasis is mediated by ERFE, produced in response to EPO. Mice lacking Erfe did not differ from wild-type mice in blood lipid parameters, blood glucose, and glucose or insulin tolerance at baseline or after chronic EPO treatment. Additionally, hepcidin suppression and the response of erythrocyte parameters to chronic EPO treatment were unaffected by the absence of Erfe. These findings suggest that the known beneficial effects of EPO on glucose metabolism are not attributable to an accompanying increase in ERFE production, and that Erfe is dispensable for normal glucose homeostasis. Furthermore, our data indicate that ERFE-independent mechanisms can suppress hepcidin in response to chronically elevated EPO levels.

Effects of Aerobic Exercises on Serum Levels of Myonectin and Insulin Resistance in Obese and Overweight Women.

Background and Aim: Obesity is associated with cardiovascular diseases, metabolic syndrome, and diabetes and insulin resistance. Myonectin is a myokine mostly secreted from skeletal muscles and inversely associated with obesity. The aim of the present study was to evaluate the effects of 8 weeks of aerobic exercises on serum levels of myonectin and insulin resistance in obese and overweight women. Materials and Methods: Eighty obese women were assigned to exercise (34) and control groups (46). The exercise program comprised three weekly 45-minute sessions of aerobic exercise training for 8 weeks that included running with 50-70% of maximum heart rate (first 2 weeks - 50%; second week - 60%; third week - 65%; and the last 2 weeks by 70% of maximum heart rate). Twenty-four hours before and after the training session, fasting myonectin serum levels were measured. ANCOVA was used to assess differences between the groups. Results: Serum levels of myonectin in the experimental group increased significantly (P=0.000); however, insulin resistance significantly decreased in the experimental group (P=0.000). Conclusion: Therefore, considering the role of myonectin in increasing fatty acid uptake, exercise training can play an essential role in decreasing obesity-related diseases and metabolic syndrome; this effect is partly related to the roles of myonectin. Therefore, the use of this type of exercise is recommended to reduce the risk of diseases associated with obesity and metabolic syndrome.

Plasma Levels of Myonectin But Not Myostatin or Fibroblast-Derived Growth Factor 21 Are Associated with Insulin Resistance in Adult Humans without Diabetes Mellitus.

BACKGROUND: Myokines are a group of protein mediators produced by skeletal muscle under stress or physical exertion. Even though their discovery and effects in cell culture and animal models of disease have elicited great enthusiasm, very little is known about their role in human metabolism. We assessed whether plasma concentrations of three known myokines [myonectin, myostatin, and fibroblast-derived growth factor 21 (FGF-21)] would be associated with direct and indirect indicators of insulin resistance (IR) in individuals who did not have a diagnosis of diabetes. METHODS: We studied 81 adults of both sexes comprising a wide range of body adiposity and insulin sensitivity. All participants underwent a thorough clinical assessment and a 5-point oral glucose tolerance test with calculation of multiple IR and insulin sensitivity indices. Twenty-one of them additionally underwent a hyperinsulinemic-euglycemic clamp with determination of steady-state whole-body insulin-stimulated glucose disposal ("M"). We compared plasma myokine concentrations across quartiles of IR indices and clinical IR surrogates, and explored the correlation of each myokine with the M-value. RESULTS: Plasma myonectin levels increased monotonically across quartiles of the incremental area under the insulin curve (higher values indicate more IR) (p-trend = 0.021) and decreased monotonically across quartiles of the insulin sensitivity index (ISI - higher values indicate less IR) (p-trend = 0.012). After multivariate adjustment for other relevant determinants of IR (body mass index, age, and sex), the negative association of myonectin with ISI persisted (standardized beta = -0.235, p = 0.023). Myostatin was not associated with any clinical IR indicator or direct IR index measure. In multivariate analyses, FGF-21 showed a trend toward a positive correlation with glucose disposal that did not reach statistical significance (standardized beta = 0.476, p = 0.091). CONCLUSION: The secretion of myonectin may constitute an attempt at a compensatory mechanism against IR in humans.

Is erythroferrone finally the long sought-after systemic erythroid regulator of iron?

Iron metabolism is regulated on the cellular and the systemic level. Over the last decade, the liver peptide "hepcidin" has emerged as the body's key irons store regulator. The long postulated "erythroid regulator of iron", however, remained elusive. Last year, evidence was provided, that a previously described myokine "myonectin" may also function as the long sought erythroid regulator of iron. Myonectin was therefore re-named "erythroferrone". This editorial provides a brief discussion on the two functions of erythroferrone and also briefly considers the emerging potential role of transferrin receptor 2 in erythropoiesis.

Regulation of tissue crosstalk by skeletal muscle-derived myonectin and other myokines.

The integrated control of animal physiology requires intimate tissue crosstalk, a vital task mediated by circulating humoral factors. As one type of these factors, adipose tissue-derived adipokines have recently garnered attention as important regulators of systemic insulin sensitivity and metabolic homeostasis. However, the realization that skeletal muscle also secretes a variety of biologically and metabolically active polypeptide factors (collectively called myokines) has provided a new conceptual framework to understand the critical role skeletal muscle plays in coordinating whole-body energy balance. Here, we highlight recent progress made in the myokine field and discuss possible roles of myonectin, which we have recently identified as a potential postprandial signal derived from skeletal muscle to integrate metabolic processes in other tissues, such as adipose and liver; one of its roles is to promote fatty acid uptake into cells. Myonectin is also likely an important mediator in inter-tissue crosstalk.