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The chemoattractant proteins (chemokines) monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) both trigger the firm adhesion of monocytes. However, there are differences in the contribution of specific integrin adhesion receptors to the induced adhesion for these two agonists. This is possibly because they use different signalling mechanisms. It has been established that IL-8 receptors on monocytes are functional. Specific chemokines are vital for monocyte recruitment.

The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions. [ABSTRACT FROM AUTHOR]

Deficiency of the immune checkpoint lymphocyte activation gene-3 (LAG3) protein is significantly associated with both elevated HDL-cholesterol (HDL-C) and myocardial infarction risk. We determined the association of genetic variants within ±500 kb of LAG3 with plasma LAG3 and defined LAG3-associated plasma proteins with HDL-C and clinical outcomes. Whole genome sequencing and plasma proteomics were obtained from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study (FHS) cohorts as part of the Trans-Omics for Precision Medicine program. In situ Hi-C chromatin capture was performed in EBV-transformed cell lines isolated from four MESA participants. Genetic association analyses were performed in MESA using multivariate regression models, with validation in FHS. A LAG3-associated protein network was tested for association with HDL-C, coronary heart disease, and all-cause mortality. We identify an association between the LAG3 rs3782735 variant and plasma LAG3 protein. Proteomics analysis reveals 183 proteins significantly associated with LAG3 with four proteins associated with HDL-C. Four proteins discovered for association with all-cause mortality in FHS shows nominal associations in MESA. Chromatin capture analysis reveals significant cis interactions between LAG3 and C1S, LRIG3, TNFRSF1A, and trans interactions between LAG3 and B2M. A LAG3-associated protein network has significant associations with HDL-C and mortality. Rodriguez et al. use whole genome sequencing and plasma proteomics from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study (FHS) cohorts of the Trans-Omics for Precision Medicine program and perform in situ Hi-C chromatin capture in cell lines isolated from four MESA participants. They demonstrate that lymphocyte activation gene-3 protein networks are associated with HDL-cholesterol and mortality, which could guide the development of precision medicine. [ABSTRACT FROM AUTHOR]

Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we investigated epigenetic control of systemic metabolism by bromodomain-containing proteins (Brds), which are transcriptional regulators binding to acetylated histone, in both intestinal cells and mice treated with the bromodomain inhibitor JQ-1. In vivo treatment with JQ-1 resulted in hyperglycemia and severe glucose intolerance. Whole-body or tissue-specific insulin sensitivity was not altered by JQ-1; however, JQ-1 treatment reduced insulin secretion during both in vivo glucose tolerance testing and ex vivo incubation of isolated islets. JQ-1 also inhibited expression of fibroblast growth factor (FGF) 15 in the ileum and decreased FGF receptor 4-related signaling in the liver. These adverse metabolic effects of Brd4 inhibition were fully reversed by in vivo overexpression of FGF19, with normalization of hyperglycemia. At a cellular level, we demonstrate Brd4 binds to the promoter region of FGF19 in human intestinal cells; Brd inhibition by JQ-1 reduces FGF19 promoter binding and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum and FGF signaling in the liver and a contributor to the gut-liver axis and systemic glucose metabolism. [ABSTRACT FROM AUTHOR]

Objectives: We investigated whether high responsiveness or low responsiveness to exercise training aggregates in the same individuals across seven cardiometabolic traits.Methods: A total of 564 adults (29.2% black, 53.7% female) from the HERITAGE family study completed a 20-week endurance training programme (at 55%-75% of participants' maximal oxygen uptake (VO2max)) with VO2max, per cent body fat, visceral adipose tissue, fasting levels of insulin, high-density lipoprotein cholesterol, small low-density lipoprotein particles and inflammatory marker GlycA measured before and after training. For each exercise response trait, we created ethnicity-specific, sex-specific and generation-specific quintiles. High responses were defined as those within the 20th percentile representing the favourable end of the response trait distribution, low responses were defined as the 20th percentile from the least favourable end, and the remaining were labelled as average responses.Results: Only one individual had universally high or low responses for all seven cardiometabolic traits. Almost half (49%) of the cohort had at least one high response and one low response across the seven traits. About 24% had at least one high response but no low responses, 24% had one or more low responses but no high responses, and 2.5% had average responses across all traits.Conclusions: Interindividual variation in exercise responses was evident in all the traits we investigated, and responsiveness did not aggregate consistently in the same individuals. While adherence to an exercise prescription is known to produce health benefits, targeted risk factors may not improve. [ABSTRACT FROM AUTHOR]

Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The genetic and molecular mechanisms underlying this phenomenon are currently not understood. By investigating genome-wide variants associated with baseline and exercise-induced changes (∆) in insulin sensitivity index (Si) in healthy volunteers, we have identified novel candidate genes whose mouse knockouts phenotypes were consistent with a causative effect on Si. An integrative analysis of functional genomic and transcriptomic profiles suggests genetic variants have an aggregate effect on baseline Si and ∆Si, focused around cholinergic signalling, including downstream calcium and chemokine signalling. The identification of calcium regulated MEF2A transcription factor as the most statistically significant candidate driving the transcriptional signature associated to ∆Si further strengthens the relevance of calcium signalling in EET mediated Si response. [ABSTRACT FROM AUTHOR]

Study of human and Xenopus thrombin receptor homologs reveals that thrombin receptor activation requires agonist interaction with the extracellular domain. Altering the xenopus receptor aminoterminal exodomain and loops with human counterparts changes the receptor specificity to human type. The extracellular surface determines thrombin receptor specificity.

Context: There is little information about fatty liver in prediabetes as it transitions to early diabetes.Objective: This study is aimed at evaluating the prevalence and determinants of fatty liver in the Diabetes Prevention Program (DPP).Methods: We measured liver fat as liver attenuation (LA) in Hounsfield units (HU) in 1876 participants at ~14 years following randomization into the DPP, which tested the effects of lifestyle or metformin interventions versus standard care to prevent diabetes. LA was compared among intervention groups and in those with versus without diabetes, and associations with baseline and follow-up measurements of anthropometric and metabolic covariates were assessed.Results: There were no differences in liver fat between treatment groups at 14 years of follow-up. Participants with diabetes had lower LA (mean ± SD: 46 ± 16 vs 51 ± 14 HU; P < 0.001) and a greater prevalence of fatty liver (LA < 40 HU) (34% vs 17%; P < 0.001). Severity of metabolic abnormalities at the time of LA evaluation was associated with lower LA categories in a graded manner and more strongly in those with diabetes. Averaged annual fasting insulin (an index of insulin resistance [OR, 95% CI 1.76, 1.41-2.20]) waist circumference (1.63, 1.17-2.26), and triglyceride (1.42, 1.13-1.78), but not glucose, were independently associated with LA < 40 HU prevalence.Conclusion: Fatty liver is common in the early phases of diabetes development. The association of LA with insulin resistance, waist circumference, and triglyceride levels emphasizes the importance of these markers for hepatic steatosis in this population and that assessment of hepatic fat in early diabetes development is warranted. [ABSTRACT FROM AUTHOR]

Background Choline is an essential nutrient; however, the associations of choline and its related metabolites with cardiometabolic risk remain unclear. Objective We examined the associations of circulating choline, betaine, carnitine, and dimethylglycine (DMG) with cardiometabolic biomarkers and their potential dietary and nondietary determinants. Methods The cross-sectional analyses included 32,853 participants from 17 studies, who were free of cancer, cardiovascular diseases, chronic kidney diseases, and inflammatory bowel disease. In each study, metabolites and biomarkers were log-transformed and standardized by means and SDs, and linear regression coefficients (β) and 95% CIs were estimated with adjustments for potential confounders. Study-specific results were combined by random-effects meta-analyses. A false discovery rate <0.05 was considered significant. Results We observed moderate positive associations of circulating choline, carnitine, and DMG with creatinine [β (95% CI): 0.136 (0.084, 0.188), 0.106 (0.045, 0.168), and 0.128 (0.087, 0.169), respectively, for each SD increase in biomarkers on the log scale], carnitine with triglycerides (β = 0.076; 95% CI: 0.042, 0.109), homocysteine (β = 0.064; 95% CI: 0.033, 0.095), and LDL cholesterol (β = 0.055; 95% CI: 0.013, 0.096), DMG with homocysteine (β = 0.068; 95% CI: 0.023, 0.114), insulin (β = 0.068; 95% CI: 0.043, 0.093), and IL-6 (β = 0.060; 95% CI: 0.027, 0.094), but moderate inverse associations of betaine with triglycerides (β = −0.146; 95% CI: −0.188, −0.104), insulin (β = −0.106; 95% CI: −0.130, −0.082), homocysteine (β = −0.097; 95% CI: −0.149, −0.045), and total cholesterol (β = −0.074; 95% CI: −0.102, −0.047). In the whole pooled population, no dietary factor was associated with circulating choline; red meat intake was associated with circulating carnitine [β = 0.092 (0.042, 0.142) for a 1 serving/d increase], whereas plant protein was associated with circulating betaine [β = 0.249 (0.110, 0.388) for a 5% energy increase]. Demographics, lifestyle, and metabolic disease history showed differential associations with these metabolites. Conclusions Circulating choline, carnitine, and DMG were associated with unfavorable cardiometabolic risk profiles, whereas circulating betaine was associated with a favorable cardiometabolic risk profile. Future prospective studies are needed to examine the associations of these metabolites with incident cardiovascular events. [ABSTRACT FROM AUTHOR]