Imeglimin modulates mitochondria biology and facilitates mitokine secretion in 3T3-L1 adipocytes.

AIMS: Imeglimin, a novel antidiabetic drug, has recently been reported to affect pancreatic ß-cells and hepatocytes. Adipose tissue plays a crucial role in systemic metabolism. However, its effect on adipocytes remains unexplored. Herein, we investigated the effects of imeglimin on adipocytes, particularly in the mitochondria. MAIN METHODS: The 3T3-L1 adipocytes were treated with imeglimin. Mitochondrial respiratory complex I activity and NAD+, NADH, and AMP levels were measured. Protein expression levels were determined by western blotting, mitochondrial DNA and mRNA expression levels were determined using quantitative polymerase chain reaction, and secreted adipocytokine and mitokine levels were determined using adipokine array and enzyme-linked immunosorbent assay. KEY FINDINGS: Imeglimin inhibited complex I activity, decreased the NAD+/NADH ratio, and increased AMP levels, which were associated with the enhanced phosphorylation of AMP-activated protein kinase. In addition, imeglimin increased the mitochondrial DNA content and levels of mitochondrial transcription factor A and peroxisome proliferator-activated receptor-γ coactivator 1-α mRNA, which were abolished by Ly294002, a phosphoinositide 3-kinase inhibitor. Furthermore, imeglimin facilitated the expression levels of markers of the mitochondrial unfolded protein response, and the gene expression and secretion of two mitokines, fibroblast growth factor 21 and growth differentiation factor 15. The production of both mitokines was transcriptionally regulated and abolished by phosphoinositide 3-kinase and Akt inhibitors. SIGNIFICANCE: Imeglimin modulates mitochondrial biology in adipocytes and may exert a mitohormetic effect through mitokine secretion.

Differential Modulation of Catecholamine and Adipokine Secretion by the Short Chain Fatty Acid Receptor FFAR3 and α2-Adrenergic Receptors in PC12 Cells.

Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α2-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α2-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gßγ-activated phospholipase C (PLC)-ß/Ca2+ signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α2A-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α2A-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α2A-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action.

Adipokines in pregnancy.

Reproductive success consists of a sequential events chronology, starting with the ovum fertilization, implantation of the embryo, placentation, and cellular processes like proliferation, apoptosis, angiogenesis, endocrinology, or metabolic changes, which taken together finally conduct the birth of healthy offspring. Currently, many factors are known that affect the regulation and proper maintenance of pregnancy in humans, domestic animals, or rodents. Among the determinants of reproductive success should be distinguished: the maternal microenvironment, genes, and proteins as well as numerous pregnancy hormones that regulate the most important processes and ensure organism homeostasis. It is well known that white adipose tissue, as the largest endocrine gland in our body, participates in the synthesis and secretion of numerous hormones belonging to the adipokine family, which also may regulate the course of pregnancy. Unfortunately, overweight and obesity lead to the expansion of adipose tissue in the body, and its excess in both women and animals contributes to changes in the synthesis and release of adipokines, which in turn translates into dramatic changes during pregnancy, including those taking place in the organ that is crucial for the proper progress of pregnancy, i.e. the placenta. In this chapter, we are summarizing the current knowledge about levels of adipokines and their role in the placenta, taking into account the physiological and pathological conditions of pregnancy, e.g. gestational diabetes mellitus, preeclampsia, or intrauterine growth restriction in humans, domestic animals, and rodents.

Expression dynamics of adipokines during induced ovulation in the bovine follicles and early corpus luteum.

The study aimed to assess the local gene expression of adipokine members, namely vaspin, adiponectin, visfatin, resistin and their associated receptors - heat shock 70 protein 5 (HSPA5), adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2) - in bovine follicles during the preovulatory period and early corpus luteum development. Follicles were collected before gonadotropin-releasing hormone (GnRH) treatment (0 h) and at 4, 10, 20, 25 and 60 h after GnRH application through transvaginal ovariectomy (n = 5 samples/group). Relative mRNA expression levels were quantified using real-time reverse transcription polymerase chain reaction (RT-qPCR). Vaspin exhibited high mRNA levels immediately 4 h after GnRH application, followed by a significant decrease. Adiponectin mRNA levels were elevated at 25 h after GnRH treatment. AdipoR2 exhibited late-stage upregulation, displaying increased expression at 20, 25 and 60 h following GnRH application. Visfatin showed upregulation at 20 h post-GnRH application. In conclusion, the observed changes in adipokine family members within preovulatory follicles, following experimentally induced ovulation, may constitute crucial components of the local mechanisms regulating final follicle growth and development.

Status of visfatin in female reproductive function under normal and pathological conditions: a mini review.

Adipokines are now well-known to regulate reproduction. Visfatin is an adipokine expressed in the hypothalamus, pituitary, ovary, uterus, and placenta of different species, and since it has been found to modulate the endocrine secretion of the hypothalamus, pituitary gland and ovary, it may be considered a novel regulator of female reproduction. Although the majority of the literature explored its role in ovarian regulation, visfatin has also been shown to regulate uterine remodeling, endometrial receptivity and embryo development, and its expression in the uterus is steroid dependent. Like other adipokines, visfatin expression and levels are deregulated in pathological conditions including polycystic ovary syndrome. Thus, the present mini-review focuses on the role of visfatin in female reproduction under both physiological and pathological conditions.

New Mediators in the Crosstalk between Different Adipose Tissues.

Adipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future.

Obesity and male fertility disorders.

Often associated with obesity, male infertility represents a widespread condition that challenges the wellbeing of the couple. In this article, we provide a comprehensive and critical analysis of studies exploring the association between obesity and male reproductive function, to evaluate the frequency of this association, and establish the effects of increased body weight on conventional and biofunctional sperm parameters and infertility. In an attempt to find possible molecular markers of infertility in obese male patients, the numerous mechanisms responsible for infertility in overweight/obese patients are reviewed in depth. These include obesity-related functional hypogonadism, insulin resistance, hyperinsulinemia, chronic inflammation, adipokines, irisin, gut hormones, gut microbiome, and sperm transcriptome. According to meta-analytic evidence, excessive body weight negatively influences male reproductive health. This can occurr through a broad array of molecular mechanisms. Some of these are not yet fully understood and need to be further elucidated in the future. A better understanding of the effects of metabolic disorders on spermatogenesis and sperm fertilizing capacity is very useful for identifying new diagnostic markers and designing therapeutic strategies for better clinical management of male infertility.

Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation­mediating treatment options (Review).

Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co­morbidities, including type­2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular diseases, non­alcoholic fatty liver disease, kidney diseases, respiratory disorders, sleep apnea, musculoskeletal disorders and osteoarthritis, subfertility, psychosocial problems and certain types of cancers. The underlying inflammatory mechanisms interconnecting obesity with metabolic dysfunction are not completely understood. Increased adiposity promotes pro­inflammatory polarization of macrophages toward the M1 phenotype, in adipose tissue (AT), with subsequent increased production of pro­inflammatory cytokines and adipokines, inducing therefore an overall, systemic, low­grade inflammation, which contributes to metabolic syndrome (MetS), insulin resistance (IR) and T2DM. Targeting inflammatory mediators could be alternative therapies to treat obesity, but their safety and efficacy remains to be studied further and confirmed in future clinical trials. The present review highlights the molecular and pathophysiological mechanisms by which the chronic low­grade inflammation in AT and the production of reactive oxygen species lead to MetS, IR and T2DM. In addition, focus is given on the role of anti­inflammatory agents, in the resolution of chronic inflammation, through the blockade of chemotactic factors, such as monocytes chemotractant protein­1, and/or the blockade of pro­inflammatory mediators, such as IL­1ß, TNF­α, visfatin, and plasminogen activator inhibitor­1, and/or the increased synthesis of adipokines, such as adiponectin and apelin, in obesity­associated metabolic dysfunction.

The adipokines progranulin and omentin - novel regulators of basic ovarian cell functions.

The present study aimed to examine the effects of progranulin and omentin on basic ovarian cell functions. For this purpose, we investigated the effects of the addition of progranulin and omentin (0, 0.1, 1, or 10 ng/ml) on the viability, proliferation, apoptosis and steroidogenesis of cultured rabbit ovarian granulosa cells. To determine the importance of the interrelationships between granulosa cells and theca cells, we compared the influence of progranulin and omentin on progesterone and estradiol release in cultured granulosa cells and ovarian fragments containing both granulosa cells and theca cells. Cell viability, proliferation, cytoplasmic apoptosis and release of progesterone and estradiol were measured by Cell Counting Kit-8 (CCK-8), BrdU incorporation, cell death detection, and ELISA. Both progranulin and omentin increased granulosa cell viability and proliferation and decreased apoptosis. Progranulin increased progesterone release by granulosa cells but reduced progesterone output by ovarian fragments. Progranulin decreased estradiol release by granulosa cells but increased it in ovarian fragments. Omentin reduced progesterone release in both models. Omentin reduced estradiol release by granulosa cells but promoted this release in ovarian fragments. The present observations are the first to demonstrate that progranulin and omentin can be direct regulators of basic ovarian cell functions. Furthermore, the differences in the effects of these adipokines on steroidogenesis via granulosa and ovarian fragments indicate that these peptides could target both granulosa and theca cells.

The Effect of Diesel Exhaust Particles on Adipose Tissue Mitochondrial Function and Inflammatory Status.

Air pollution poses a significant global health risk, with fine particulate matter (PM2.5) such as diesel exhaust particles (DEPs) being of particular concern due to their potential to drive systemic toxicities through bloodstream infiltration. The association between PM2.5 exposure and an increased prevalence of metabolic disorders, including obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), is evident against a backdrop of rising global obesity and poor metabolic health. This paper examines the role of adipose tissue in mediating the effects of PM2.5 on metabolic health. Adipose tissue, beyond its energy storage function, is responsive to inhaled noxious stimuli, thus disrupting metabolic homeostasis and responding to particulate exposure with pro-inflammatory cytokine release, contributing to systemic inflammation. The purpose of this study was to characterize the metabolic response of adipose tissue in mice exposed to either DEPs or room air (RA), exploring both the adipokine profile and mitochondrial bioenergetics. In addition to a slight change in fat mass and a robust shift in adipocyte hypertrophy in the DEP-exposed animals, we found significant changes in adipose mitochondrial bioenergetics. Furthermore, the DEP-exposed animals had a significantly higher expression of adipose inflammatory markers compared with the adipose from RA-exposed mice. Despite the nearly exclusive focus on dietary factors in an effort to better understand metabolic health, these results highlight the novel role of environmental factors that may contribute to the growing global burden of poor metabolic health.

New insights of acylation stimulating protein in modulating the pathological progression of metabolic syndromes.

Obesity is associated with insulin resistance, hypertension, and coronary artery diseases which are grouped as metabolic syndrome. Rather than being a storage for energy, the adipocytes could synthesis and secret diverse hormones and molecules, named as adipokines. Under obese status, the adipocytes are dysfunctional with excessively producing the inflammatory related cytokines, such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor α (TNF-α). Concerning on the vital role of adipokines, it is proposed that one of the critical pathological factors of obesity is the dysfunctional adipocytic pathways. Among these adipokines, acylation stimulating protein, as an adipokine synthesized by adipocytes during the process of cell differentiation, is shown to activate the metabolism of triglyceride (TG) by regulating the catabolism of glucose and free fatty acid (FFA). Recent attention has paid to explore the underlying mechanism whereby acylation stimulating protein influences the biological function of adipocyte and the pathological development of obesity. In the present review, we summarized the progression of acylation stimulating protein in modulating the physiological and hormonal catabolism which affects fat distribution. Furthermore, the potential mechanisms which acylation stimulating protein regulates the metabolism of adipose tissue and the process of metabolic syndrome were also summarized.

Ameliorative Effect of Coenzyme Q10 on Phenotypic Transformation in Human Smooth Muscle Cells with FBN1 Knockdown.

Mutations of the FBN1 gene lead to Marfan syndrome (MFS), which is an autosomal dominant connective tissue disorder featured by thoracic aortic aneurysm risk. There is currently no effective treatment for MFS. Here, we studied the role of mitochondrial dysfunction in the phenotypic transformation of human smooth muscle cells (SMCs) and whether a mitochondrial boosting strategy can be a potential treatment. We knocked down FBN1 in SMCs to create an MFS cell model and used rotenone to induce mitochondrial dysfunction. Furthermore, we incubated the shFBN1 SMCs with Coenzyme Q10 (CoQ10) to assess whether restoring mitochondrial function can reverse the phenotypic transformation. The results showed that shFBN1 SMCs had decreased TFAM (mitochondrial transcription factor A), mtDNA levels and mitochondrial mass, lost their contractile capacity and had increased synthetic phenotype markers. Inhibiting the mitochondrial function of SMCs can decrease the expression of contractile markers and increase the expression of synthetic genes. Imposing mitochondrial stress causes a double-hit effect on the TFAM level, oxidative phosphorylation and phenotypic transformation of FBN1-knockdown SMCs while restoring mitochondrial metabolism with CoQ10 can rapidly reverse the synthetic phenotype. Our results suggest that mitochondria function is a potential therapeutic target for the phenotypic transformation of SMCs in MFS.

Roles of organokines in intervertebral disc homeostasis and degeneration.

The intervertebral disc is not isolated from other tissues. Recently, abundant research has linked intervertebral disc homeostasis and degeneration to various systemic diseases, including obesity, metabolic syndrome, and diabetes. Organokines are a group of diverse factors named for the tissue of origin, including adipokines, osteokines, myokines, cardiokines, gastrointestinal hormones, and hepatokines. Through endocrine, paracrine, and autocrine mechanisms, organokines modulate energy homeostasis, oxidative stress, and metabolic balance in various tissues to mediate cross-organ communication. These molecules are involved in the regulation of cellular behavior, inflammation, and matrix metabolism under physiological and pathological conditions. In this review, we aimed to summarize the impact of organokines on disc homeostasis and degeneration and the underlying signaling mechanism. We focused on the regulatory mechanisms of organokines to provide a basis for the development of early diagnostic and therapeutic strategies for disc degeneration.

The role of adipokines in osteoporosis management: a mini review.

The prevalence of osteoporosis has been on the rise globally. With ageing populations, research has sought therapeutic solutions in novel areas. One such area is that of the adipokines. Current literature points to an important role for these chemical mediators in relation to bone metabolism. Well-established adipokines have been broadly reported upon. These include adiponectin and leptin. However, other novel adipokines such as visfatin, nesfatin-1, meteorin-like protein (Metrnl), apelin and lipocalin-2 are starting to be addressed pre-clinically and clinically. Adipokines hold pro-inflammatory and anti-inflammatory properties that influence the pathophysiology of various bone diseases. Omentin-1 and vaspin, two novel adipokines, share cardioprotective effects and play essential roles in bone metabolism. Studies have reported bone-protective effects of omentin-1, whilst others report negative associations between omentin-1 and bone mineral density. Lipocalin-2 is linked to poor bone microarchitecture in mice and is even suggested to mediate osteoporosis development from prolonged disuse. Nesfatin-1, an anorexigenic adipokine, has been known to preserve bone density. Animal studies have demonstrated that nesfatin-1 treatment limits bone loss and increases bone strength, suggesting exogenous use as a potential treatment for osteopenic disorders. Pre-clinical studies have shown adipokine apelin to have a role in bone metabolism, mediated by the enhancement of osteoblast genesis and the inhibition of programmed cell death. Although many investigations have reported conflicting findings, sufficient literature supports the notion that adipokines have a significant influence on the metabolism of bone. This review aims at highlighting the role of novel adipokines in osteoporosis while also discussing their potential for treating osteoporosis.

Adipokines in depressed women with and without adverse childhood experiences.

BACKGROUND: Adverse childhood experiences (ACE) elevate the risk of both major depressive disorder (MDD) and metabolic diseases. The underlying pathophysiology might include alterations of adipokine levels as a consequence of ACE. In this study, we used a full-factorial design to investigate the levels of select adipokines in women with ACE-only (n = 23), MDD-only (n = 27), ACE+MDD (n = 25) and healthy controls (HC, n = 29) to identify metabolic makers associated with vulnerability and resilience of developing MDD after ACE exposure. METHODS: Serum levels of adiponectin, leptin, adiponectin-to-leptin (A/L) ratio, and retinol binding protein 4 (RBP4) were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Adiponectin levels did not differ between groups. Individuals with vs. without MDD showed higher leptin serum concentrations. As predicted, A/L ratio indicated lower values in individuals with vs. without ACE. RBP4 showed a more nuanced pattern with reduced levels in the ACE-only and MDD-only groups compared to HC. Furthermore, the ACE-only group showed lower RBP4 concentrations compared to ACE+MDD. These results were not accounted by BMI or medication status. CONCLUSION: Our results do not support the utility of adiponectin and leptin as predictors of vulnerability or resilience of developing MDD after ACE. In contrast, RBP4 might play a role in resilience towards the development of MDD following ACE. Further research on this more recently discovered adipokine seems warranted.

The role of novel adipokines and adipose-derived extracellular vesicles (ADEVs): Connections and interactions in liver diseases.

Adipose tissues (AT) are an important endocrine organ that secretes various functional adipokines, peptides, non-coding RNAs, and acts on AT themselves or other distant tissues or organs through autocrine, paracrine, or endocrine manners. An accumulating body of evidence has suggested that many adipokines play an important role in liver metabolism. Besides the traditional adipokines such as adiponectin and leptin, many novel adipokines have recently been identified to have regulatory effects on the liver. Additionally, AT can produce extracellular vesicles (EVs) that act on peripheral tissues. However, under pathological conditions, such as obesity and diabetes, dysregulation of adipokines is associated with functional changes in AT, which may cause liver diseases. In this review, we focus on the newly discovered adipokines and EVs secreted by AT and highlight their actions on the liver under the context of obesity, nonalcoholic fatty liver diseases (NAFLD), and some other liver diseases. Clarifying the action of adipokines and adipose tissue-derived EVs on the liver would help to identify novel therapeutic targets or biomarkers for metabolic diseases.

Exosomal or follicular FNDC3A decreases FOLR1 mRNA abundance and progesterone and lactate synthesis in bovine granulosa cells.

In brief: Dairy cattle experience a period of infertility postpartum that is caused in part by the development of IGF1/insulin resistance. This study suggests that an adipokine, FNDC3A, reduces IGF1-dependent glycolysis and may contribute to postpartum infertility. Abstract: Dairy cows go through a period of subfertility after parturition, triggered in part by a disruption of energy homeostasis. The mobilization of body fat alters the secretion of adipokines, which have been shown to impact ovarian function. Fibronectin type III domain-containing 3A (FNDC3A) is a recently discovered adipokine-myokine, and FNDC3A mRNA abundance in subcutaneous adipose tissue is increased postpartum in cattle. In this study, we hypothesized that FNDC3A may compromise granulosa cell function in cattle and investigated this using a well-established in vitro cell culture model. Here, we demonstrate the presence of FNDC3A protein associated with extracellular vesicles in follicular fluid and in plasma, suggesting an endocrine role for this adipokine. FNDC3A protein and mRNA was also detected in the bovine ovary (cortex, granulosa and theca cells, cumulus, oocyte and corpus luteum). Abundance of FNDC3A mRNA in granulosa cells from small follicles was increased by in vitro treatment with the adipokines leptin and TNF but not by visfatin, resistin, adiponectin, chemerin or IGF1. Addition of recombinant FNDC3A at physiological doses (10 ng/mL) to granulosa cells decreased IGF1-dependent progesterone but not estradiol secretion and IGF1-dependent lactate secretion and abundance of GLUT3 and GLUT4 mRNA. This concentration of FNDC3A increased cell viability, abundance of mRNA encoding a putative receptor FOLR1, and increased phosphorylation of Akt. Collectively, these data suggest that FNDC3A may regulate folliculogenesis in cattle by modulating IGF1-dependent granulosa cell steroidogenesis and glucose metabolism.

The Role of Adipocytokines and their Receptors in Prostate Cancer: Adiponectin May Protect Against Progression.

BACKGROUND/AIM: Obesity is correlated with an increased risk of developing malignancies, including prostate cancer. Adipocytokines, such as leptin and adiponectin, are a family of hormones derived from adipose tissue that are involved not only in metabolism, but also in the development and progression of various malignancies. However, little is known about their role in prostate cancer. This study aimed to determine how leptin, adiponectin, and their receptors impact the spread of prostate cancer. MATERIALS AND METHODS: We first performed immunohistochemical analysis of prostate cancer tissue microarrays to detect leptin, leptin receptor (Ob-R), adiponectin, and adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). Wound healing assays and western blot analysis were then performed in human prostate cancer cell lines. RESULTS: Immunohistochemistry showed that prostate tissue was not significantly positive for adiponectin. However, its expression tended to decrease according to the International Society of Urological Pathology (ISUP) grade of prostate cancer (p=0.056). In prostate cancer cell lines, administration of the synthetic adiponectin AdipoRon suppressed cell migration as well as the expression of phospho-NF-[Formula: see text]B and cyclooxygenase-2, whereas leptin stimulated these effects. CONCLUSION: Adiponectin expression tended to be suppressed according to ISUP grade in prostate cancer tissues. In vitro, tumor cell migration was induced by leptin but suppressed by adiponectin. Targeting adipocytokines could be a novel treatment strategy for prostate cancer.