Disulfide bond, an important post-translational modification in peptides or proteins, is of great significance for stabilizing the three-dimensional spatial structure of peptides and proteins, maintaining correct folding conformation, and regulating biological activity. The medicinal peptide with unexpected disulfide connectivity might not have efficacy, even induce immunogenicity. Therefore, it is of importance to assign disulfide connectivity for a peptide.

A relatively simple method based on partial reduction without alkylation was developed. For demonstration, ziconotide was chosen as a model establishing the method. After a partial reduction reaction by using tris(2-carboxyethyl)phosphine, the partially reduced ziconotide products containing one disulfide bond were analyzed by liquid chromatography tandem mass spectrometry. The information about the sequence uninvolved in the cyclic structure was obtained by tandem mass spectrometry, which reveals the connectivity of the disulfide bridges forming the cyclic structure.

Based on the results of only two partially reduced products, accurate connectivity of all disulfide bridges in ziconotide was obtained. Six cysteine moieties present in a ziconotide molecule form three disulfide bonds, which could produce 15 possible disulfide isoforms with different disulfide connectivities. The actual disulfide connectivity was easily identified using this novel method.

A relatively simple method based on partial reduction without alkylation, followed by analysis with liquid chromatography-tandem mass spectrometry, was developed, assigning disulfide connectivity for a disulfide-rich peptide. This method is useful in the quality control of medicinal peptides with an extensive disulfide network.

Adipose tissue is an immunologically active organ that controls host physiology, partly through the release of mediators termed adipokines. In obesity, adipocytes and infiltrating leukocytes produce adipokines, which include the hormones adiponectin and leptin and cytokines such as tumour necrosis factor and IL-1β. These adipokines orchestrate immune responses that are collectively referred to as metabolic inflammation. Consequently, metabolic inflammation characterizes metabolic disorders and promotes distinct disease aspects, such as insulin resistance, metabolic dysfunction-associated liver disease and cardiovascular complications. In this unifying concept, adipokines participate in the immunological cross-talk that occurs between metabolically active organs in metabolic diseases, highlighting the fundamental role of adipokines in obesity and their potential for therapeutic intervention. Here, we summarize how adipokines shape metabolic inflammation in mice and humans, focusing on their contribution to metabolic disorders in the setting of obesity and discussing their value as therapeutic targets.

Adiponectin (APN) is a multimeric protein with anti-inflammatory properties that is specifically secreted by adipocytes. Continuous plasma exchange with dialysis (cPED) is a blood purification therapy in which plasma exchange is performed using a selective membrane plasma separator while the dialysate flows outside the hollow fibers.

Patients with sepsis were divided into two groups based on the presence or absence of acute kidney injury (AKI) complications: AKI and non-AKI group.

Plasma APN levels significantly increased after cPED in both groups. The creatinine levels in the AKI group before cPED were significantly higher than those in the non- AKI group. The plasma APN levels in the AKI group before cPED were significantly higher than those in the non-AKI group.

cPED increased APN levels in both patients with and without AKI. Therefore, cPED therapy may be a promising intervention for increasing APN levels in patients with sepsis.

Adiponectin is an anti-diabetic and anti-atherogenic protein secreted primarily from adipose tissue. Adiponectin and modified LDL (mLDL) form a complex to modulate their biological activity. To elucidate the significance of the complex formation, we analyzed its effects on vascular tissue and developed and verified novel quantifying methods for adiponectin.

To study the significance of the mLDL-adiponectin complex (MAC) formation, we used the wire-myography method on rat mesenteric artery. We developed a method to measure MAC by using LOX-1 as the capture protein and anti-adiponectin antibody for detection. We compared serum MAC levels between hemodialysis patients and control subjects.

Administering mLDL alone to rat mesenteric artery impaired endothelium-dependent vasorelaxation, whereas simultaneously administering adiponectin with mLDL protected rat mesenteric artery from the mLDL-induced impairment of vasorelaxation. This finding indicates MAC formation prevents endothelium from mLDL-induced dysfunction in tissue. Using our novel ELISA for MAC, we found that MAC was increasingly detectable depending on the doses of mLDL and adiponectin in vitro. In serum, hemodialysis patients showed a significantly higher ratio of MAC-high patients (higher than the median level of MAC) than did healthy controls. Furthermore, the MAC-high hemodialysis group had lower mLDL activity measured as LOX-1 ligand containing apoB.

Using our ELISA, we detected MAC in human serum that protected blood vessels from the deleterious effects of oxidized LDL.

The metabolic response to a maximal exercise test in physically inactive adults remains poorly understood, particularly regarding the role of adiponectin, an adipokine with insulin-sensitizing and anti-inflammatory properties. Adiponectin circulates in three isoforms-low (LMW), medium (MMW), and high-molecular-weight (HMW)-with differing bioactivities. While exercise is known to influence adiponectin levels, evidence is conflicting, and few studies have explored isoform-specific changes. This study aimed to evaluate the effects of a single maximal exercise session on circulating adiponectin isoforms and their associations with metabolic and kidney function markers in physically inactive young adults. In this quasi-experimental study, twenty-one physically inactive participants (mean age 24.6 ± 2.1 years, 85.7% women) completed a progressive cycle ergometer test. Circulating levels of LMW and MMW adiponectin, metabolic outcomes (e.g., cholesterol, triglycerides, fibroblast growth factor 21 (FGF21)), and kidney function markers (e.g., creatinine, proteinuria) were assessed before and after exercise using biochemical assays and Western blotting. Comparisons between pre- and post-exercise values were made with the Wilcoxon test. Exercise increased lipid metabolism markers (total cholesterol, triglycerides, HDL) and kidney stress indicators (albuminuria, proteinuria) (p < 0.05). LMW and MMW adiponectin levels showed no significant overall changes, but LMW adiponectin positively correlated with changes in total cholesterol and FGF21, while MMW adiponectin negatively correlated with creatinine and proteinuria (p < 0.05). HMW adiponectin was undetectable by our methods. A single maximal exercise session revealed isoform-specific associations between adiponectin and metabolic or kidney stress markers, emphasizing the complex role of adiponectin in exercise-induced metabolic responses. Future research should explore mechanisms underlying these differential associations to optimize exercise interventions for metabolic health improvement.

Diabetes and depression have a bidirectional relationship, with negative impacts on glycemia, self-care, long-term complications, quality of life, and mortality. This review highlights key aspects of the interconnected and complex relationship between diabetes and depression, including how it affects health outcomes, depression duration and recurrence, age-specific manifestations, and recommendations for screening and nonpharmacological treatment.

Adiponectin is an abundantly secreted hormone that communicates information between the adipose tissue, and the immune and cardiovascular systems. In metabolically healthy individuals, adiponectin is usually found at high levels and helps improve insulin responsiveness of peripheral tissues, glucose tolerance, and fatty acid oxidation. Beyond its metabolic functions in insulin-sensitive tissues, adiponectin plays a prominent role in attenuating the development of atherosclerotic plaques, partially through regulating macrophage-mediated responses. In this context, adiponectin binds to its receptors, adiponectin receptor 1 (AdipoR1) and AdipoR2 on the cell surface of macrophages to activate a downstream signaling cascade and induce specific atheroprotective functions. Notably, macrophages modulate the stability of the plaque through their ability to switch between proinflammatory responders, and anti-inflammatory proresolving mediators. Traditionally, the extremes of the macrophage polarization spectrum span from M1 proinflammatory and M2 anti-inflammatory phenotypes. Previous evidence has demonstrated that the adiponectin-AdipoR pathway influences M1-M2 macrophage polarization; adiponectin promotes a shift toward an M2-like state, whereas AdipoR1- and AdipoR2-specific contributions are more nuanced. To explore these concepts in depth, we discuss in this review the effect of adiponectin and AdipoR1/R2 on 1) metabolic and immune responses, and 2) M1-M2 macrophage polarization, including their ability to attenuate atherosclerotic plaque inflammation, and their potential as therapeutic targets for clinical applications.

The increasing incidence of metabolic diseases, including obesity and diabetes, is a serious social public problem. Therefore, there is an urgent need to find effective prevention and treatment measures for these diseases. DsbA-L is a protein that is widely expressed in many tissues and is closely related to metabolism. Emerging evidence shows that DsbA-L plays an important role in antioxidative stress, promoting the synthesis and secretion of adiponectin and maintaining mitochondrial homeostasis, and the abnormalities of these functions are also closely related to the occurrence and development of metabolic diseases. Here, we reviewed the tissue expression patterns and regulatory factors of DsbA-L, summarized its biological functions and the current research progress of DsbA-L in metabolic diseases, and found that DsbA-L may be a promising target for metabolic diseases.

Current research has found that adipose tissue is not only involved in energy metabolism, but also a highly active endocrine organ that secretes various adipokines, including adiponectin, leptin, resistin and apelin, which are involved in the regulation of physiology and pathology of tissues and organs throughout the body. With the yearly increasing incidence, obesity has become a risk factor for a variety of pathological changes, including inflammation and metabolic syndrome in various system (endocrine, circulatory, locomotor and central nervous system). Thus these symptoms lead to multi-organ dysfunctions, including the heart, liver, kidneys, brain and joints. An in-depth summary of the roles of adipokines in the regulation of other tissues and organs can help to provide more effective therapeutic strategies for obesity-related diseases and explore potential therapeutic targets. Therefore, this review has retrospected the endocrine function of adipose tissue under obesity and the role of dysregulated adipokine secretion in related diseases and the underlying mechanisms, in order to provide a theoretical basis for targeting adipokine-mediated systemic dysregulation.

Hepatic fibrosis, a degenerative liver lesion, significantly contributes to the deterioration and mortality among patients with chronic liver diseases. The condition arises from various factors including toxins, such as alcohol, infections like different types of viral hepatitis, and metabolic diseases. Currently, there are no effective treatments available for liver fibrosis. Recent research has shown that adiponectin (ADPN) exhibits inhibitory effects on hepatic fibrosis. ADPN, an adipocytokine secreted by mature adipocytes, features receptors that are widely distributed across multiple tissues, especially the liver. In the liver, direct effects of ADPN on liver fibrosis include reducing inflammation and regulating hepatic stellate cell proliferation and migration. And its indirect effects include alleviating hepatic endoplasmic reticulum stress and reducing inflammation in hepatic lobules, thereby mitigating hepatic fibrosis. This review aims to elucidate the regulatory role of ADPN in liver fibrosis, explore how ADPN and its receptors alleviate endoplasmic reticulum stress, summarize ADPN detection methods, and discuss its potential as a novel marker and therapeutic agent in combating hepatic fibrosis.

Oxidative stress in adipose tissue may alter the secretion pattern of adipocytokines and potentially promote atherosclerosis. However, the therapeutic role of hydrogen in adipose tissue under oxidative stress remains unclear. In this study, subcutaneous adipose tissue (SCAT) was collected from the mid-thoracic wounds of 12 patients who underwent open-heart surgery with a mid-thoracic incision. The adipose tissue was then immersed in a culture medium dissolved with hydrogen, which was generated using a hydrogen-generating device. The weight of the adipose tissue was measured before and after hydrogenation, and the tissue was immunostained for nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase (SOD), which are markers of oxidative stress. The immunostaining results showed that HO-1 and Nrf2 expression levels were significantly decreased in the hydrogenated group, whereas SOD expression levels increased, but did not attain statistical significance. Image analysis of adipose tissue revealed that a reduction in adipocyte size. Furthermore, hydrogenated adipose tissue showed a trend toward increased gene expression levels of adiponectin and decreased gene expression levels of chemerin, an adipocytokine involved in adipogenesis. These results demonstrated the therapeutic potential of hydrogen gas for oxidative stress in adipose tissue and for reducing adipocyte size.

Adipose tissues produce a variety of biologically active compounds, including cytokines, growth factors and adipokines. Adipokines are important as they function as endocrine hormones that are related to various metabolic and reproductive diseases. The goal of this review was to summarise the role of asprosin, a recently discovered adipokine, and compare its role in ovarian steroidogenesis with that of other adipokines including adiponectin, leptin, resistin, apelin, visfatin, chemerin, irisin, and gremlin 1. The summary of concentrations of these adipokines in humans, rats and other animals will help researchers identify appropriate doses to test in future studies. Review of the literature indicated that asprosin increases androstenedione production in theca cells (Tc), and when cotreated with FSH increases oestradiol production in granulosa cells (Gc). In comparison, other adipokines (1) stimulate Gc oestradiol production but inhibit Tc androgen production (adiponectin), (2) inhibit Gc oestradiol production and Tc androstenedione production (leptin and chemerin), (3) inhibit Gc steroidogenesis with no effect on Tc (resistin), (4) inhibit Gc oestradiol production but stimulate Tc androgen production (gremlin 1), and (5) increase steroid secretion by Gc, with unknown effects on Tc steroidogenesis (apelin and visfatin). Irisin has direct effects on Gc but its precise role (inhibitory or stimulatory) may be species dependent and its effects on Tc will require additional research. Thus, most adipokines have direct effects (either positive or negative) on steroid production in ovarian cells, but how they all work together to create a cumulative effect or disease will require further research.

Adiponectin (ADPN), which serum/plasma adiponectin levels are closely associated with insulin resistance and type 2 diabetes, and lower adiponectin levels predict an increased risk of diabetes, is a strong indicator of diabetes risk in people at high risk of diabetes in different races. Using the unique principle and performance advantages of chemiluminescence immunoassay (CLIA), an ADPN-CLIA method with high sensitivity, high specificity and wide detection range was established based on the principle of two-steps method of sandwich-type, with the magnetic particles (MPs) as the solid phase carrier and acridinium ester (AE) as the chemiluminescence reaction system. The selection of the main raw materials required, the preparation conditions of MPs-coated antibodies, the methods of AE-labeled antibodies, sample requirements and reaction modes were optimized and evaluated. AE labeling experiment was successfully performed with the labeling efficiency of 8.366 and the antibody utilization rate of 96.8%. The chemiluminescent immunoassay for ADPN had a good linear relationship from 0 ng/mL to 250 ng/mL (R2 =0.9993), with the detection limit of 0.05 ng/mL. The coefficient of variation (CV) of intra-assay and inter-assay precision were both less than 5% respectively. The recovery rates for accuracy were from 91.26% to 107.46%. The comparison experiment of 80 clinical serum samples between the developed ADPN-CLIA with the immunoturbidimetry showed that the correlation coefficient was 0.956, and the Bland-Altman analysis showed that the limits of agreement were - 0.364 and 0.433.

The potential benefits of adiponectin replacement therapy extend to numerous human diseases, with current research showing particular interest in its effectiveness against specific cancer forms, especially hormone-related. However, limitations in the pharmacological use of the intact protein have led to a focus on alternative options. AdipoRon is an extensively studied non-peptidic drug candidate for adiponectin replacement therapy. While researchers have explored the efficacy and therapeutic applications of AdipoRon in various disease conditions, their effects against cancer models advanced more, with no review regarding AdipoRon's efficacy against hormone-related cancers being published. The present systematic review aims to fill this gap. Preclinical evidence was compiled from PubMed, EMBASE, COCHRANE, and Google Scholar following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the manuscript's quality assessment was conducted using the Joanna Briggs Institute (JBI) Checklist Critical Appraisal Tool for Systematic Reviews' Quality. The included nine studies incorporated various cell and animal models of the pancreas, gynaecological system, and osteosarcoma cancers. AdipoRon demonstrated effectiveness against pancreatic cancer by activating p44/42 MAPK, mitochondrial dysfunction, and AMPK-mediated inhibition of ACC1. In gynaecological cancers, it exhibited promising anticancer effects through the activation of AMPK, potential inhibition of mTOR, and modulation of the SET1B/BOD1/AdipoR1 signaling cascade. Against osteosarcoma, AdipoRon worked by perturbing ERK1/2 signaling and reducing p70S6K phosphorylation. AdipoRon shows promise in preclinical studies, but human trials are crucial for clinical safety and effectiveness. Caution is needed due to potential off-target effects, especially in cancer therapy with multi-target approaches. Structural biology and computational methods can help predict these effects.

In addition to their pivotal roles in energy storage and expenditure, adipose tissues play a crucial part in the secretion of bioactive molecules, including peptides, lipids, metabolites, and extracellular vesicles, in response to physiological stimulation and metabolic stress. These secretory factors, through autocrine and paracrine mechanisms, regulate various processes within adipose tissues. These processes include adipogenesis, glucose and lipid metabolism, inflammation, and adaptive thermogenesis, all of which are essential for the maintenance of the balance and functionality of the adipose tissue micro-environment. A subset of these adipose-derived secretory factors can enter the circulation and target the distant tissues to regulate appetite, cognitive function, energy expenditure, insulin secretion and sensitivity, gluconeogenesis, cardiovascular remodeling, and exercise capacity. In this review, we highlight the role of adipose-derived secretory factors and their signaling pathways in modulating metabolic homeostasis. Furthermore, we delve into the alterations in both the content and secretion processes of these factors under various physiological and pathological conditions, shedding light on potential pharmacological treatment strategies for related diseases.

The carotid bodies (CBs) have been implicated in glucose abnormalities in obesity via elevation of activity of the sympathetic nervous system. Obesity-induced hypertension is mediated by insulin receptor (INSR) signaling and by leptin, which binds to the leptin receptor (LEPRb) in CB and activates transient receptor potential channel subfamily M member 7 (TRPM7). We hypothesize that in mice with diet-induced obesity, hyperglycemia, glucose intolerance, and insulin resistance will be attenuated by the CB denervation (carotid sinus nerve dissection, CSND) and by knockdown of Leprb, Trpm7, and Insr gene expression in CB. In series of experiments in 75 male diet-induced obese (DIO) mice, we performed either CSND (vs. sham) surgeries or shRNA-induced suppression of Leprb, Trpm7, or Insr gene expression in CB, followed by blood pressure telemetry, intraperitoneal glucose tolerance and insulin tolerance tests, and measurements of fasting plasma insulin, leptin, corticosterone, glucagon and free fatty acids (FFAs) levels, hepatic expression of gluconeogenesis enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G-6-Pase) mRNA and liver glycogen levels. CSND decreased blood pressure, fasting blood glucose levels and improved glucose tolerance without any effect on insulin resistance. CSND did not affect any hormone levels and gluconeogenesis enzymes, but increased liver glycogen level. Genetic knockdown of CB Leprb, Trpm7, and Insr had no effect on glucose metabolism. We conclude that CB contributes to hyperglycemia of obesity, probably by modulation of the glycogen-glucose equilibrium. Diabetogenic effects of obesity on CB in mice do not occur via activation of CB Leprb, Trpm7, and Insr.NEW & NOTEWORTHY This paper provides first evidence that carotid body denervation abolishes hypertension and improves fasting blood glucose levels and glucose tolerance in mice with diet-induced obesity. Furthermore, we have shown that this phenomenon is associated with increased liver glycogen content, whereas insulin sensitivity and enzymes of gluconeogenesis were not affected.

The endocrine function of white adipose tissue is characterized by the synthesis of one its main hormones: adiponectin. Although the biological role of adiponectin has not been fully defined, clinical and experimental observations have shown that low plasma concentrations of adiponectin participate in the prevalence of insulin resistance and cardiovascular diseases, mainly in obese patients. Adiponectin also exerts its effects on the heart and blood vessels, thereby influencing their physiology. Studying the effects of adiponectin presents some complexities, primarily due to potential cross-interactions and interference with other pathways, such as the AdipoR1/R2 pathways. Under optimal conditions, the activation of the adiponectin cascade may involve signals such as AMPK and PPARα. Interestingly, these pathways may trigger similar responses, such as fatty acid oxidation. Understanding the downstream effectors of these pathways is crucial to comprehend the extent to which adiponectin signaling impacts metabolism. In this review, the aim is to explore the current mechanisms that regulate the adiponectin pathways. Additionally, updates on the major downstream factors involved in adiponectin signaling are provided, specifically in relation to metabolic syndrome and atherosclerosis.

Adiponectin, an adipose-derived hormone, plays a pivotal role in glucose regulation and lipid metabolism, with a decrease in circulating adiponectin levels being linked to insulin resistance and prediabetes. This review examines the therapeutic potential of adiponectin in managing prediabetes, elucidating on multiple aspects including its role in glucose and lipid metabolism, influence on insulin sensitivity, and anti-inflammatory properties. Moreover, the paper highlights the latest strategies to augment adiponectin levels, such as gene therapy, pharmacological interventions, dietary modifications, and lifestyle changes. It also addresses the challenges encountered in translating preclinical findings into clinical practice, primarily related to drug delivery, safety, and efficacy. Lastly, the review proposes future directions, underlining the need for large-scale human trials, novel adiponectin analogs, and personalized treatment strategies to harness adiponectin's full therapeutic potential in preventing the transition from prediabetes to diabetes.

The adiponectin (APN) levels in obesity are negatively correlated with chronic subclinical inflammation markers. The hypertrophic adipocytes cause obesity-linked insulin resistance and metabolic syndrome. Furthermore, macrophage polarization is a key determinant regulating adiponectin receptor (AdipoR1/R2) expression and differential adiponectin-mediated macrophage inflammatory responses in obese individuals. In addition to decrease in adiponectin concentrations, the decline in AdipoR1/R2 messenger ribonucleic acid (mRNA) expression leads to a decrement in adiponectin binding to cell membrane, and this turns into attenuation in the adiponectin effects. This is defined as APN resistance, and it is linked with insulin resistance in high-fat diet-fed subjects. The insulin-resistant group has a significantly higher leptin-to-APN ratio. The leptin-to-APN ratio is more than twofold higher in obese individuals. An increase in expression of AdipoRs restores insulin sensitivity and β-oxidation of fatty acids via triggering intracellular signal cascades. The ratio of high molecular weight to total APN is defined as the APN sensitivity index (ASI). This index is correlated to insulin sensitivity. Homeostasis model of assessment (HOMA)-APN and HOMA-estimated insulin resistance (HOMA-IR) are the most suitable methods to estimate the metabolic risk in metabolic syndrome. While morbidly obese patients display a significantly higher plasma leptin and soluble (s)E-selectin concentrations, leptin-to-APN ratio, there is a significant negative correlation between leptin-to-APN ratio and sP-selectin in obese patients. When comparing the metabolic dysregulated obese group with the metabolically healthy obese group, postprandial triglyceride clearance, insulin resistance, and leptin resistance are significantly delayed following the oral fat tolerance test in the first group. A neuropeptide, Spexin (SPX), is positively correlated with the quantitative insulin sensitivity check index (QUICKI) and APN. APN resistance together with insulin resistance forms a vicious cycle. Despite normal or high APN levels, an impaired post-receptor signaling due to adaptor protein-containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif 1 (APPL1)/APPL2 may alter APN efficiency and activity. However, APPL2 blocks adiponectin signaling through AdipoR1 and AdipoR2 because of the competitive inhibition of APPL1. APPL1, the intracellular binding partner of AdipoRs, is also an important mediator of adiponectin-dependent insulin sensitization. The elevated adiponectin levels with adiponectin resistance are compensatory responses in the condition of an unusual discordance between insulin resistance and APN unresponsiveness. Hypothalamic recombinant adeno-associated virus (rAAV)-leptin (Lep) gene therapy reduces serum APN levels, and it is a more efficient strategy for long-term weight maintenance.

Cholangiocarcinoma (CCA) has a poor prognosis and only limited palliative treatment options. The deficiency of adiponectin and adenosine monophosphate-activated protein kinase (AMPK) signaling was reported in several malignancies, but the alteration of these proteins in CCA is still unclear.

This study aimed to assess the role of adiponectin and AMPK signaling in CCA. Furthermore, AdipoRon, a novel adiponectin receptor (AdipoR) agonist, was evaluated in vitro and in vivo as a new anti-tumor therapy for CCA.

The expression of AdipoR1 and p-AMPKα in human tissue microarrays (TMAs) was evaluated by immunohistochemistry staining (IHC). The effect of 2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide (AdipoRon) was investigated in vitro with proliferation, crystal violet, migration, invasion, colony formation, senescence, cell cycle and apoptosis assays and in vivo using a CCA engineered mouse model (AlbCre/LSL-KRASG12D/p53L/L). RT-qPCR and western blot methods were applied to study molecular alterations in murine tissues.

AdipoR1 and p-AMPKα were impaired in human CCA tissues, compared to adjacent non-tumor tissue. There was a positive correlation between the AdipoR1 and p-AMPKα levels in CCA tissues. Treatment with AdipoRon inhibited proliferation, migration, invasion and colony formation and induced apoptosis in a time- and dose-dependent manner in vitro (p<0.05). In addition, AdipoRon reduced the number of CCA and tumor volume, prolonged survival, and decreased metastasis and ascites in the treated group compared to the control group (p<0.05).

AdipoR1 and p-AMPKα are impaired in CCA tissues, and AdipoRon effectively inhibits CCA in vitro and in vivo. Thus, AdipoRon may be considered as a potential anti-tumor therapy in CCA.

Obesity is rapidly becoming a global health problem affecting about 13% of the world's population affecting women and children the most. Recent studies have stated that obese asthmatic subjects suffer from an increased risk of asthma, encounter severe symptoms, respond poorly to anti-asthmatic drugs, and ultimately their quality-of-life decreases. Although, the association between airway hyperresponsiveness (AHR) and obesity is a growing concern among the public due to lifestyle and environmental etiologies, however, the precise mechanism underlying this association is yet to establish. Apart from aiming at the conventional antiasthmatic targets, treatment should be directed towards ameliorating obesity pathogenesis too. Understanding the pathogenesis underlying the association between obesity and AHR is limited, however, a plethora of obesity pathologies have been reported viz., increased pro-inflammatory and decreased anti-inflammatory adipokines, depletion of ROS controller Nrf2/HO-1 axis, NLRP3 associated macrophage polarization, hypertrophy of WAT, and down-regulation of UCP1 in BAT following down-regulated AMPKα and melanocortin pathway that may be correlated with AHR. Increased waist circumference (WC) or central obesity was thought to be related to severe AHR, however, some recent reports suggest body mass index (BMI), not WC tends to exaggerate airway closure in AHR due to some unknown mechanisms. This review aims to co-relate the above-mentioned mechanisms that may explain the copious relation underlying obesity and AHR with the help of published reports. A proper understanding of these mechanisms discussed in this review will ensure an appropriate treatment plan for patients through advanced pharmacological interventions.

Iron delivery to the plasma is closely coupled to erythropoiesis, the production of red blood cells, as this process consumes most of the circulating plasma iron. In response to hemorrhage and other erythropoietic stresses, increased erythropoietin stimulates the production of the hormone erythroferrone (ERFE) by erythrocyte precursors (erythroblasts) developing in erythropoietic tissues. ERFE acts on the liver to inhibit bone morphogenetic protein (BMP) signaling and thereby decrease hepcidin production. Decreased circulating hepcidin concentrations then allow the release of iron from stores and increase iron absorption from the diet. Guided by evolutionary analysis and Alphafold2 protein complex modeling, we used targeted ERFE mutations, deletions, and synthetic ERFE segments together with cell-based bioassays and surface plasmon resonance to probe the structural features required for bioactivity and BMP binding. We define the ERFE active domain and multiple structural features that act together to entrap BMP ligands. In particular, the hydrophobic helical segment 81 to 86 and specifically the highly conserved tryptophan W82 in the N-terminal region are essential for ERFE bioactivity and Alphafold2 modeling places W82 between two tryptophans in its ligands BMP2, BMP6, and the BMP2/6 heterodimer, an interaction similar to those that bind BMPs to their cognate receptors. Finally, we identify the cationic region 96-107 and the globular TNFα-like domain 186-354 as structural determinants of ERFE multimerization that increase the avidity of ERFE for BMP ligands. Collectively, our results provide further insight into the ERFE-mediated inhibition of BMP signaling in response to erythropoietic stress.

Adipose tissue is now recognized as an endocrine organ that secretes bioactive molecules called adipokines. These biomolecules regulate key physiological functions, including insulin sensitivity, energy metabolism, appetite regulation, endothelial function and immunity. Dysregulated secretion of adipokines is intimately associated with obesity, and translates into increased risk of obesity-related cardiovasculo-metabolic diseases. In particular, emerging evidence suggests that adipokine imbalance contributes to the pathogenesis of atherosclerosis. One of the promising diet regimens that is beneficial in the fight against obesity and cardiometabolic disorders is intermittent fasting (IF). Indeed, IF robustly suppresses inflammation, meditates weight loss and mitigates many aspects of the cardiometabolic syndrome. In this paper, we review the main adipokines and their role in atherosclerosis, which remains a major contributor to cardiovascular-associated morbidity and mortality. We further discuss how IF can be employed as an effective management modality for obesity-associated atherosclerosis. By exploring a plethora of the beneficial effects of IF, particularly on inflammatory markers, we present IF as a possible intervention to help prevent atherosclerosis.

Adiponectin has also been associated with diabetic retinopathy, a diabetic microvascular complication. However, the mechanism of action of adiponectin in retinopathy is still under investigation. This review summarizes emerging evidence on the association with diabetic retinopathy in type 2 diabetes.

We reviwed papers from 2004 to 2022 and included studies related to retinopathy and its association with blood and intraocular adiponectin in type 2 diabetes.

Most of the studies analyzed in this review suggested an association between the diabetic retinopathy progression and intraocular, serum, or plasma adiponectin levels. Increased levels of adiponectin contributed to the development of the disease in diabetic patients. In a minority of studies, it was indicated an inversely proportional relationship between adiponectin concentration and diabetic retinopathy severity.

The high levels of adiponectin in diabetic patients may be related to the decrease in renal clearance. Under this situation, if the predominant isoform is globular adiponectin, this may explain the retinopathy progression, considering a pro-inflammatory response induced by this isoform. However, the actions of adiponectin in diabetic retinopathy pathophysiology are still controversial.

High levels of circulating adiponectin are associated with increased insulin sensitivity, low prevalence of diabetes, and low body mass index (BMI); however, high levels of circulating adiponectin are also associated with increased mortality in the 60-70 age group. In this study, we aimed to clarify factors associated with circulating high-molecular-weight (cHMW) adiponectin levels and their association with mortality in the very old (85-89 years of age) and centenarians.

The study included 812 (women: 84.4%) for centenarians and 1498 (women: 51.7%) for the very old. The genomic DNA sequence data were obtained by whole-genome sequencing or DNA microarray-imputation methods. Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate regression analyses were used to evaluate cHMW adiponectin characteristics and associated factors. All-cause mortality was analyzed in three quantile groups of cHMW adiponectin levels using Cox regression.

The cHMW adiponectin levels were increased significantly beyond 100 years of age, were negatively associated with diabetes prevalence, and were associated with SNVs in CDH13 (p=2.21 × 10-22) and ADIPOQ (p=5.72 × 10-7). Multivariate regression analysis revealed that genetic variants, BMI, and high-density lipoprotein cholesterol (HDLC) were the main factors associated with cHMW adiponectin levels in the very old, whereas the BMI showed no association in centenarians. The hazard ratios for all-cause mortality in the intermediate and high cHMW adiponectin groups in very old men were significantly higher rather than those for all-cause mortality in the low-level cHMW adiponectin group, even after adjustment with BMI. In contrast, the hazard ratios for all-cause mortality were significantly higher for high cHMW adiponectin groups in very old women, but were not significant after adjustment with BMI.

cHMW adiponectin levels increased with age until centenarians, and the contribution of known major factors associated with cHMW adiponectin levels, including BMI and HDLC, varies with age, suggesting that its physiological significance also varies with age in the oldest old.

This study was supported by grants from the Ministry of Health, Welfare, and Labour for the Scientific Research Projects for Longevity; a Grant-in-Aid for Scientific Research (No 21590775, 24590898, 15KT0009, 18H03055, 20K20409, 20K07792, 23H03337) from the Japan Society for the Promotion of Science; Keio University Global Research Institute (KGRI), Kanagawa Institute of Industrial Science and Technology (KISTEC), Japan Science and Technology Agency (JST) Research Complex Program "Tonomachi Research Complex" Wellbeing Research Campus: Creating new values through technological and social innovation (JP15667051), the Program for an Integrated Database of Clinical and Genomic Information from the Japan Agency for Medical Research and Development (No. 16kk0205009h001, 17jm0210051h0001, 19dk0207045h0001); the medical-welfare-food-agriculture collaborative consortium project from the Japan Ministry of Agriculture, Forestry, and Fisheries; and the Biobank Japan Program from the Ministry of Education, Culture, Sports, and Technology.

The interplay between adipokines and pancreatic beta cells, often referred to as the adipo-insular axis, plays a crucial role in regulating metabolic homeostasis. Adipokines are signaling molecules secreted by adipocytes that have profound effects on several physiological processes. Adipokines such as adiponectin, leptin, resistin, and visfatin influence the function of pancreatic beta cells. The reciprocal communication between adipocytes and beta cells is remarkable. Insulin secreted by beta cells affects adipose tissue metabolism, influencing lipid storage and lipolysis. Conversely, adipokines released from adipocytes can influence beta cell function and survival. Chronic obesity and insulin resistance can lead to the release of excess fatty acids and inflammatory molecules from the adipose tissue, contributing to beta cell dysfunction and apoptosis, which are key factors in developing type 2 diabetes. Understanding the complex interplay of the adipo-insular axis provides insights into the mechanisms underlying metabolic regulation and pathogenesis of metabolic disorders. By elucidating the molecular mediators involved in this interaction, new therapeutic targets and strategies may emerge to reduce the risk and progression of diseases, such as type 2 diabetes and its associated complications. This review summarizes the interactions between adipokines and pancreatic beta cells, and their roles in the pathogenesis of diabetes and metabolic diseases.

Recent evidence supporting that adipose tissue (AT)-derived extracellular vesicles (EVs) carry an important part of the AT secretome led us to characterize the EV-adipokine profile. In addition to evidencing a high AT-derived EV secretion ability that is further increased by obesity, we identify enrichment of oligomeric forms of adiponectin in small EVs (sEVs). This adipokine is mainly distributed at the EV external surface as a result of nonspecific adsorption of soluble adiponectin. EVs also constitute stable conveyors of adiponectin in the blood circulation. Adiponectin-enriched sEVs display in vitro insulin-sensitizing effects by binding to regular adiponectin receptors. Adoptive transfer of adiponectin-enriched sEVs in high-fat-diet-fed mice prevents animals from gaining weight and ameliorated insulin resistance and tissue inflammation, with major effects observed in the AT and liver. Our results therefore provide information regarding adiponectin-related metabolic responses by highlighting EVs as delivery platforms of metabolically active forms of adiponectin molecules.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and right-heart complications. So, this study aimed to evaluate the role of right atrial volume index (RAVI), inflammatory biomarkers and functional capacity in predicting poor outcomes for patients with COPD, classified by COPD assessment test (CAT) questionnaire, as early predictors of right heart diseases.

151 patients with COPD with ejection fraction (LVEF) > 55% were enrolled and classified according to CAT questionnaire into CAT ≥ 10 (group I) and CAT < 10 (group II). RAVI was calculated using Echocardiography. Assessment of RV systolic function was done by Doppler imaging. Functional capacity parameters were assessed by modified medical research council dyspnea scale (mMRC). IL-1β, adiponectin, hs-CRP and neopterin were evaluated by ELSA kits.

Group I (CAT ≥ 10) had higher RAVI (73.92 ± 21.20 ml/m2 vs 22.73 ± 6.24 ml/m2, p < 0.001), lower S`tri (0.05 ± 0.01 vs 0.13 ± 0.03 m/s, p < 0.001), lower tricuspid annular plane systolic excursion (TAPSE) (1.20 ± 0.17 cm vs 2.17 ± 0.48 cm, p < 0.001), higher RVSP (54.88 ± 7.97 vs 26.79 ± 9.84 mmHg, p < 0.001) compared with group II (CAT < 10). RAVI was good predictor of CAT (r = 0.954, p < 0.001) and strongly correlated with tricuspid S`tri, RVSP, tricuspid E/e' and Mitral E/e' (r = -0.737, r = 0.753, r = 0.817 and r = 0.515, respectively, p < 0.001). RAVI was correlated with TAPSE (r = -0.673, p < 0.001) and with tricuspid E/A ratio & LVEF (r = 0.628, r = -0.407, respectively, p < 0.001). Hs-CRP: 2.50 ± 1.43 vs 2.03 ± 1.19, IL-1β: 37.96 ± 14.35 vs 27.57 ± 8.06, neopterin: 91.37 ± 17.30 vs 76.90 ± 16.75, p < 0.05) were significantly higher besides lower adiponectin levels (3.19 ± 1.98 vs 5.32 ± 1.33 p < 0.05) in group I as compared to group II.

Functional capacity might be useful predictor for right heart diseases in COPD patients. Inflammatory biomarkers, low adiponectin and high Hs-CRP, IL-1β and neopterin levels, might not only be useful to monitor treatment response but may also help to discriminate patients with a worsen prognosis.

Obesity has a noteworthy role in breast tumor initiation and progression. Among the mechanisms proposed, the most validated is the development of chronic low-grade inflammation, supported by immune cell infiltration along with dysfunction in adipose tissue biology, characterized by an imbalance in adipocytokines secretion and alteration of their receptors within the tumor microenvironment. Many of these receptors belong to the seven-transmembrane receptor family, which are involved in physiological features, such as immune responses and metabolism, as well as in the development and progression of several malignancies, including breast cancer. These receptors are classified as canonical (G protein-coupled receptors, GPCRs) and atypical receptors, which fail to interact and activate G proteins. Among the atypical receptors, adiponectin receptors (AdipoRs) mediate the effect of adiponectin, the most abundant adipocytes-derived hormone, on breast cancer cell proliferation, whose serum levels are reduced in obesity. The adiponectin/AdipoRs axis is becoming increasingly important regarding its role in breast tumorigenesis and as a therapeutic target for breast cancer treatment. The objectives of this review are as follows: to point out the structural and functional differences between GPCRs and AdipoRs, and to focus on the effect of AdipoRs activation in the development and progression of obesity-dependent breast cancer.

Adiponectin (APN) is an essential adipokine for a variety of reproductive processes. To investigate the role of APN in goat corpora lutea (CLs), CLs and sera from different luteal phases were collected for analysis. The results showed that the APN structure and content had no significant divergence in different luteal phases both in CLs and sera; however, high molecular weight APN was dominant in serum, while low molecular weight APN was more present in CLs. The luteal expression of both AdipoR1/2 and T-cadherin (T-Ca) increased on D11 and 17. APN and its receptors (AdipoR1/2 and T-Ca) were mainly expressed in goat luteal steroidogenic cells. The steroidogenesis and APN structure in pregnant CLs had a similar model as in the mid-cycle CLs. To further explore the effects and mechanisms of APN in CLs, steroidogenic cells from pregnant CLs were isolated to detect the AMPK-mediated pathway by the activation of APN (AdipoRon) and knockdown of APN receptors. The results revealed that P-AMPK in goat luteal cells increased after incubation with APN (1 μg/mL) or AdipoRon (25 μM) for 1 h, and progesterone (P4) and steroidogenic proteins levels (STAR/CYP11A1/HSD3B) decreased after 24 h. APN did not affect the steroidogenic protein expression when cells were pretreated with Compound C or SiAMPK. APN increased P-AMPK and reduced the CYP11A1 expression and P4 levels when cells were pretreated with SiAdipoR1 or SiT-Ca, while APN failed to affect P-AMPK, the CYP11A1 expression or the P4 levels when pretreated with SiAdipoR2. Therefore, the different structural forms of APN in CLs and sera may possess distinct functions; APN might regulate luteal steroidogenesis through AdipoR2 which is most likely dependent on AMPK.

Obesity significantly decreases life expectancy and increases the incidence of age-related dysfunctions, including β-cell dysregulation leading to inadequate insulin secretion. Here, we show that diluted plasma from obese human donors acutely impairs β-cell integrity and insulin secretion relative to plasma from lean subjects. Similar results were observed with diluted sera from obese rats fed ad libitum, when compared to sera from lean, calorically restricted, animals. The damaging effects of obese circulating factors on β-cells occurs in the absence of nutrient overload, and mechanistically involves mitochondrial dysfunction, limiting glucose-supported oxidative phosphorylation and ATP production. We demonstrate that increased levels of adiponectin, as found in lean plasma, are the protective characteristic preserving β-cell function; indeed, sera from adiponectin knockout mice limits β-cell metabolic fluxes relative to controls. Furthermore, oxidative phosphorylation and glucose-sensitive insulin secretion, which are completely abrogated in the absence of this hormone, are restored by the presence of adiponectin alone, surprisingly even in the absence of other serological components, for both the insulin-secreting INS1 cell line and primary islets. The addition of adiponectin to cells treated with plasma from obese donors completely restored β-cell functional integrity, indicating the lack of this hormone was causative of the dysfunction. Overall, our results demonstrate that low circulating adiponectin is a key damaging element for β-cells, and suggest strong therapeutic potential for the modulation of the adiponectin signaling pathway in the prevention of age-related β-cell dysfunction.

In normal circumstances, AT secretes anti-inflammatory adipokines (AAKs) which regulates lipid metabolism, insulin sensitivity, vascular hemostasis, and angiogenesis. However, during obesity AT dysfunction occurs and leads to microvascular imbalance and secretes several pro-inflammatory adipokines (PAKs), thereby favoring atherogenic dyslipidemia and insulin resistance. Literature suggests decreased levels of circulating AAKs and increased levels of PAKs in obesity-linked disorders. Importantly, AAKs have been reported to play a vital role in obesity-linked metabolic disorders mainly insulin resistance, type-2 diabetes mellitus and coronary heart diseases. Interestingly, AAKs counteract the microvascular imbalance in AT and exert cardioprotection via several signaling pathways such as PI3-AKT/PKB pathway. Although literature reviews have presented a number of investigations detailing specific pathways involved in obesity-linked disorders, literature concerning AT dysfunction and AAKs remains sketchy. In view of the above, in the present contribution an effort has been made to provide an insight on the AT dysfunction and role of AAKs in modulating the obesity and obesity-linked atherogenesis and insulin resistance.

"Obesity-linked insulin resistance", "obesity-linked cardiometabolic disease", "anti-inflammatory adipokines", "pro-inflammatory adipokines", "adipose tissue dysfunction" and "obesity-linked microvascular dysfunction" are the keywords used for searching article. Google scholar, Google, Pubmed and Scopus were used as search engines for the articles.

This review offers an overview on the pathophysiology of obesity, management of obesity-linked disorders, and areas in need of attention such as novel therapeutic adipokines and their possible future perspectives as therapeutic agents.

Epilepsy is a common and severe neurological disorder in which impaired glucose metabolism leads to changes in neuronal excitability that slow or promote the development of epilepsy. Leptin and adiponectin are important mediators regulating glucose metabolism in the peripheral and central nervous systems. Many studies have reported a strong association between epilepsy and these two adipokines involved in multiple signaling cascades and glucose metabolism. Due to the complex regulatory mechanisms between them and various signal activation networks, their role in epilepsy involves many aspects, including the release of inflammatory mediators, oxidative damage, and neuronal apoptosis. This paper aims to summarize the signaling pathways involved in leptin and adiponectin and the regulation of glucose metabolism from the perspective of the pathogenesis of epilepsy. In particular, we discuss the dual effects of leptin in epilepsy and the relationship between antiepileptic drugs and changes in the levels of these two adipokines. Clinical practitioners may need to consider these factors in evaluating clinical drugs. Through this review, we can better understand the specific involvement of leptin and adiponectin in the pathogenesis of epilepsy, provide ideas for further exploration, and bring about practical significance for the treatment of epilepsy, especially for the development of personalized treatment according to individual metabolic characteristics.

Obesity and type 2 diabetes account for a considerable proportion of the global burden of age-related metabolic diseases. In age-related metabolic diseases, tissue crosstalk and metabolic regulation have been primarily linked to endocrine processes. Skeletal muscle and adipose tissue are endocrine organs that release myokines and adipokines into the bloodstream, respectively. These cytokines regulate metabolic responses in a variety of tissues, including skeletal muscle and adipose tissue. However, the intricate mechanisms underlying adipose-muscle crosstalk in age-related metabolic diseases are not fully understood. Recent exciting evidence suggests that myokines act to control adipose tissue functions, including lipolysis, browning, and inflammation, whereas adipokines mediate the beneficial actions of adipose tissue in the muscle, such as glucose uptake and metabolism. In this review, we assess the mechanisms of adipose-muscle crosstalk in age-related disorders and propose that the adipokines adiponectin and spexin, as well as the myokines irisin and interleukin-6 (IL-6), are crucial for maintaining the body's metabolic balance in age-related metabolic disorders. In addition, these changes of adipose-muscle crosstalk in response to exercise or dietary flavonoid consumption are part of the mechanisms of both functions in the remission of age-related metabolic disorders. A better understanding of the intricate relationships between adipose tissue and skeletal muscle could lead to more potent therapeutic approaches to prolong life and prevent age-related metabolic diseases.

The prevalence of obesity-related metabolic diseases caused by insulin resistance is rapidly increasing worldwide. Adiponectin (ADPN), a hormone derived from adipose tissue, is a potential therapeutic agent for insulin resistance. Chickens are considered efficient bioreactors for recombinant protein production because they secrete large amounts of high-concentration proteins from the oviduct. Additionally, chickens express high levels of high-molecular-weight (HMW) ADPN, which is considered the active form in the body. Therefore, in this study, a gene-targeted chicken model was produced in which the gene encoding human ADPN was inserted into Ovalbumin (OVA) using the CRISPR/Cas9 system, and the characteristics of the resulting recombinant ADPN protein were evaluated. As a result, human ADPN was expressed in G₁ hen oviducts and egg whites of OVA ADPN knock-in (KI) chickens. The concentration of ADPN in egg white ranged from 1.47 to 4.59 mg/mL, of which HMW ADPN accounted for ∼29% (0.24-1.49 mg/mL). Importantly, egg white-derived ADPN promoted expression of genes related to fatty acid oxidation and activated the 5'-AMP-activated protein kinase (AMPK) signaling pathway in muscle cells. In summary, the OVA gene-targeted chicken bioreactor proved to be an advantageous model for production of human ADPN, and the resulting protein was of sufficient quantity and efficacy for industrial use.

The effects of exercise training (Ex), dietary interventions (DIs), and a combination of Ex and DI (Ex + DI) on leptin and adiponectin have been established. However, less is known regarding the comparisons of Ex with DI and of Ex + DI with either Ex or DI alone. The aim of the present meta-analysis is to compare the effects of Ex with those of DI and those of Ex + DI with those of either Ex or DI alone on circulating leptin and adiponectin in individuals who are overweight and those with obesity. PubMed, Web of Science, and MEDLINE were searched to identify original articles, published through June 2022, that compared the effects of Ex with those of DI and/or the effects of Ex + DI with those of Ex and/or DI on leptin and adiponectin in individuals with BMIs (in kg/m²) of ≥25 and aged 7-70 y. Standardized mean differences (SMDs), weighted mean differences, and 95% CIs were calculated using random-effect models for outcomes. Forty-seven studies, comprising 3872 participants who were overweight and those with obesity, were included in the current meta-analysis. DI reduced the concentration of leptin (SMD: -0.30; P = 0.001) and increased the concentration of adiponectin (SMD: 0.23; P = 0.001) compared with Ex, as did Ex + DI (leptin: SMD: -0.34; P = 0.001; adiponectin: SMD: 0.37; P = 0.004) compared with Ex alone. However, Ex + DI did not affect the concentration of adiponectin (SMD: 0.10; P = 0.11) and led to inconsistent and nonsignificant changes in the concentration of leptin (SMD: -0.13; P = 0.06) compared with DI alone. Subgroup analyses showed that age, BMI, duration of intervention, type of supervision, quality of the study, and magnitude of energy restriction are sources of heterogeneity. Our results suggest that Ex alone was not as effective as DI or Ex + DI for decreasing leptin and increasing adiponectin in individuals with overweight and obesity. However, Ex + DI was not more effective than DI alone, suggesting that diet plays a critical role in beneficially altering the concentrations of leptin and adiponectin. This review was registered at PROSPERO as CRD42021283532.

Hormone-dependent cancers are a major cause of morbidity and mortality in both genders. Accumulating evidence suggest that adiponectin, an adipokine with multifaceted functions, is implicated in the pathogenesis of several malignancies. In the present review, we discuss the existing data regarding this relationship. Several observational studies showed that low adiponectin levels are associated with higher risk for breast, cervical, endometrial, ovarian and prostate cancer. A relationship between adiponectin and the aggressiveness of some of these tumors has also been reported. In vitro studies reported that adiponectin inhibits the proliferation and induces apoptosis of breast, cervical, endometrial, ovarian and prostate cancer cells. Given the high prevalence of these cancers and the substantial associated morbidity and mortality, the role of agents that increase adiponectin levels and/or stimulate its activity should be evaluated for the prevention and management of these common tumors.

Rising rates of obesity are intricately tied to the type 2 diabetes epidemic. The adipose tissues can play a central role in protection against or triggering metabolic diseases through the secretion of adipokines. Many adipokines may improve peripheral insulin sensitivity through a variety of mechanisms, thereby indirectly reducing the strain on beta cells and thus improving their viability and functionality. Such effects will not be the focus of this article. Rather, we will focus on adipocyte-secreted molecules that have a direct effect on pancreatic islets. By their nature, adipokines represent potential druggable targets that can reach the islets and improve beta-cell function or preserve beta cells in the face of metabolic stress. © 2022 American Physiological Society. Compr Physiol 12:1-27, 2022.

Adiponectin is an adipokine predominantly produced by fat cells, circulates and exerts insulin-sensitizing, cardioprotective and anti-inflammatory effects. Dysregulation of adiponectin and/or adiponectin signaling is implicated in a number of metabolic diseases such as obesity, insulin resistance, diabetes, and cardiovascular diseases. However, while the insulin-sensitizing and cardioprotective effects of adiponectin have been widely appreciated in the field, the obesogenic and anti-inflammatory effects of adiponectin are still of much debate. Understanding the physiological function of adiponectin is critical for adiponectin-based therapeutics for the treatment of metabolic diseases.

Limited data are available about the functions and expressions of leptin and adiponectin receptors (LEPR, AdipoRs) in the uterus. Our aim was to investigate the effects of leptin and adiponectin on the contractions of intact and denuded nonpregnant and pregnant uteri, as well as the changes in mRNA and protein expressions of LEPR and AdipoRs during the gestational period.

Contractions of nonpregnant and 5-, 15-, 18-, 20- or 22-day pregnant uterine rings were measured in an isolated organ bath system. The tissue contractions were stimulated with KCl and modified by cumulative concentrations of leptin or adiponectin. The mRNAs, protein expressions and localizations of LEPR and AdipoRs were determined by RT-PCR, Western blot and immunohistochemistry, respectively.

Both adipokines relaxed the nonpregnant intact uterus more effectively than the denuded myometrium. Leptin inhibited the contractions of endometrium-denuded uteri throughout pregnancy, while its action was weakened on intact uteri towards term. The changes in LEPR receptor densities were independent of the relaxing effect. Adiponectin inhibited contractions, but this effect ceased on pregnancy day 22, while a gradual decrease was detected towards term on denuded myometria. These modifications were in harmony with changes in the expressions of AdipoRs.

Both leptin and adiponectin play a role in the relaxation of the pregnant uterus, but their efficacy significantly decreases towards the end of gestation. Their endometrial receptors may have a fine-tuning role in uterine contractions, predicting the importance of these adipokines in uterine contractions under altered adipokine level conditions.