Adipokine Secretion Research Articles

Perivascular Adipose Tissue Inflammation: The Anti-Inflammatory Role of Ghrelin in Atherosclerosis Progression

Perivascular adipose tissue (PVAT) and its adipokines engage in bidirectional crosstalk with the vascular wall. Atherosclerosis disrupts this interaction through inflammation, rupture-prone plaques, and subsequent thrombosis. The cardioprotective effects of ghrelin are in contradiction to its adipogenic properties. The concurrent research of anti-/pro-atherogenic mechanisms of ghrelin and PVAT-derived adipokines provides a better understanding of atherosclerosis progression in metabolic disorders. In-depth coverage of the characteristic features of PVAT concerning vascular dysfunction, with a survey of ghrelin-induced anti-inflammatory effects on adipose tissue macrophage infiltration and the inhibitory activity of ghrelin on the proinflammatory adipokine secretion, show that the impact of ghrelin on the endothelial function should be studied in relation to PVAT.

Comparing the effects of tumor necrosis factor alpha, lipopolysaccharide and palmitic acid on lipid metabolism and inflammation in murine 3T3-L1 adipocytes

AimsThis study aimed to develop a model of dysregulated lipid metabolism and inflammation by treating 3T3-L1 adipocytes with tumor necrosis factor alpha (TNFα), lipopolysaccharide (LPS), and palmitic acid (PA) individually or in combination to assess their effects and mechanism of action. Main methodsDifferentiated 3T3-L1 adipocytes were treated with TNFα (10 ng/mL), LPS (100 ng/mL), and PA (0.75 mM) individually or in combination for 24 h. Lipolysis, lipid content, inflammation, and the expression of lipid metabolism and inflammation genes were assessed by glycerol release quantification, Oil Red O staining, enzyme-linked immunosorbent assays, and quantitative reverse transcription-polymerase chain reaction, respectively. Key findingsExposure of 3T3-L1 adipocytes to TNFα stimulated lipolysis, reduced lipid accumulation, decreased adiponectin (ADIPOQ) secretion, and increased secretion of pro-inflammatory adipokines, monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), and interleukin 1 beta (IL-1β). These changes were accompanied by decreased expression of lipid metabolism genes, increased expression of pro-inflammatory genes (MCP-1 and IL-6), and decreased expression of the anti-inflammatory gene, ADIPOQ. Exposure to LPS and PA, alone or in combination did not affect these parameters, while co-treatment with TNFα, LPS, and PA enhanced lipolysis and decreased ADIPOQ secretion compared to TNFα treatment. SignificanceDysregulation of lipid metabolism and inflammation in 3T3-L1 adipocytes is attributed to TNFα rather than LPS and PA. We propose that exposing 3T3-L1 adipocytes to TNFα presents a suitable in vitro model of adipocyte dysfunction that closely resembles the complexity of obesity in vivo.

Secretome of Adipose Tissue as the Key to Understanding the Endocrine Function of Adipose Tissue.

The prevalence of obesity has reached pandemic levels and is becoming a serious health problem in developed and developing countries. Obesity is associated with an increased prevalence of comorbidities that include type II diabetes, cardiovascular diseases and some cancers. The recognition of adipose tissue as an endocrine organ capable of secreting adipokines that influence whole-body energy homeostasis was a breakthrough leading to a better molecular understanding of obesity. Of the adipokines known to be involved in the regulation of energy metabolism, very few are considered central regulators of insulin sensitivity, metabolism and energy homeostasis, and the discovery and characterization of new adipocyte-derived factors are still ongoing. Proteomics techniques, such as liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry, have proven to be useful tools for analyzing the secretory function of adipose tissue (the secretome), providing insights into molecular events that influence body weight. Apart from the identification of novel proteins, the considerable advantage of this approach is the ability to detect post-translational modifications that cannot be predicted in genomic studies. In this review, we summarize recent efforts to identify novel bioactive secretory factors through proteomics.

Ocimum basilicum L. Methanol Extract Enhances Mitochondrial Efficiency and Decreases Adipokine Levels in Maturing Adipocytes Which Regulate Macrophage Systemic Inflammation.

Excessive storage of lipids in visceral or ectopic sites stimulates adipokine production, which attracts macrophages. This process determines the pro- and anti-inflammatory response regulation in adipose tissue during obesity-associated systemic inflammation. The present study aimed to identify the composition of Ocimum basilicum L. (basil) seed extract and to determine its bio-efficacy on adipocyte thermogenesis or fatty acid oxidation and inhibition of lipid accumulation and adipokine secretion. Ocimum basilicum L. seed methanol extract (BSME) was utilized to analyze the cytotoxicity vs. control; lipid accumulation assay (oil red O and Nile red staining), adipogenesis and mitochondrial-thermogenesis-related gene expression vs. vehicle control were analyzed by PCR assay. In addition, vehicle control and BSME-treated adipocytes condition media were collected and treated with lipopolysaccharide (LPS)-induced macrophage to identify the macrophage polarization. The results shown that the active components present in BSME did not produce significant cytotoxicity in preadipocytes or macrophages in the MTT assay. Furthermore, oil red O and Nile red staining assay confirmed that 80 and 160 μg/dL concentrations of BSME effectively arrested lipid accumulation and inhibited adipocyte maturation, when compared with tea polyphenols. Gene expression level of adipocyte hyperplasia (CEBPα, PPARγ) and lipogenesis (LPL)-related genes have been significantly (p ≤ 0.05) downregulated, and mitochondrial-thermogenesis-associated genes (PPARγc1α, UCP-1, prdm16) have been significantly (p ≤ 0.001) upregulated. The BSME-treated, maturing, adipocyte-secreted proteins were detected with a decreased protein level of leptin, TNF-α, IL-6 and STAT-6, which are associated with insulin resistance and macrophage recruitment. The “LPS-stimulated macrophage” treated with “BSME-treated adipocytes condition media”, shown with significant (p ≤ 0.001) decrease in metabolic-inflammation-related proteins—such as PGE-2, MCP-1, TNF-α and NF-κB—were majorly associated with the development of foam cell formation and progression of atherosclerotic lesion. The present findings concluded that the availability of active principles in basil seed effectively inhibit adipocyte hypertrophy, macrophage polarization, and the inflammation associated with insulin resistance and thrombosis development. Ocimum basilicum L. seed may be useful as a dietary supplement to enhance fatty acid oxidation, which aids in overcoming metabolic complications.

Abstract P5-02-05: Optimizing the differentiation of the 3T3-L1 MBX mouse cell line to mature and obese adipocytes for in vitro breast cancer studies

Abstract White adipocytes are considered an endocrine organ. Present in breast tissue, they crosstalk in a paracrine manner with breast cells, secreting signals into the tumor microenvironment to drive cancer development as well as metastasis. 3T3-L1, a mouse fibroblast cell line, is widely used as an in vitro experimental model of white adipocytes for fat cell and cancer cell interaction studies. 3T3-L1 can be differentiated from the fibroblast cell line to adipocytes using a pharmacological cocktail of dexamethasone, methyl-3-isobutyl xanthine (IBMX) and insulin. Recently, ATCC has derived a clone from 3T3-L1 (ATCC CL-173), 3T3-L1 MBX, which has been claimed to have close to 100% differentiation. This 3T3-L1 MBX cell line has been recommended as a more suitable model for obesity research. However, there are few reported results describing their optimized differentiation conditions and/or any fat-cancer cell interactions. The current study has explored and optimized the concentrations of the differentiation cocktail for 3T3-L1 cells (ATCC CL-173) to differentiate its cloned derivative 3T3-L1 MBX. In the pharmacological cocktail, rosiglitazone was added as the 4th component as a prodifferentiative agent. Furthermore, the study has documented the differentiation of 3T3-L-MBX in the presence of the above-mentioned pharmacological cocktail with fatty acid combinations (palmitic acid, oleic acid, linoleic acid), to determine its applicability as an in vitro experimental model of obese adipocytes. The optimized concentrations of fatty acids that yielded the highest cell viability of 3T3-L1 MBX was determined using MTT assay. Additionally, the optimized combination of fatty acids was confirmed using oil-red-o adipogenesis staining. The adipocytokine levels of all the above mentioned in-vitro adipogenesis phases was evaluated using a mouse adipokine array kit as well as comparing the level of adipocytokines with those of fat tissue harvested from 6 month and 12 months old obese C3Hhej mice. Lastly, the study evaluated viability of three types of breast cells (non-tumorigenic, low metastatic, and highly metastatic) in the presence of conditioned medium collected from in-vitro 3T3-L1 MBX differentiated mature and obese adipocytes using an Annexin V-FITC assay kit. The study has found 3 days differentiation cycle of 3T3-L1 MBX with the addition of specific concentration of IBMX (0.5 mM), dexamethasone (1 µM), insulin (10 µg/ml) and rosiglitazone (2 µM) to be promising for its maximum differentiation. Further, 3T3-L1 MBX differentiated in presence of fatty acid were characterized to have higher lipid accumulation and adipokine secretion than the normally differentiated adipocytes. Citation Format: Noshin Mubtasim, Dr. Lauren Gollahon. Optimizing the differentiation of the 3T3-L1 MBX mouse cell line to mature and obese adipocytes for in vitro breast cancer studies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-02-05.

Asprosin induces vascular endothelial-to-mesenchymal transition in diabetic lower extremity peripheral artery disease

BackgroundAltered adipokine secretion in dysfunctional adipose tissue facilitates the development of atherosclerotic diseases including lower extremity peripheral artery disease (PAD). Asprosin is a recently identified adipokine and displays potent regulatory role in metabolism, but the relationship between asprosin and lower extremity PAD remains uninvestigated.Methods33 type 2 diabetes mellitus (T2DM) patients (DM), 51 T2DM patients with PAD (DM + PAD) and 30 healthy normal control (NC) volunteers were recruited and the blood samples were collected for detecting the circulatory asprosin level and metabolomic screening. RNA sequencing was performed using the aorta tissues from the type 2 diabetic db/db mice and human umbilical vein endothelial cells (HUVECs) were treated with asprosin to determine its impact on the endothelial-to-mesenchymal transition (EndMT).ResultsThe circulating levels of asprosin in DM + PAD group were significantly higher than that of NC group and the DM group. Circulating asprosin level was remarkably negatively correlated with ankle-brachial index (ABI), even after adjusting for age, sex, body mass index (BMI) and other traditional risk factors of PAD. Logistic regression analysis revealed that asprosin is an independent risk factor for PAD and receiver-operator characteristic (ROC) curve determined a good sensitivity (74.5%) and specificity (74.6%) of asprosin to distinguish PAD. Data from metabolomics displayed a typical characteristics of de novo amino acid synthesis in collagen protein production by myofibroblasts in patients with PAD and activation of TGF-β signaling pathway appeared in the aortic tissue of db/db mice. Asprosin directly induces EndMT in HUVECs in a TGF-β-dependent manner as TGF-β signaling pathway inhibitor SB431542 erased the promotional effect of asprosin on EndMT.ConclusionsElevated circulatory asprosin level is an independent risk factor of lower extremity PAD and might serve as a diagnostic marker. Mechanistically, asprosin directly induces EndMT that participates in vascular injury via activation of TGF-β signaling pathway.Trial registration This trial was registered at clinicaltrials.gov as NCT05068895

The association between epicardial adipose tissue and prognosis in heart failure with preserved and reduced ejection fraction

Abstract Funding Acknowledgements Type of funding sources: None. Background. Recent evidence shows that increased epicardial adipose tissue (EAT) thickness is associated with metabolic syndrome, microvascular dysfunction and enhanced pericardial restraint. Purpose. We measured echocardiography-derived EAT thickness in a population of heart failure (HF) patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction to examine the relationship between EAT and prognosis at clinical follow-up. Methods. We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) who had been referred to our hospital due to dyspnoea and/or effort intolerance. We performed a resting clinical and biohumoral evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. We considered a composite endpoint of cardiovascular death and HF-related hospitalization during follow-up. Results. Patients with HFpEF displayed greater EAT thickness (median 8 mm, interquartile range [IQR] 4–12 mm) than HFrEF (median 3 mm, IQR 2–6 mm; p < 0.0001). During a median follow-up of 20.9 months (IQR 15-25 months), 34 cardiovascular deaths and 146 HF hospitalizations were reported, with no significant differences between the two HF phenotypes. EAT was shown to predict adverse events independently from body mass index, waist circumference and other well-established prognostic markers in HF (such as NT-proBNP and peak oxygen consumption). The risk of adverse events increased with increasing EAT thickness in HFpEF and with EAT thinning in HFrEF. Kaplan-Meier analyses for the composite endpoint showed that in HFpEF, the survival probability was significantly lower in patients with thicker EAT than those with thinner EAT. In HFrEF, conversely, patients with increased EAT thickness had a higher survival probability than those with reduced EAT thickness (Figure 1). Conclusion. EAT accumulation is increased in HFpEF compared to HFrEF and carries different prognostic meanings in the two subsets. In HFpEF, EAT thickening portends adverse outcomes, which may be due to the secretion of pro-inflammatory and pro-atherogenic adipokines and increased mechanical restraint. In HFrEF, EAT thinning is associated with a worse prognosis, probably reflecting a more advanced catabolic state (e.g., cardiac cachexia). Larger studies are needed to determine whether or not EAT has a causal role in influencing progression and survival in the different HF phenotypes. Abstract Figure 1

Punicalagin and Ketogenic Amino Acids Loaded Organic Lipid Carriers Enhance the Bioavailability, Mitochondrial β-Oxidation, and Ketogenesis in Maturing Adipocytes.

The identification of lipolytic bioactive compounds via the functional stimulation of carbohydrate response element-binding protein-1 (CREBp-1) and AMP-activated protein kinase (AMPK) is most warranted. Nano lipid carriers (NLCs) are currently being considered within drug delivery development as they facilitate controlled drug release and have intracellular bioavailability after encapsulating the active principles with lipid matrix. The present study has been designed to synthesize punicalagin, and ketogenic amino acids (KAA) loaded with organic lipid carriers to optimize the liposome-assisted intracellular delivery’s bioavailability. Punicalagin (PUNI) and KAA (tryptophan, methionine, threonine, lysine, and leucine) were encapsulated with chia seed phospholipids by homogenization, emulsification, and cold ultra-sonication method to obtain nano lipid carriers (NLC). The physicochemical characterization of NLCs has been carried out using Zetasizer, FT-IR, and TEM analysis. Punicalagin and ketogenic amino acid-loaded NLCs (NLC-PUNI-KAA) were identified with an average diameter of 240 to 800 nm. The biosafety of NLC-PUNI-KAA has been evaluated in human mesenchymal stem cells. PI staining confirmed that a 0.4, 0.8 or 1.6μg/dL dose of NLC-PUNI-KAA potentially maintains nuclear integration. NLC-PUNI-KAA treated with maturing adipocytes decreased lipid accumulation and significantly increased the gene expression levels of fatty acid beta-oxidation (PPARγC1α, UCP-1 and PRDM-16) pathways when compared to free PUNI (5 μg/dL) treatment. The lipolytic potential has been confirmed by the functional activation of AMPK and CREBp-1 protein levels. In conclusion, NLC-PUNI-KAA treatment effectively increased mitochondrial efficiency more than free punicalagin or orlistat treated maturing adipocyte. Enhanced lipolysis and decreased hypertrophic adipocyte resulted in decreased adipokine secretion, which has been associated with the suppression of obesity-associated comorbidities and vascular cell inflammation. The bioefficacy and lipolytic potential of water-soluble punicalagin have been improved after functional modification into NLCs.

The Effect of the Ketogenic Diet on Adiponectin, Omentin and Vaspin in Children with Drug-Resistant Epilepsy.

Background: Changes in adipokine secretion may be involved in the anti-epileptic effect of a ketogenic diet (KD) in drug-resistant epilepsy (DRE). Objectives: The assessment of the influence of KD on serum adiponectin, omentin-1, and vaspin in children with DRE. Methods: Anthropometric measurements (weight, height, BMI, and waist-to-hip circumference ratio) were performed in 72 children aged 3–9 years, divided into 3 groups: 24 children with DRE treated with KD, 26—treated with valproic acid (VPA), and a control group of 22 children. Biochemical tests included fasting glucose, insulin, beta-hydroxybutyric acid, lipid profile, aminotransferases activities, and blood gasometry. Serum levels of adiponectin, omentin-1 and vaspin were assayed using commercially available ELISA tests. Results: Serum levels of adiponectin and omentin-1 in the KD group were significantly higher and vaspin—lower in comparison to patients receiving VPA and the control group. In all examined children, serum adiponectin and omentin-1 correlated negatively with WHR and serum triglycerides, insulin, fasting glucose, and HOMA-IR. Vaspin levels correlated negatively with serum triglycerides and positively with body weight, BMI, fasting glucose, insulin, and HOMA-IR. Conclusion: One of the potential mechanisms of KD in children with drug-resistant epilepsy may be a modulation of metabolically beneficial and anti-inflammatory adipokine levels.

Correlation of Leptin, Proinflammatory Cytokines and Oxidative Stress with Tumor Size and Disease Stage of Endometrioid (Type I) Endometrial Cancer and Review of the Underlying Mechanisms.

Simple SummaryEndometrioid endometrial cancer is typically estrogen-positive and associated with obesity. Indeed, circulating estrogens are strongly and linearly related to adiposity and increased BMI, which have been identified as the most important risk factors for endometrioid endometrial cancer. However, the relationship between excess body weight and endometrial cancer is more complex, and, besides the unopposed estrogens, involves multiple mechanisms, including hyperinsulinemia, altered adipokines, inflammation, and oxidative stress associated with obesity. We investigated the association between classical tumor prognostic factors (i.e., tumor size (T), and nodal (N) and metastatic (M) status) and the levels of leptin, proinflammatory cytokines, and oxidative stress, together with BMI, among type I (endometrioid) and type II endometrial cancer patients. We found that BMI, leptin, IL-6, and reactive oxygen species correlated with T, N, and M status in type I, but not in type II endometrial cancers. This could open new therapeutic perspectives based on the specific pathogenetic mechanisms involved.Endometrioid endometrial cancer is associated with increased BMI and obesity through multiple pathogenetic mechanisms involving hyperestrogenism, hyperinsulinemia, altered adipokine secretion, inflammation, and oxidative stress. In the present study, we aimed to investigate the correlation between BMI, leptin, the proinflammatory cytokines IL-6 and TNFα, reactive oxygen species (ROS), and the traditional prognostic factors T, G, N and M status among type I endometrioid and type II endometrial cancer patients. We enrolled 305 consecutive endometrial cancer patients prospectively. We found that BMI, leptin, and IL-6 significantly correlated with T status, N status, and M status among endometrioid type I endometrial cancer patients. Among type II endometrial cancer patients, BMI and leptin did not correlate with any of the prognostic parameters, whereas there was a positive correlation between IL-6 and the presence of distant metastases. In the multivariate regression analysis, BMI, leptin, and IL-6 were independent predictive variables of T, N, and M status in endometrioid type I endometrial cancer patients. Our study demonstrates that weight gain, adiposity-related adipokines, inflammation, and oxidative stress correlate with the prognostic factors of endometrioid endometrial cancer. Knowledge of the role of obesity-related biological pathways and mediators in the pathogenesis and prognosis of endometrioid endometrial malignancies may offer new perspectives on combined therapeutic strategies that have not been explored to date, both in the advanced disease and in the adjuvant setting.

DNA Methylation Modulates Aging Process in Adipocytes.

Aging has been recognized to be a highly complex biological health problem with a high risk of chronic diseases, including type 2 diabetes, atherosclerosis, chronic bronchitis or emphysema, cancer and Alzheimer's disease. Particularly, age-related turnover in adipose tissue is a major contributor to metabolic syndromes and shortened lifespan. Adipocytes undergo senescence in early stage, which results in adipose tissue metabolic dysfunction, redistribution, and inflammation. The well-established association between DNA methylation (DNAm) and aging has been observed in the past few decades. Indeed, age-related alteration in DNAm is highly tissue-specific. This review intends to summarize the advancements how DNAm changes coupled with aging process in adipose tissue, by which DNAm regulates cellular senescence, metabolic function, adipokine secretion and beiging process in adipocytes. Elucidation of the effect of DNAm on adipose aging would have great potential to the development of epigenetic therapeutic strategies against aging-related diseases in clinical settings.

Leptin and adiponectin synthesis and secretion in mature 3T3-L1 adipocytes are differentially down-regulated by arsenic and palmitic acid exposure throughout different stages of adipogenesis

AimsArsenic is a risk factor for type 2 diabetes and cardiovascular disease. However, little is known about arsenic effects over adipocyte endocrine functionality, particularly for leptin and adiponectin, and about its interaction with dietary components, which are the main environmental regulators of adipose tissue functionality. The aim of this work was to evaluate leptin and adiponectin in mature 3T3-L1 adipocytes exposed to palmitate (simulating excess fat intake), arsenite, or both throughout two different stages of adipogenesis. Material and methods3T3-L1 adipocytes were exposed starting from the beginning of its differentiation process during 11 d or once adipocytes were mature for 72 h. Adipokines secretion was evaluated by ELISA, intracellular protein levels and secreted adiponectin multimers by Western blot and mRNA abundance by qPCR. Key findingsLeptin and adiponectin secretion decreased by arsenite alone or in combination with palmitate due to reduced gene and protein expression of both adipokines. However, leptin was impaired more at the transcriptional level, whereas affections to adiponectin were more relevant at the intracellular protein amount level with changes in the multimers proportion. The gene expression of several of their transcription factors was altered. Additionally, the magnitude of the effects depends on the adipocyte cell stage at which exposure began; adiponectin was more affected when exposure started from differentiation and leptin once adipocytes were mature. SignificanceThese results in an in vivo model could be translated into less satiety and reduced insulin sensitivity.

Role of adipokines in regulation of colonic motor activity in overweight and obese individuals

The increasing proportion of the population suffering from overweight or obesity is now taking on the character of a pandemic. In the literature, there have begun to appear reports of associations in individuals with impaired colonic motility and a body mass index above 25 kg/m2. The present publication was prepared to systematize data on possible mechanisms of colonic motility disorders in overweight and obese individuals, including through changes in adipokine secretion and function. The literature search was performed in Embase, PubMed, and Google Scholar, using the key words ‘colon motility regulation’, ‘adipokines’, ‘gastrointestinal hormones’, ‘intestinal microbiota’, ‘overweight’, ‘obesity’, ‘visceral fat’.

Cardiovascular risks in patients with psoriasis (literature review)

The article is of an overview nature and contains up-to-date information on comorbid cardiovascular pathology in psoriasis. Various studies have shown that psoriasis is associated with a higher prevalence of CVD risk factors, including hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome. The relationship between the severity of psoriasis and the risk of cardiovascular disease, as well as the prognostic risks with mortality rates, are discussed. Proposed common pathogenetic mechanisms include genetic factors, inflammatory pathways, adipokine secretion, insulin resistance, lipoprotein composition and function, angiogenesis, oxidative stress, and hypercoagulability.

CHARACTERISTICS OF METABOLIC PROCESSES IN THE FORMATION OF MENSTRUAL FUNCTION DISORDERS IN ADOLESCENT GIRLS WITH OBESITY

Іntroduction. Today, a quarter of the population of economically developed countries has a body weight that is 15% larger than the norm. According to various authors, the timely onset of menarche in women with various forms of obesity and reproductive dysfunction is observed in 31% of cases only.
 Obesity results in insulin resistance, which in its turn results in hyperinsulinemia. The main reason of the connection of insulin resistance with reproductive function disorders consists in the specific influence of insulin on ovaries. Insulin suppresses apoptosis, binding to receptors of various growth factors that promotes long existence of atresizing follicles. In the pathogenesis of the metabolic syndrome, along with the development of hyperinsulinemia and insulin resistance, a significant role belongs to the imbalance of adipocytokines, one of which is adiponectin.
 The aim is to analyze metabolic processes in the formation of menstrual dysfunction in adolescent girls with obesity to improve diagnostic methods of menstrual disorders.
 Material and methods. Clinical and laboratory examination of adolescent girls aged 12-18 years was held, among which 79 had obesity and complaints about menstrual dysfunction (the main group); 31 with normal body weight and regular menstrual cycle (the control group).
 Research methods: general clinical, biochemical (indicators of lipid and carbohydrate metabolism were determined), instrumental (ultrasound), statistical.
 Results. It was found that 53.3% of the girls from the main group had the beginning of the first menstruation after 14 years, delayed menstruation from 42 days to 6 days, duration 2.1 ± 0.05 days, which was significantly shorter, the volume of 10.2 ± 0.05; 0.4 points (average 1-2 pads per day) was significantly lower (p <0.05).
 Ultrasound showed uterine hypoplasia in almost every second girl in the main group - 36 (45.46%).
 Hyperleptinemia and leptin resistance was found in obesity of the first degree 34.8 ± 1.75, in obesity of the second degree 37.15 ± 2.12, in obesity of the third degree 40.64 ± 2.0. It was 14.35 ng / ml in the control group, p<0,01.
 Hyperleptinemia in the main group was accompanied by hyperinsulinemia in 26% of cases and insulin resistance. The relationship between low values of adiponectin and elevated body mass index in patients of the main group was established, which was confirmed by the results of correlation analysis (adiponectin & body mass index: ρ = -0.74).
 Analysis of the results revealed a decrease of A/L level in the main group by 4.3 times. Based on our own results, the A/L and HOMA-AD models can be considered more accurate for determining insulin resistance.
 Conclusions. 1. Changes of the menstrual cycle in overweight girls were found.
 
 The association of adipokines secretion disorders is characterized by hyperleptinemia, leptin resistance, decreased Adiponectin / Leptin index and hypoadiponectinemia, which, in combination with insulin resistance, indicates the participation of adipokines in the genesis of oligomenorrhea.
 The algorithm of adolescents’ treatment with menstrual dysfunction on the background of obesity must include the calculation of Adiponectin/Leptin and HOMA-AD, which will make it possible to avoid overdiagnosis of insulin resistance.

The role of melatonin in the molecular mechanisms underlying metaflammation and infections in obesity: A narrative review.

SummaryObesity is a chronic condition whose management is a critical challenge for physicians. The scientific community has increased its focus on the molecular mechanisms involved in obesity etiopathogenesis to better manage patients with obesity and its associated complications. The tight connection between adipose tissue and the immune system has been demonstrated to play a crucial role in inflammation, and melatonin is important for circadian rhythm regulation and metabolic homeostasis, in which it orchestrates several molecular mechanisms involved in obesity and associated inflammation. Melatonin also regulates innate and adaptive immunity; its antioxidant properties are linked to reduced predisposition to infection and weight gain in patients with obesity through the modulation of the immune response, which has a significant beneficial effect on inflammation and, consequently, on the metabolic state. Low melatonin levels have been linked to obesity, and melatonin supplementation can reduce body weight, improve metabolic profile, and ameliorate immune responses and pro‐inflammatory stimuli. The role of melatonin in obesity is mainly related to improved oxidative stress signaling, modulation of adipokine secretion, and a switching from white‐to‐brown adipose tissue phenotype and activity. Moreover, the role of melatonin in obesity modulation by controlling circadian rhythm has recently emerged as a pivotal mechanism for lipid and glucose metabolism dysfunction in adipose, muscle, and liver tissues. Melatonin may also regulate the immune system by acting directly on thymus morphology and activity as well as by modulating oxidative stress and inflammatory states during infections. The tight association between melatonin and immune response regulation is coordinated by Toll‐like receptors, which are rhythmically expressed during the day. Their expression may be strongly modulated by melatonin as their signaling is highly inhibited by melatonin. The current review summarizes studies of melatonin‐induced mechanisms involved in infection regulation, particularly the modulation of obesity‐associated inflammation and systemic complications.

MicroRNAs in Human Adipose Tissue Physiology and Dysfunction.

In recent years, there has been a large amount of evidence on the role of microRNA (miRNA) in regulating adipose tissue physiology. Indeed, miRNAs control critical steps in adipocyte differentiation, proliferation and browning, as well as lipolysis, lipogenesis and adipokine secretion. Overnutrition leads to a significant change in the adipocyte miRNOME, resulting in adipose tissue dysfunction. Moreover, via secreted mediators, dysfunctional adipocytes may impair the function of other organs and tissues. However, given their potential to control cell and whole-body energy expenditure, miRNAs also represent critical therapeutic targets for treating obesity and related metabolic complications. This review attempts to integrate present concepts on the role miRNAs play in adipose tissue physiology and obesity-related dysfunction and data from pre-clinical and clinical studies on the diagnostic or therapeutic potential of miRNA in obesity and its related complications.

Therapeutic radiation exposure of the abdomen during childhood induces chronic adipose tissue dysfunction.

BACKGROUNDChildhood cancer survivors who received abdominal radiotherapy (RT) or total body irradiation (TBI) are at increased risk for cardiometabolic disease, but the underlying mechanisms are unknown. We hypothesize that RT-induced adipose tissue dysfunction contributes to the development of cardiometabolic disease in the expanding population of childhood cancer survivors.METHODSWe performed clinical metabolic profiling of adult childhood cancer survivors previously exposed to TBI, abdominal RT, or chemotherapy alone, alongside a group of healthy controls. Study participants underwent abdominal s.c. adipose biopsies to obtain tissue for bulk RNA sequencing. Transcriptional signatures were analyzed using pathway and network analyses and cellular deconvolution.RESULTSIrradiated adipose tissue is characterized by a gene expression signature indicative of a complex macrophage expansion. This signature includes activation of the TREM2-TYROBP network, a pathway described in diseases of chronic tissue injury. Radiation exposure of adipose is further associated with dysregulated adipokine secretion, specifically a decrease in insulin-sensitizing adiponectin and an increase in insulin resistance–promoting plasminogen activator inhibitor-1. Accordingly, survivors exhibiting these changes have early signs of clinical metabolic derangement, such as increased fasting glucose and hemoglobin A1c.CONCLUSIONChildhood cancer survivors exposed to abdominal RT or TBI during treatment exhibit signs of chronic s.c. adipose tissue dysfunction, manifested as dysregulated adipokine secretion that may negatively impact their systemic metabolic health.FUNDINGThis study was supported by Rockefeller University Hospital; National Institute of General Medical Sciences (T32GM007739); National Center for Advancing Translational Sciences (UL1 TR001866); National Cancer Institute (P30CA008748); American Cancer Society (133831-CSDG-19-117-01-CPHPS); American Diabetes Association (1-17-ACE-17); and an anonymous donor (MSKCC).

Bone Marrow Adipocyte Promotes Epithelial-Mesenchymal-Transition-like Activation in Multiple Myeloma Via CXCL-12/CXCR4 Axis

Extra-medullary disease (EMD) in multiple myeloma (MM) is associated with poor prognosis and resistance to chemotherapy. The bone marrow microenvironment is a key regulator of myeloma metastatic progression through the secretion of growth factors that activate epithelial-mesenchymal transition (EMT)-like characters. Bone marrow adipocyte (BMA) accumulates in obese patients and displays distinct immune regulatory properties rather than provides energy substrates, forming a bulk portion of the bone marrow microenvironment. Emerging evidence indicates the potential for adipocytes to influence cancer cell progression through the secretion of adipokines that can induce EMT activation. The molecular mechanisms underlying how adipocytes enhance multiple myeloma progression is largely unknown. The present study aims to investigate the precise mechanism of BMA promoting myeloma EMT-like activation and new potential therapeutic strategies targeting bone marrow adipocytes.Newly diagnosed MM patients in our cancer center were recruited and divided into lean or obese group according to their body mass index (BMI). The bioinformatics-based analysis of transcriptome sequencing data for bone marrow stromal cells (BMSCs) derived from lean and obese MM patients identified that obese patients showed more obvious EMT-like transcriptional regulation characteristics and altered the expression of genes regulating EMT (Fig A), which was further confirmed by the immunohistochemistry staining of bone marrow biopsy (Fig B). Co-culture bone marrow adipocytes with myeloma cells significantly enhanced the proliferation and migration (Fig C-D). The transcriptome sequencing data of BMA further demonstrated that CXCL12 was enriched in BMA derived from obese MM patients (Fig E). We further confirmed that CXCL12 secreted by adipocytes induce EMT-like activation in myeloma cells, and the effect of CXCL12 expression on EMT is mediated through activation of CXCR4 (Fig F-G). Blocking of CXCR4 signaling in myeloma cells, decreased proliferation and invasion capabilities of myeloma cells cultured with CXCL12 (Fig H-I). Together, our results suggest that bone marrow adipocytes can enhance the aggressive behavior of myeloma cells and induce an EMT-like activation through paracrine CXCL12/CXCR4 signaling (Fig J).In conclusion, paracrine signaling by BMAs can induce EMT-like activation and results in increased proliferation and invasion characteristics of myeloma cells. These results suggested that targeting CXCL12/CXCR4 may act as a regulator of EMD through EMT-like transcriptional modulation, thus representing a potential therapeutic strategy to prevent MM disease progression. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Short S-Equol Exposure Has a Long-Term Inhibitory Effect on Adipogenesis in Mouse 3T3-L1 Cells

In the search for new drugs against obesity, the chronic disease that threatens human health worldwide, several works have focused on the study of estrogen homologs because of the role of estrogen receptors (ERs) in adipocyte growth. The isoflavone equol, an ERβ agonist, has shown beneficial metabolic effects in in vivo and in vitro assays; however, additional studies are required to better characterize its potential for body weight control. Here, we showed that the treatment of 3T3-L1 cells with 10 μM of S-equol for the first three days of the adipocyte differentiation protocol was able to prevent cells becoming semi-rounded and having a lipid droplet formation until the seventh day of culture; moreover, lipid accumulation was reduced by about 50%. Congruently, S-equol induced a reduction in mRNA expression of the adipogenic markers C/EBPα and PPARγ, and adipokines secretion, mainly Adiponectin, Leptin, Resistin, and MCP-1, while the release of PAI-1 was augmented. Moreover, it also reduced the expression of ERα and attenuated the subexpression of ERβ associated with adipogenesis. Altogether, our data suggested that S-equol binding to ERβ affects the transcriptional program that regulates adipogenesis and alters adipocyte functions. Future efforts will focus on studying the impact of S-equol on ER signaling pathways.