The Role of Lymph-Adipose Crosstalk in Alcohol-Induced Perilymphatic Adipose Tissue Dysfunction.

Chronic alcohol use leads to metabolic dysfunction in adipose tissue. The underlying mechanisms and the contribution of alcohol-induced adipose tissue dysfunction to systemic metabolic dysregulation are not well understood. In our previous studies, we found that chronic alcohol feeding induces mesenteric lymphatic leakage, perilymphatic adipose tissue (PLAT) inflammation, and local insulin resistance in rats. The goal of this study was to further explore the link between alcohol-induced lymphatic leakage and PLAT immunometabolic dysregulation, locally and systemically, using in vivo and ex vivo approaches. Male rats received a Lieber-DeCarli liquid diet, of which 36% of the calories were from alcohol, for 10 weeks. Time-matched control animals were pair-fed. Adipokine levels were measured in PLAT, subcutaneous fat, plasma, and mesenteric lymph samples. Glucose tolerance was assessed after 10 weeks. Further, we used a novel ex vivo lymph-stimulated naïve PLAT explant approach to modeling lymph leakage to assess changes in adipokine secretion and expression of proinflammatory markers after stimulation with lymph from alcohol- or pair-fed animals. Our data show that chronic alcohol-fed rats presented PLAT-specific decreases in adiponectin and leptin levels, alterations in the expression of genes involved in lipid metabolic pathways, and associated impaired whole-body glucose homeostasis. Further, we found that direct naïve PLAT stimulation with lymph contents from alcohol-fed animals increased IL-6 expression in demonstrating the ability of lymph contents to differentially impact naïve adipose tissue. Overall, chronic alcohol feeding leads to depot-specific alterations in metabolic profile, impaired systemic glucose tolerance, and lymph-induced adipose tissue inflammation. The specific lymph components leading to PLAT immunometabolic dysregulation remain to be determined.

The Role of Adipokines between Genders in the Pathogenesis of Osteoarthritis.

Osteoarthritis (OA) is a chronic, progressive, degenerative joint disease characterized by joint pain, stiffness, and limited movement. It presents significant intra- and inter-individual variability-in particular, between genders. Recent research has increasingly focused on the role of adipokines-especially leptin, adiponectin, and resistin-in the development of OA. Adipokines, peptide hormones primarily secreted by adipose tissue, are involved in crucial physiological processes related to metabolism and immunity. They can also impact bone and cartilage turnover by interacting with joint cells such as osteoblasts, osteoclasts, chondrocytes, and mesenchymal stem cells, thereby linking inflammation with bone cartilage homeostasis. This review aims to elucidate the structure and functions of various adipokines, their serum and synovial levels, and their association with clinical presentation and radiographic progression in OA patients, with a focus on differences between sexes. A narrative literature review was conducted using three databases specifically analyzing sex differences. OA patients generally show elevated serum and synovial levels of leptin, chemerin, and visfatin, as well as high plasma levels of resistin and visfatin. In contrast, synovial levels of adiponectin and omentin are reduced in OA patients compared to healthy individuals, with an inverse relationship to disease severity, suggesting a potential protective role. Resistin and leptin were positively correlated with pain severity and radiographic progression, while adiponectin's role in OA remains controversial. Regarding sex differences, male OA patients exhibited higher serum levels of leptin, chemerin, and omentin compared to healthy controls, with a positive correlation to the BMI and estrogen levels, potentially explaining the sexual dimorphism observed in this condition. Studies on visfatin and lipocalin did not reveal significant differences in synovial or serum levels between the sexes. The role of resistin remains controversial. Adipokines influence the joint microenvironment and contribute to the progression of osteoarthritis (OA). However, the precise biological mechanisms are not yet fully understood due to the complex interactions between the metabolic, mechanical, and immune systems. Further research is needed to clarify their roles in OA and to identify targeted therapies for managing this degenerative disease.

Metabolic Functions of the Infrapatellar Fat Pad: Implications for Knee Health and Pathology.

¼ Despite being historically viewed as a vestigial structure, the infrapatellar fat pad (IPFP) is now recognized as a metabolically active structure, influencing knee health through cytokine production and metabolic pathways.¼ With distinct anatomical regions, the IPFP contains diverse cell types including adipocytes, fibroblasts, and immune cells, influencing its functional roles, pathology, and contributions to knee disorders.¼ The IPFP acts as an endocrine organ by releasing adipokines such as adiponectin, leptin, and tumor necrosis factor α, regulating energy balance, immune responses, and tissue remodelling, with implications for knee joint health.¼ The IPFP's metabolic interactions with neighboring tissues influence joint health, clinical conditions such as knee pain, osteoarthritis, postoperative complications, and ganglion cysts, highlighting its therapeutic potential and clinical relevance.¼ Understanding the multifaceted metabolic role of the IPFP opens avenues for collaborative approaches that integrate orthopaedics, endocrinology, and immunology to develop innovative therapeutic strategies targeting the intricate connections between adipokines, joint health, and immune responses.

Investigation of serum Metrnl levels in pregnant women with gestational diabetes mellitus: a prospective non-interventional cohort study.

OBJECTIVE: The objective of this study was to investigate serum Metrnl levels in pregnant women with gestational diabetes mellitus and compare them with pregnant women without gestational diabetes mellitus. METHODS: The gestational diabetes mellitus group consisted of 87 pregnant women diagnosed with gestational diabetes mellitus, and the control group consisted of 93 healthy pregnant women without gestational diabetes mellitus. Serum Metrnl levels were determined by the enzyme-linked immunosorbent assay method. RESULTS: The two groups were similar in terms of demographic features. The median serum Metrnl level was found to be 1.16 ng/mL in the gestational diabetes mellitus group, while it was determined as 2.2 ng/mL in the control group (p=0.001). The two groups were divided into two subgroups based on participants' body mass index, normal weight and overweight. The lowest median Metrnl level was detected in the normal weight gestational diabetes mellitus group, followed by the overweight gestational diabetes mellitus group, normal weight control group, and overweight control group (1.1, 1.2, 2, and 2.4 ng/mL, respectively). Receiver operating curve analysis was performed to determine the value of the serum Metrnl level in terms of predicting gestational diabetes mellitus. The area under the curve analysis of serum Metrnl for gestational diabetes mellitus estimation was 0.768 (p=0.000, 95%CI 0.698-0.839). The optimal cutoff value for serum Metrnl level was determined as 1.53 ng/mL with 69% sensitivity and 70% specificity. CONCLUSION: Serum Metrnl levels in pregnant women with gestational diabetes mellitus were found to be significantly lower than in pregnant women without gestational diabetes mellitus. The mechanisms underlying the decrease in serum Metrnl levels in gestational diabetes mellitus remain unclear for now, and future studies will reveal the role of Metrnl in the pathophysiology of gestational diabetes mellitus.

Association of serum Metrnl levels and high-density lipoprotein cholesterol in patients with type 2 diabetes mellitus: a cross-sectional study.

Purpose: Meteorin-like (Metrnl) is a novel adipokine which is highly expressed in adipose tissue and has a beneficial effect on glucose and lipid metabolism. High density lipoprotein cholesterol (HDL-C) is well recognized to be inversely associated with cardiovascular events. However, the relationship between serum Metrnl levels and HDL-C in the type 2 diabetes mellitus (T2DM) remains unclear. Therefore, the present study aimed to evaluate the association of serum Metrnl with HDL-C levels in T2DM. Materials and Methods: Eighty participants with T2DM were included in this cross-sectional study. They were divided into two groups according to HDL-C levels: Group1 (lower HDL-C group): HDL-C < 1.04 mmol/L; Group2 (higher HDL-C group): HDL-C ≥ 1.04 mmol/L. Serum Metrnl levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: As compared with lower HDL-C levels groups, serum Metrnl levels were significantly higher in the group with higher HDL-C. Binary logistic regression analysis showed serum Metrnl levels were positively associated with HDL-C group after adjustment with sex, age, body mass index (BMI), mean arterial pressure (MAP), fasting blood glucose (FPG), triglyceride (TG). Furthermore, serum Metrnl levels were inversely correlated with insulin resistance index (HOMA-IR). HDL-C levels were lowest in the group with the lowest Metrnl levels group and remained positively associated with Metrnl after adjustment for sex, age, BMI, TG, and HOMA-IR by using multivariate logistic regression analysis. Conclusion: Serum Metrnl levels were positively associated with HDL-C levels in patients with T2DM.This suggests that increasing serum Metrnl levels maybe a candidate for improving lipid metabolism and preventing cardiovascular events in T2DM. Registry and the Registration No of the Study/Trial: The study was registered in the Chinese clinical trial registry (ChiCTR- 2100047148).

Influence of Type 2 Diabetes and Adipose Tissue Dysfunction on Breast Cancer and Potential Benefits from Nutraceuticals Inducible in Microalgae.

Breast cancer (BC) represents the most prevalent cancer in women at any age after puberty. From a pathogenetic prospective, despite a wide array of risk factors being identified thus far, poor metabolic health is emerging as a putative risk factor for BC. In particular, type 2 diabetes mellitus (T2DM) provides a perfect example bridging the gap between poor metabolic health and BC risk. Indeed, T2DM is preceded by a status of hyperinsulinemia and is characterised by hyperglycaemia, with both factors representing potential contributors to BC onset and progression. Additionally, the aberrant secretome of the dysfunctional, hypertrophic adipocytes, typical of obesity, characterised by pro-inflammatory mediators, is a shared pathogenetic factor between T2DM and BC. In this review, we provide an overview on the effects of hyperglycaemia and hyperinsulinemia, hallmarks of type 2 diabetes mellitus, on breast cancer risk, progression, treatment and prognosis. Furthermore, we dissect the role of the adipose-tissue-secreted adipokines as additional players in the pathogenesis of BC. Finally, we focus on microalgae as a novel superfood and a source of nutraceuticals able to mitigate BC risk by improving metabolic health and targeting cellular pathways, which are disrupted in the context of T2DM and obesity.

Rosehip Extract Decreases Reactive Oxygen Species Production and Lipid Accumulation in Hypertrophic 3T3-L1 Adipocytes with the Modulation of Inflammatory State.

BACKGROUND: Rosa canina L. (rosehip) is used worldwide in traditional medicine as a plant with medicinal properties. However, its anti-obesity effects are not fully explained on a transcriptional level. METHODS: In the present work, the 3T3-L preadipocytes were utilized to explore the impact of R. canina fruit extract (RCE) on the cellular and molecular pathways involved in adipocyte hypertrophy. RESULTS: Obtained results showed the ability of RCE to reduce lipid overloads in hypertrophic adipocytes associated with the down-regulation of mRNA expressions of adipogenic transcription factors such as PPARγ, C/EBPα, and SREBP-1c as well as genes involved in lipid biosyntheses such as FAS, LPL, and aP2. Moreover, obesity-associated oxidative stress (antioxidant enzyme activities and ROS generation) and inflammation were ameliorated in RCE-treated hypertrophic adipocytes. The mRNA and protein levels of adipokines such as leptin, resistin, and adiponectin were restored to more favorable levels. CONCLUSIONS: Rosa canina fruit might be a valuable source of phytochemicals in preventing obesity and obesity-related metabolic complications.

Reclassification of an FBN1 variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease.

Marfan syndrome (MFS) is a complex connective tissue disorder characterized by considerable clinical variability. The diagnosis of MFS is based on the Ghent criteria, which require the presence of both clinical and genetic features. MFS is primarily caused by pathogenic alterations in FBN1, which encodes the fibrillin-1 protein. Fibrillin-1 comprises multiple domains rich in cysteine residues, with disulfide bonds formed between these residues. It has long been recognized that variants that alter or introduce cysteine residues damage protein function, leading to the development of MFS. In this study, we report a cysteine-introducing variant: FBN1 variant, c.6724C>T (p.[Arg2242Cys]). We have observed this variant in several individuals without MFS, challenging our previous understanding of the underlying mechanism of MFS. This finding emphasizes the importance of revisiting and reevaluating our current knowledge in light of new and unexpected observations. Moreover, our study highlights the significance of incorporating local and national data on allele frequencies, as well as employing multidisciplinary phenotyping approaches, in the classification of genetic variants. By considering a wide range of information, we can enhance the accuracy and reliability of variant classification, ultimately improving the diagnosis and management of individuals with genetic disorders like MFS.

The Contribution of Mast Cells to the Regulation of Elastic Fiber Tensometry in the Skin Dermis of Children with Marfan Syndrome.

Marfan syndrome (MFS) is a hereditary condition accompanied by disorders in the structural and regulatory properties of connective tissue, including elastic fibers, due to a mutation in the gene encodes for fibrillin-1 protein (FBN1 gene) and the synthesis of abnormal fibrillin-1 glycoprotein. Despite the high potential of mast cells (MCs) to remodel the extracellular matrix (ECM), their pathogenetic significance in MFS has not been considered yet. The group of patients with Marfan syndrome included two mothers and five children (three girls aged 4, 11, and 11 and two boys aged 12 and 13). Normal skin was examined in two children aged 11 and 12. Histochemical, monoplex, and multiplex immunohistochemical techniques; combined protocols of simultaneous histochemical and immunohistochemical staining (the results of staining were assessed using light, epifluorescence, and confocal microscopy); and bioinformatics algorithms for the quantitative analysis of detected targets were used to evaluate mast cells and their relationship with other cells from extracellular structures in the skin dermis. Analysis of the skin MC population in children with Marfan syndrome revealed a considerably increased number of intra-organic populations with the preservation of the specific Tryptase+Chymase+CPA3+ protease profile typical of the skin. The features of the MC histotopography phenotype in MFS consisted of closer colocalization with elastic fibers, smooth muscle cells, and fibroblasts. MCs formed many intradermal clusters that synchronized the activity of cell functions in the stromal landscape of the tissue microenvironment with the help of spatial architectonics, including the formation of cell chains and the creation of fibrous niches. In MCs, the expression of specific proteases, TGF-ß, and heparin increased, with targeted secretion of biologically active substances relative to the dermal elastic fibers, which had specific structural features in MFS, including abnormal variability in thickness along their entire length, alternating thickened and thinned areas, and uneven surface topography. This paper discusses the potential role of MCs in strain analysis (tensometry) of the tissue microenvironment in MFS. Thus, the quantitative and qualitative rearrangements of the skin MC population in MFS are aimed at altering the stromal landscape of the connective tissue. The results obtained should be taken into account when managing clinical signs of MFS manifested in other pathogenetically critical structures of internal organs, including the aorta, tendons, cartilage, and parenchymal organs.

New Insights into the Link Between Melanoma and Obesity.

The significant increase in the incidence of obesity represents a global health crisis. Obesity is actually a multi-organ disease affecting the entire organism; hence, skin is no exception. As the functional alterations in the adipose tissue are contributing factors to many diseases, including cancer, recently, the link between the development of melanoma skin cancer and obesity gains increased attention. Besides several other factors, the increase of adipose stromal/stem cells (ASCs) impacts cancer progression. Moreover, increased production of cytokines and growth factors done by ASCs induces tumorigenesis and metastasis. The chronic inflammatory state that is sustained by this metabolic imbalance favors skin malignancies, melanoma included. Cutaneous melanoma, as an aggressive skin cancer, has both intrinsic and extrinsic risk factors where sun exposure and lifestyles are the main environmental factors inducing this skin cancer. With the advent of recent targeted and immune-based therapies in melanoma, the link between obesity and the efficacy of these therapies in melanoma remains controversial. A recent molecular relationship between the melanocortin pathway appending to both melanin synthesis and obesity was established. The biology of adipokines, molecules secreted by the adipose tissue, is linked to inflammation, and their molecular pathways can be involved in angiogenesis, migration, invasion, and proliferation of melanoma cells. In melanoma cells, among the most noticeable metabolic reprogramming characteristics is an increased rate of lipid synthesis. Lipid mediators impact classical oncogenic pathways, affecting melanoma progression. The chapter will tackle also the practical implications for melanoma prevention and treatment, namely, how metabolic manipulation can be exploited to overcome immunosuppression and support immune checkpoint blockade efficacy.

Biomolecules of Adipose Tissue in Atherosclerotic Plaques of Men With Coronary Atherosclerosis.

AIM: To study metabolic molecules (adiponectin, adipsin, resistin, glucagon-like peptide-1 (GLP-1), glucagon, secretin) of adipose tissue in atherosclerotic plaques (AP) and their associations with AP instability in men with coronary atherosclerosis. MATERIAL AND METHODS: Metabolic molecules (adipocytokines and metabolic hormones) of adipose tissue can act as enzymes, hormones or growth factors in modulating insulin resistance and lipid and glucose metabolism and indirectly influence the course of the atherosclerotic process. This study included 48 men from whom 139 coronary artery (CA) samples were collected during coronary artery bypass grafting, after obtaining the informed consent. According to the histological conclusion, 84 (60.4%) CA plaques were stable, 44 (31.7%) were unstable, and 11 histological samples had a conditionally unchanged CA intima (7.9%). The concentrations of adiponectin, adipsin, resistin, GLP-1, glucagon, and secretin were measured in AP homogenates by multiplex analysis using the Human Metabolic Hormone V3 panel (MILLIPLEX, Germany). During the study, demographic and anthropometric characteristics, medical history, and presence of chronic diseases were recorded. RESULTS: The glucagon concentration in the conditionally unchanged intima was 16.7% lower and in the fragments of unstable atherosclerotic plaques 41.2% lower than in fragments of stable APs. However, the glucagon concentration in stable APs was 28% higher than in unstable APs. The secretin concentration in the conditionally unchanged intima was also lower than in stable APs by 41.2%, while in stable APs, the secretin concentration was 20% higher than in unstable APs. The adiponectin concentrations were directly correlated with serum high-density lipoprotein cholesterol (HDL-C) concentrations (r=0.286; p=0.002), while the secretin concentrations were inversely correlated with serum HDL-C concentrations (r= -0.199; p=0.038). The probability of having an unstable AP (in relation to conditionally unchanged intima) increases by 35.8% with an increase in the AP glucagon concentration by 1 pg/mg protein. The probability of having a stable AP (in relation to unchanged intima) increases by 29.4% with an increase in the AP glucagon concentration by 1 pg/mg protein and by 10.1% with an increase in the AP secretin concentration by 1 pg/mg protein. CONCLUSION: The AP adiponectin concentration directly correlates and the AP secretin concentration inversely correlates with the serum concentration of HDL-C. The presence of both stable and unstable APs is directly associated with the AP glucagon concentration in men with coronary atherosclerosis. The AP secretin concentration is directly associated with plaque stability in men with coronary atherosclerosis. Further thorough study of the identified markers in atherosclerotic lesions will allow using them as potential targets for therapy.

Maid gene dysfunction promotes hyperobesity via the reduction of adipose tissue inflammation in Mc4r gene-deficient mice.

The onset and progression mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are being studied. We developed and analyzed a new mouse model of obesity by combining maternal Id-like molecule (Maid) and melanocortin-4 receptor (Mc4r) gene deletions. Four mice, each at 12 and 28 weeks of age, were analyzed for each genotype: Maid gene knockout, Mc4r gene knockout, combined Mc4r and Maid gene knockout, and Mc4r gene knockout with a high-fat diet. Mice with a combined deficiency of Mc4r and Maid gene showed significantly more severe obesity compared to all other genotypes, but no liver fibrosis or a decline in metabolic status were observed. In visceral white adipose tissue, Maid and Mc4r gene knockout mice had fewer CD11c-positive cells and lower mRNA expression of both inflammatory and anti-inflammatory cytokines. Furthermore, Maid and Mc4r gene knockout mice showed lower expression of adipocytokines in visceral white adipose tissue and uncoupling protein-1 in scapular brown adipose tissue. The expression of adipocytokines and uncoupling protein-1 is regulated by sympathetic nerve signaling that contribute severe obesity in Maid and Mc4r gene knockout mice. These mechanisms contribute hyperobesity in Maid and Mc4r gene knockout mice.

Significance of Fibrillin-1, Filamin A, MMP2 and SOX9 in Mitral Valve Pathology.

Genetic factors play a significant role in the pathogenesis of mitral valve diseases, including mitral valve prolapse (MVP) and mitral valve regurgitation. Genes like Fibrillin-1 (FBN1), Filamin A (FLNA), matrix metalloproteinase 2 (MMP2), and SRY-box transcription factor 9 (SOX9) are known to influence mitral valve pathology but knowledge of the exact mechanism is far from clear. Data regarding serum parameters, transesophageal echocardiography, and genetic and histopathologic parameters were investigated in 54 patients who underwent cardiovascular surgery for mitral valve regurgitation. The possible association between Fibrillin-1, Filamin A, MMP2, and SOX9 gene expressions was checked in relationship with the parameters of systemic inflammatory response. The mRNA expression levels (RQ-relative quantification) were categorized into three distinct groups: low (RQ < 1), medium/normal (RQ = 1-2), and high (RQ > 2). Severe fibrosis of the mitral valve was reflected by high expression of FBN1 and low expression of MMP2 (p < 0.05). The myxoid degeneration level was associated with the mRNA expression level for FBN1 and a low lymphocyte-monocyte ratio was associated with an increased mRNA expression of FBN1 (p < 0.05). A high number of monocytes was associated with high values of FBN1 whereas the increase in the number of lymphocytes was associated with high levels of MMP2. In addition, we observed that the risk of severe hyalinization was enhanced by a low mRNA expression of FLNA and/or SOX9. In conclusion, a lower FLNA mRNA expression can reflect the aging process that is highlighted in mitral valve pathology as a higher risk for hyalinization, especially in males, that might be prevented by upregulation of the SOX9 gene. FBN1 and MMP2 influence the inflammation-related fibrotic degeneration of the mitral valve. Understanding the genetic base of mitral valve pathology can provide insights into disease mechanisms, risk stratification, and potential therapeutic targets.

Roles of extracellular vesicles derived from healthy and obese adipose tissue in inter-organ crosstalk and potential clinical implication.

Extracellular vesicles (EVs) are nanovesicles containing bioactive molecules including proteins, nucleic acids and lipids that mediate intercellular and inter-organ communications, holding promise as potential therapeutics for multiple diseases. Adipose tissue (AT) serves as a dynamically distributed energy storage organ throughout the body, whose accumulation leads to obesity, a condition characterized by infiltration with abundant immune cells. Emerging evidence has illustrated that EVs secreted by AT are the novel class of adipokines that regulate the homeostasis between AT and peripheral organs. However, most of the studies focused on the investigations of EVs derived from adipocytes or adipose-derived stem cells (ADSCs), the summarization of functions in cellular and inter-organ crosstalk of EVs directly derived from adipose tissue (AT-EVs) are still limited. Here, we provide a systemic summary on the key components and functions of EVs derived from healthy adipose tissue, showing their significance on the tissue recovery and metabolic homeostasis regulation. Also, we discuss the harmful influences of EVs derived from obese adipose tissue on the distal organs. Furthermore, we elucidate the potential applications and constraints of EVs from healthy patients lipoaspirates as therapeutic agents, highlighting the potential of AT-EVs as a valuable biological material with broad prospects for future clinical use.

Correlation between Overweight, Obesity, Gestational Diabetes Mellitus, Adipokines (Adipolin and Adiponectin), and Adverse Pregnancy Outcomes: A Pilot Study.

Background: The prevalence of overweight (OW), obesity (OB), and gestational diabetes mellitus (GDM) has been increasing worldwide in recent years. Adipolin is a new adipokine with reduced circulating levels in obesity and type 2 diabetes mellitus (T2DM). Objectives: Our prospective case-control study aimed to evaluate the maternal serum levels of adipolin and adiponectin, metabolic parameters, and anthropometric characteristics at the time of oral glucose tolerance test (OGTT) in pregnant women with a pre-pregnancy body mass index (BMI) ≥ 25 Kg/m2 and correlate them with newborn adipolin, adiponectin levels, and anthropometric characteristics of the newborns, and secondly to evaluate pregnancy outcomes. Material and Methods: After the OGTT results, we had 44 OW/OB pregnant women with GDM, 30 OW/OB pregnant women without GDM, and 92 lean healthy (LH) pregnant women. Data were analyzed by ANOVA and correlation tests, with a p-value < 0.05 considered significant. Results: We found no differences between adipolin values of the OW/OB pregnant women with GDM and the LH group (p > 0.99), OW/OB without GDM and the LH group (p = 0.56), and between OW/OB groups (p = 0.57). OW/OB pregnant women with GDM had a higher rate of gestational hypertension compared with the LH group (p < 0.0001). Newborns from OW/OB pregnant women with GDM were more frequently diagnosed with jaundice (p = 0.02), and they required more frequent admission to the neonatal intensive care unit (NICU) for treatment of respiratory distress (p = 0.01) compared with newborns from LH mothers. Conclusions: Our study revealed that the serum levels of adipolin in the second trimester among the group of OW/OB pregnant women with GDM, matched for age and BMI with OW/OB pregnant women without GDM, were not significantly different. This suggests that adipolin may not play an essential role in the occurrence of GDM in these patients. Despite good glycemic control during pregnancy, OW/OB pregnant women with GDM and their newborns tend to have more complications (gestational hypertension, jaundice, NICU admission) than LH pregnant women and their newborns, highlighting the importance of weight control before pregnancy.

Effects of Omega-3 Polyunsaturated Fatty Acids on the Formation of Adipokines, Cytokines, and Oxylipins in Retroperitoneal Adi-Pose Tissue of Mice.

Oxylipins and specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) are mediators that coordinate an active process of inflammation resolution. While these mediators have potential as circulating biomarkers for several disease states with inflammatory components, the source of plasma oxylipins/SPMs remains a matter of debate but may involve white adipose tissue (WAT). Here, we aimed to investigate to what extent high or low omega (n)-3 PUFA enrichment affects the production of cytokines and adipokines (RT-PCR), as well as oxylipins/SPMs (liquid chromatography-tandem mass spectrometry) in the WAT of mice during lipopolysaccharide (LPS)-induced systemic inflammation (intraperitoneal injection, 2.5 mg/kg, 24 h). For this purpose, n-3 PUFA genetically enriched mice (FAT-1), which endogenously synthesize n-3 PUFAs, were compared to wild-type mice (WT) and combined with n-3 PUFA-sufficient or deficient diets. LPS-induced systemic inflammation resulted in the decreased expression of most adipokines and interleukin-6 in WAT, whereas the n-3-sufficient diet increased them compared to the deficient diet. The n-6 PUFA arachidonic acid was decreased in WAT of FAT-1 mice, while n-3 derived PUFAs (eicosapentaenoic acid, docosahexaenoic acid) and their metabolites (oxylipins/SPMs) were increased in WAT by genetic and nutritional n-3 enrichment. Several oxylipins/SPMs were increased by LPS treatment in WAT compared to PBS-treated controls in genetically n-3 enriched FAT-1 mice. Overall, we show that WAT may significantly contribute to circulating oxylipin production. Moreover, n-3-sufficient or n-3-deficient diets alter adipokine production. The precise interplay between cytokines, adipokines, and oxylipins remains to be further investigated.

Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.

Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.

Immunological roles for resistin and related adipokines in obesity-associated tumors.

Rationale Obesity is an independent risk factor for the occurrence and development of tumors. Obesity is influenced by signaling of adipokines, which are secreted factors from adipocytes and resident immune cells within adipose tissues that mediate lipid metabolism. More recently, adipokines have been implicated in chronic inflammation as well as in tumor formation and growth. Among them, resistin has received increasing attention in research related to the growth and expansion of solid tumors and hematological cancers through various signaling pathways. Objective and findings We reviewed the physiological, biochemical, and immune functions of adipose tissue, with a focus on the structure and expression of resistin and adipokines within multiple adipose cell types, their signaling pathways and putative effects on tumor cells, as well as their in vivo regulation. Current evidence indicates that adipokines such as resistin act as pro-inflammatory factors to stimulate immune cells which, in turn, promotes tumor angiogenesis, connective tissue proliferation, and matrix fibrosis. Concurrently, in states of metabolic dysfunction and lipotoxicity in obese individuals, the numbers and functions of immune cells are compromised, leading to an immunosuppressive environment that fosters tumor cell survival and weak cancer immune monitoring. Conclusion Adipokines such as resistin are important to the development of obesity-related tumors. Clarifying the roles for obesity-related factors in immune regulation and tumor progression may lead to the discovery of novel anti-tumor strategies for targeting obesity factors such as resistin to limit tumor growth and manage obesity, or both.

A Novel Heterozygous Intronic FBN1 Variant Contributes to Aberrant RNA Splicing in Marfan Syndrome.

BACKGROUND: Marfan syndrome (MFS) is a complex genetic systemic connective tissue disorder. It is well known that genetic factors play a critical role in the progression of MFS, with nearly all cases attributed to variants in the FBN1 gene. METHODS: We investigated a Chinese family with MFS spanning two generations. Whole exome sequencing, in silico analysis, minigene constructs, transfection, RT-PCR, and protein secondary structure analysis were used to analyze the genotype of the proband and his father. RESULTS: The main clinical manifestations of the proband and his father were subluxation of the left lens and high myopia with pectus deformity. Whole exome sequencing identified a novel single nucleotide variant (SNV) in the FBN1 gene at a non-canonical splice site, c.443-3C>G. This variant resulted in two abnormal mRNA transcripts, leading to a frameshift and an in-frame insertion. Further in vitro experiments indicated that the c.443-3C>G variant in FBN1 was pathogenic and functionally harmful. CONCLUSION: This research identified a novel intronic pathogenic FBN1: c.443-3C>G gene variant, which led to two different aberrant splicing effects. Further functional analysis expands the variant spectrum and provides a strong indication and sufficient basis for preimplantation genetic testing for monogenic disease (PGT-M).

Impact of Lifestyle Interventions on Multiple Sclerosis: Focus on Adipose Tissue.

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by demyelination in the central nervous system (CNS), affecting individuals globally. The pathological mechanisms underlying MS remain unclear, but current evidence suggests that inflammation and immune dysfunction play a critical role in the pathogenesis of MS disease. Adipose tissue (AT) is a dynamic multifunctional organ involved in various immune diseases, including MS, due to its endocrine function and the secretion of adipokines, which can influence inflammation and immune responses. Physical activity represents an efficacious non-pharmacological strategy for the management of a spectrum of conditions that not only improves inflammatory and immune functions but also directly affects the status and function of AT. Additionally, the exploration of nutritional supplementation represents an important field of MS research aimed at enhancing clinical symptoms and is closely tied to the regulation of metabolic responses, including adipokine secretion. This review, therefore, aims to elucidate the intricate relationship between lifestyle and MS by providing an overview of the latest published data about the involvement of AT and the main adipokines, such as adiponectin, leptin, and tumor necrosis factor α (TNFα) in the pathogenesis of MS. Furthermore, we explore whether physical activity and dietary management could serve as useful strategies to improve the quality of life of MS patients.