Adipokine Secretion Research Articles

Brown and beige adipose tissue-derived metabokine and lipokine inter-organ signalling in health and disease.

Adipose tissue has an established endocrine function through the secretion of adipokines. However, a role for bioactive metabolites and lipids, termed metabokines and lipokines, is emerging in adipose tissue-mediated autocrine, paracrine and endocrine signalling and inter-organ communication. Traditionally seen as passive entities, metabolites are now recognized for their active roles in regulating cellular signalling and local and systemic metabolism. Distinct from white adipose tissue, specific endocrine functions have been attributed to thermogenic brown and beige adipose tissues. Brown and beige adipose tissues have been identified as sources of metabokines and lipokines, which influence diverse metabolic pathways, such as fatty acid β-oxidation, mitochondrial function and glucose homeostasis, across a range of tissues, including skeletal muscle, adipose tissue and heart. This review explores the intricate signalling mechanisms of brown and beige adipose tissue-derived metabokines and lipokines, emphasizing their roles in maintaining metabolic homeostasis and their potential dysregulation in metabolic diseases. Furthermore, we discuss the therapeutic potential of targeting these pathways, proposing that precise modulation of metabokine receptors and transporters could offer superior specificity and efficacy in comparison to conventional approaches, such as β-adrenergic signalling-stimulated activation of brown adipose tissue thermogenesis. Understanding the complex interactions between adipokines, metabokines and lipokines is essential for developing a systems-level approach to new interventions for metabolic disorders, underscoring the need for continued research in this rapidly evolving field.

The Role of Sarcopenic Obesity in Hyperlipidemia and Its Impact on Metabolic Health

Sarcopenic obesity, a condition characterized by the simultaneous presence of reduced muscle mass and increased adiposity, has emerged as a critical health concern in the context of metabolic disorders. This review examines the complex interplay between sarcopenic obesity and hyperlipidemia, focusing on the implications for metabolic health. The coexistence of diminished muscle mass and excess fat alters lipid metabolism, leading to elevated circulating lipid levels and exacerbating cardiovascular risks. Mechanisms contributing to this dysregulation include insulin resistance, chronic low-grade inflammation, and altered adipokine secretion, all of which are exacerbated in sarcopenic obesity. Moreover, the condition predisposes individuals to metabolic syndrome, type 2 diabetes, and cardiovascular diseases, highlighting the need for targeted therapeutic strategies. This article discusses the underlying pathophysiology, the role of lifestyle factors, and potential interventions aimed at mitigating the impact of sarcopenic obesity on hyperlipidemia and overall metabolic health. Keywords: Sarcopenic obesity, hyperlipidemia, metabolic health, insulin resistance, inflammation, adipokines, cardiovascular disease, metabolic syndrome

Somatic Changes of Maternal High-Fat Diet on Offspring—Possible Deleterious Effects of Flavonoids?

Background/Objectives: The rapidly increasing rate of obesity has become an extremely important public health problem, particularly in developed countries. Obesity is associated with a range of health problems, often referred to as the metabolic syndrome. Adipose tissue is now regarded as an endocrine organ responsible for the hormonal secretion of adipokines, which are cytokines involved in various physiological processes. It has been established that adipokines play a key role in the regulation of many processes in the human body. The aim of the current study was to use an animal model to investigate the possible influence of obesity and adipokines on the gestational period, on the development of offspring, and to assess whether these changes are influenced by the administration of antioxidant agents and flavonoids. Methods: The present study was performed using 5 groups of 7 female Wistar albino rats. A control group was used to which a 5% lipid diet was administered, and the other 4 groups were fed an obesogenic 65% lipid diet. From the 4 groups that received obesogenic diet one group received no supplement, and the rest of 3 received Detralex, Sel-E-Vit and Rutin (antioxidants and flavonoids). Study times for both pregnant groups and offsprings: on day 15 of gestation, venous blood was drawn to determine adipokine (leptin and visfatin) levels; on days 18–22 ultrasound examination was performed to measure the thickness of adipose tissue in the abdominal wall; for each batch a number of 10 offspring were selected for the measurements (pup weight, brain weight, head length, head width, spine length, width between shoulder blades, coxal bone length), adipokine levels in the offspring (from brain tissue) were also determined, as well as the existence of changes in the brain tissue of the offspring identified by electron microscopy. Results: The results of the study showed that the high-fat diet (HFD) led to a significant increase in body weight and abdominal wall thickness in pregnant females compared to the control group. The levels of leptin and visfatin were also affected by the HFD, with leptin levels being significantly higher in the HFD group and visfatin levels being lower. In the offspring, the HFD group had a significantly higher body mass and brain weight compared to the control group. The anthropometric measurements of the offspring were also affected by the maternal diet, with the HFD group having larger dimensions overall. Interestingly, the offspring of the groups that received flavonoids in addition to the HFD had significantly smaller dimensions compared to both the HFD group and the control group. Conclusions: The results of this experimental study reinforce what is already known about the effects of obesity on the gestation period and offspring and at the same time, the current study highlights the existence of possible adverse effects of flavonoid compounds on the development of pregnancy and offspring, opening the way for future studies on the benefits and risks of using these compounds during gestational period.

The effects of WWP1 overexpression on the golgi apparatus stress response and proteoglycan production in adipocytes

White adipocytes are a major component of white adipose tissue (WAT) and help to maintain systemic metabolic homeostasis by storing energy and secreting adipokines. In mice deficient in the protein WWP1 (WW domain-containing E3 ubiquitin protein ligase 1), oxidative stress in adipocytes increases but insulin resistance induced by obesity improves. However, the specific roles of WWP1 in adipocytes remain unclear. Here, we show that in 3T3L1 adipocytes, WWP1 localized in the Golgi apparatus via its C2 domain, where it protected the Golgi apparatus from monensin-induced disruption. By contrast, WWP1 knockdown by short hairpin RNA failed to protect the Golgi apparatus and enhanced Golgi apparatus disruption by monensin. The Golgi apparatus acts as a central organelle to establish accurate protein glycosylation of proteoglycans containing glycosaminoglycans, including chondroitin sulfate and heparan sulfate (HS). WWP1 overexpression increased chondroitin sulfate and HS levels, whereas WWP1 knockdown decreased them. Furthermore, obesity-related increases in HS were prevented by WWP1 knockout in adipose tissue. In summary, our results demonstrate a novel role for WWP1 in maintaining Golgi apparatus morphology and proteoglycan synthesis in adipocytes.

Resistin concentrations in perivascular adipose tissue as a highly sensitive marker of smoking status in patients with advanced coronary artery disease requiring coronary artery bypass grafting.

Smoking is a significant risk factor for numerous diseases, including coronary artery disease (CAD). Chronic inflammation from smoking affects endothelial function and may alter adipokine secretion, particularly resistin, in perivascular adipose tissue (PVAT). This study investigated the association between resistin concentrations in PVAT and smoking status in CAD patients undergoing coronary artery bypass grafting (CABG). The study included 110 patients with advanced CAD scheduled for CABG. Patients were categorized into never-smokers and ever-smokers, with the latter further divided into current and past smokers. Resistin concentrations in PVAT and plasma, along with plasma interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) concentrations, were measured using ELISA. Significant differences in PVAT resistin concentrations were observed between never-smokers and ever-smokers (p < 0.0001), as well as between never-smokers and both current (p < 0.0001) and past smokers (p < 0.0001). PVAT resistin concentrations correlated positively with the number of pack-years (p < 0.0001) and plasma resistin (p < 0.0001) and IL-6 concentrations (p < 0.0001). Plasma resistin, IL-6, and hs-CRP concentrations were higher in ever-smokers compared with never-smokers. Multiple regression analysis indicated that smoking is significantly correlated with higher PVAT resistin concentrations, with increased pack-years (p = 0.0002), higher plasma resistin concentrations (p < 0.0001), and IL-6 concentrations (p < 0.0001), all contributing to elevated PVAT resistin. Smoking status in advanced CAD patients requiring CABG is positively associated with PVAT resistin concentrations, with a clear demonstration of dose-dependency.

Abstract B047: Understanding the role of cancer-associated adipocytes in breast tumor microenvironment to delineate the relationship between obesity and cancer

Abstract Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Our results reveal that the activation of YAP/TAZ signaling in CAAs induces adipocyte dedifferentiation and the formation of a malignant TME. The additional deletion of YAP/TAZ significantly led to tumor regression by mitigating adipokine secretion such as Lipocalin2 and TNFα. Furthermore, mice fed a high- fat diet exhibit increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppressed tumor progression, highlighting its efficacy against mice with metabolic dysregulation. These findings provide insights into the key mediators of CAA transformation and their significance in developing a TME. Our study extends to the impact of maladaptive adipocytes as a TME component. We gather multi-omics results including single-nucleus RNA sequencing and spatial transcriptomics (Xenium) to identify the CAA population in the peritumoral region. CAAs are found to modulate the TME via interacting with multiple immune cells, especially macrophages. Xenium result visualizes the proximity between CAAs and macrophages, indicating their cellular interaction. Additionally, our in-vitro co- culture system shows that CAAs recruit macrophages more effectively compared to normal adipocytes. Overall, we strive to understand the importance of adipocyte quality in forming a malignant TME and ultimately introduce therapeutic strategies targeting the tumor microenvironment, especially adipocytes. Citation Format: Yaechan Song, Hee Ju Na, Han Woong Lee. Understanding the role of cancer-associated adipocytes in breast tumor microenvironment to delineate the relationship between obesity and cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B047.

Effect of Comparable Carbon Chain Length Short- and Branched-Chain Fatty Acids on Adipokine Secretion from Normoxic and Hypoxic Lipopolysaccharide-Stimulated 3T3-L1 Adipocytes.

Background: Microbial fermentation of non-digestible carbohydrates and/or protein produces short-chain fatty acids (SCFA), whereas branched-chain fatty acids (BCFA) are produced from protein fermentation. The effects of individual SCFA and BCFA of comparable carbon chain length on adipocyte inflammation have not been investigated. Objective: To compare the effects of SCFA and BCFA on inflammatory mediator secretion in an adipocyte cell culture model designed to recapitulate obesity-associated adipocyte inflammation under normoxic and hypoxic conditions. Methods: The 3T3-L1 adipocytes were cultured (24 h) without (Control, Con) and with 1 mmol/L of SCFA (butyric acid (But) or valeric acid (Val)) or 1 mmol/L of BCFA (isobutyric acid (IsoBut) or isovaleric acid (IsoVal)) and were unstimulated (cells alone, n = 6/treatment), or stimulated with 10 ng/mL lipopolysaccharide (LPS, inflammatory stimulus, n = 8/treatment) or 10 ng/mL LPS + 100 µmol/L of the hypoxia memetic cobalt chloride (LPS/CC, inflammatory/hypoxic stimulus, n = 8/treatment). Results: Compared to Con + LPS, But + LPS reduced secreted protein levels of interleukin (IL)-1β, IL-6, macrophage chemoattractant protein (MCP)-1/chemokine ligand (CCL)2, MCP3/CCL7, macrophage inflammatory protein (MIP)-1α/CCL3 and regulated upon activation, normal T cell expressed, and secreted (RANTES)/CCL5 and decreased intracellular protein expression of the ratio of phosphorylated to total signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NFκB) p65 (p < 0.05). Val + LPS reduced IL-6 secretion and increased MCP-1/CCL2 secretion compared to Con + LPS and exhibited a different inflammatory mediator secretory profile from But + LPS (p < 0.05), indicating that individual SCFA exert individual effects. There were no differences in the secretory profile of the BCFA IsoBut + LPS and IsoVal + LPS (p > 0.05). Alternatively, under inflammatory hypoxic conditions (LPS/CC) Val, IsoVal, and IsoBut all increased secretion of IL-6, MCP-1/CCL2 and MIP-1α/CCL3 compared to Con (p < 0.05), whereas mediator secretion did not differ between But and Con (p > 0.05), indicating that the proinflammatory effects of SCFA and BCFA was attenuated by But. Interestingly, But + LPS/CC decreased STAT3 activation versus Con + LPS/CC (p < 0.05). Conclusions: The decreased secretion of inflammatory mediators that is attributable to But highlights the fact that individual SCFA and BCFA exert differential effects on adipocyte inflammation under normoxic and hypoxic conditions.

Adipose Tissues Have Been Overlooked as Players in Prostate Cancer Progression.

Obesity is a common risk factor in multiple tumor types, including prostate cancer. Obesity has been associated with driving metastasis, therapeutic resistance, and increased mortality. The effect of adipose tissue on the tumor microenvironment is still poorly understood. This review aims to highlight the work conducted in the field of obesity and prostate cancer and bring attention to areas where more research is needed. In this review, we have described key differences between healthy adipose tissues and obese adipose tissues, as they relate to the tumor microenvironment, focusing on mechanisms related to metabolic changes, abnormal adipokine secretion, altered immune cell presence, and heightened oxidative stress as drivers of prostate cancer formation and progression. Interestingly, common treatment options for prostate cancer ignore the adipose tissue located near the site of the tumor. Because of this, we have outlined how excess adipose tissue potentially affects therapeutics' efficacy, such as androgen deprivation, chemotherapy, and radiation treatment, and identified possible drug targets to increase prostate cancer responsiveness to clinical treatments. Understanding how obesity affects the tumor microenvironment will pave the way for understanding why some prostate cancers become metastatic or treatment-resistant, and why patients experience recurrence.

Influence of melatonin on the development of obesity

In recent years, increasing attention of researchers has been paid to the role of melatonin in the regulation of body weight. When analyzing literature data, the problem of the mechanism of action of melatonin on the body and its use in the correction of metabolic disorders is considered. Disruption of circadian rhythms caused by the use of artificial light at night leads to decreased melatonin secretion. This helps increase appetite and reduce energy costs. In addition, melatonin plays a major role in modulating the secretion of adipokines by influencing lipid metabolism. Decreased melatonin production causes insulin resistance and metabolic circadian disorganization, leading to obesity. Assessing the role of melatonin in the development of obesity and its accompanying pathologies is a promising area of scientific research in the field of diagnosis, prevention and treatment of endocrine and cardiovascular pathologies.

Human peripancreatic adipose tissue paracrine signaling impacts insulin secretion, blood flow, and gene transcription.

Adipose tissue accumulation around non-adipose tissues is associated with obesity and metabolic disease. One relatively unstudied depot is peripancreatic adipose tissue (PAT) that accumulates in obesity and insulin resistance and may impact beta cell function. Pancreatic lipid accumulation and PAT content are negatively related to metabolic outcomes in humans, but these studies are limited by the inability to pursue mechanisms. We obtained PAT from human donors through the Human Pancreas Analysis Program to evaluate differences in paracrine signaling compared to subcutaneous adipose tissue (SAT), as well as effects of the PAT secretome on aortic vasodilation, human islet insulin secretion, and gene transcription using RNAseq. PAT had greater secretion of IFN-γ and most inflammatory eicosanoids compared to SAT. Secretion of adipokines negatively related to metabolic health were also increased in PAT compared to SAT. We found no overall effects of PAT compared to SAT on human islet insulin secretion, however, insulin secretion was suppressed after PAT exposure from men compared to women. Vasodilation was significantly dampened by PAT conditioned media, an effect explained almost completely by PAT from men and not women. Islets treated with PAT showed selective changes in lipid metabolism pathways while SAT altered cellular signaling and growth. RNAseq analysis showed changes in islet gene transcription impacted by PAT compared to SAT, with the biggest changes found between PAT based on sex. The PAT secretome is metabolically negative compared to SAT, and impacts islet insulin secretion, blood flow, and gene transcription in a sex dependent manner.

Diverse Cytokines Secreted by Adipocyte in Linking Cardio-Metabolic Disorder and SLE.

Systemic lupus erythematosus (SLE) is a multi-factorial autoimmune-mediated disease with hyper-stimulation of immune cells especially the T lymphocytes. By this method, it might facilitate the systematic damages in multiple tissues and organs. Otherwise, SLE is also correlated with diverse cardio-metabolic comorbidities, including dyslipidemia, insulin resistance, and hypertension. It is worth-noting that the risk of cardio-metabolic disorders is significantly higher compared with the healthy patients which was reported as approximately one-third of SLE patients were proved as obesity. Notably, current focus is shifting to implementing cardio-metabolic protective strategies as well as elucidating underlying mechanisms of lupus-mediated obese status. On the other hand, adipocyte, as the most abundant endocrine cell in fat tissue, are dysfunctional in obese individuals with aberrant secretion of adipokines. It is proposing that the adipokine might link the pathology of cardio-metabolic disorders and SLE, whereas the related mechanism is complicated. In the current review, the functions of adipokine and the potential mechanisms by which the adipokine link cardio-metabolic disorders and SLE was well listed. Furthermore, the recommendations, which identify the adipokine as the potential therapeutic targets for the treatment of cardio-metabolic disorders and SLE, were also summarized.

The Complement System as a Part of Immunometabolic Post-Exercise Response in Adipose and Muscle Tissue.

The precise molecular processes underlying the complement's activation, which follows exposure to physical stress still remain to be fully elucidated. However, some possible mechanisms could play a role in initiating changes in the complement's activity, which are observed post-exposure to physical stress stimuli. These are mainly based on metabolic shifts that occur in the microenvironment of muscle tissue while performing its function with increased intensity, as well as the adipose tissue's role in sterile inflammation and adipokine secretion. This review aims to discuss the current opinions on the possible link between the complement activation and diet, age, sex, and health disorders with a particular emphasis on endocrinopathies and, furthermore, the type of physical activity and overall physical fitness. It has been indicated that regular physical activity incorporated into therapeutic strategies potentially improves the management of particular diseases, such as, e.g., autoimmune conditions. Moreover, it represents a favorable influence on immunoaging processes. A better understanding of the complement system's interaction with physical activity will support established clinical therapies targeting complement components.

Body mass index as a contributor to the accumulation of lipidic plaque materials in statin-treated type 2 diabetic patients with coronary artery disease: sub-analysis from the OPTIMAL randomized study

Abstract Background Patients with type 2 diabetes mellitus more likely exhibit obesity. Pathophysiologically, obesity promotes a range of metabolic disturbances including insulin resistance, dyslipidemia and hypertension, in addition to the secretion of adipokines and pro-inflammatory cytokines from excessive fat accumulation. These atherogenic features may promote instability of atherosclerotic plaques, which ultimately result in elevating a risk of atherosclerotic cardiovascular disease. However, it remains to be fully elucidated how obesity affects atherosclerotic plaque features in type 2 diabetic patients with coronary artery disease (CAD). Near-infrared spectroscopy (NIRS) imaging enables to quantitatively visualize lipidic plaque materials in vivo. This imaging modality provides insights into lipidic plaque features in obese patients with type 2 diabetes mellitus. Purpose To elucidate the association of body mass index (BMI, kg/m2) with lipidic plaque materials in type 2 diabetic patients. Methods The OPTIMAL study was a prospective randomized controlled trial to evaluate the efficacy of continuous glucose monitoring (CGM) guided glycemic control on coronary atherosclerosis in statin-treated type 2 diabetic participants with CAD requiring PCI. 94 patients were randomized into CGM-guided or HbA1c-guided glycemic control. Serial NIRS imaging was conducted to monitor non-culprit lesions at baseline and week 48. The current sub-analysis included 78 patients with both baseline BMI data and evaluable baseline NIRS/IVUS images. Results All of study subjects received a statin (high-intensity statin use=36%), and the averaged LDL-C level was 86.7±26.3 mg/dL. The average BMI and HbA1c level were 24.7±3.1 kg/m2 and 7.5±0.9%, respectively (Table 1). On NIRS imaging analysis, maxLCBI4mm at non-culprit lesions was 286.2±167.0, and 21.8% of study subjects exhibited maxLCBI4mm &amp;gt;400 (Table 2). BMI was associated with maxLCBI4mm (p&amp;lt;0.001). Multivariate analysis adjusting clinical characteristics and LDL-C demonstrated that BMI was an independent contributor to maxLCBI4mm [estimate=17.15 (12.88-21.42), p&amp;lt;0.001] (Table 2). Even in patients receiving high-intensity statin, BMI was still associated with maxLCBI4mm (p&amp;lt;0.001). Conclusions A greater accumulation of lipidic plaque materials was observed in association with BMI in statin-treated type 2 diabetic patients with CAD. This presence of enhanced plaque vulnerability at non-culprit lesions, in the setting of obesity, may contribute to an increased risk of cardiovascular events in type 2 diabetic patients with CAD. The current finding suggests the need to adopt further therapeutic approaches to favourably modify plaque vulnerability in type 2 diabetic patients exhibiting obesity.Table 1:Clinical DemographicsTable 2:Factors Associated with maxLCBI

Tributyltin Enhances Macrophage Inflammation and Lipolysis, Contributing to Adipose Tissue Dysfunction.

Tributyltin (TBT) is a synthetic chemical widely used in industrial and commercial applications. TBT exposure has been proven to elicit obesogenic effects. Gestational exposure led to increased white adipose tissue depot size in exposed (F1, F2) animals and in unexposed generations (F3, F4), an example of transgenerational inheritance. TBT exerts these effects in part by increasing the number and size of white adipocytes, altering the fate of multipotent mesenchymal stromal stem cells to favor the adipocyte lineage, altering adipokine secretion, and modulating chromatin structure. Adipose tissue resident macrophages are critical regulators in adipose tissue; however, the effects of TBT on adipose tissue macrophages remained unclear. Here we investigated the effects of TBT on macrophages and consequent impacts on adipocyte function. TBT significantly enhanced palmitate-induced inflammatory gene expression in mouse bone marrow derived macrophages and this effect was attenuated by the antagonizing action of the nuclear receptor peroxisome proliferator activated receptor gamma. TBT-treated macrophages decreased lipid accumulation in white adipocytes differentiated from mesenchymal stromal stem cells accompanied by increased expression of lipolysis genes. Lastly, ancestral TBT exposure increased Tnf expression in adipose tissue resident macrophages in both exposed (F2) and unexposed (F3) generations, suggesting that TBT exposure led to an inherited predisposition toward inflammatory adipose tissue macrophages that can manipulate adipose tissue function. These findings provide new insights into the interplay between adipocytes and adipose tissue macrophages in obesity, further establishing a role for obesogens such as TBT in the development of obesity-related metabolic disorders.

Amphiregulin Upregulation in Visfatin-Stimulated Colorectal Cancer Cells Reduces Sensitivity to 5-Fluororacil Cytotoxicity.

Colorectal cancer (CRC) has become a prevalent and deadly malignancy over the years. Drug resistance remains a major challenge in CRC treatment, significantly affecting patient survival rates. Obesity is a key risk factor for CRC development, and accumulating evidence indicates that increased secretion of adipokines, including Visfatin, under obese conditions contributes to the development of resistance in CRC to various therapeutic methods. Amphiregulin (AREG) is a member of the epidermal growth factor (EGF) family, which activates the EGF receptor (EGFR), influencing multiple tumorigenic characteristics of cancers. Abnormal expression levels of AREG in cancer cells have been associated with resistance to anti-EGFR therapy in patients. However, it remains unclear whether this abnormal expression also impacts CRC resistance to other chemotherapeutic drugs. The aim of this study is to examine whether AREG expression levels could be affected in CRC cells under Visfatin stimulation, thereby initiating the development of resistance to 5-fluororacil (5-FU). Through our results, we found that Visfatin indeed increases AREG expression, reducing the sensitivity of HCT-116 CRC cells to 5-FU cytotoxicity. Moreover, AREG upregulation is regulated by STAT3-CREB transcription factors activated by JNK1/2 and p38 signaling. This study highlights the significant role of AREG upregulation in CRC cells in initiating chemotherapeutic resistance to 5-FU under Visfatin stimulation. These findings provide a deeper understanding of drug resistance development in CRC under obese conditions and offer new insights into the correlation between an abnormal increase in AREG levels and the development of 5-FU-resistance in CRC cells, which should be considered in future clinical applications.

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.

8550 Processing Technique Affects Aromatase Expression in Fat Grafts for Breast Reconstruction

Abstract Disclosure: S. Arbuiso: None. Y. Chen: None. N.A. Vernice: None. A. Zhang: None. I.J. Rhodes: None. C.C. Alston: None. S. Hanif: None. S. Liu: None. P. Bhardwaj: None. D. Janhofer: None. G.G. Black: None. D.M. Otterburn: None. K.A. Brown: None. Introduction: Autologous fat grafting is commonly used in breast reconstruction as it is associated with good cosmetic outcomes, high patient satisfaction, and minimal risks. Adipose tissue is known to support cancer growth via the secretion of adipokines and the modulation of estrogen levels due to aromatase expressed in adipose stromal cells. A higher body mass index (BMI) and postmenopausal status are associated with higher levels of aromatase. With novel processing techniques being developed to increase fat graft retention, there is a need to better understand how these will affect the biology of lipoaspirates for women who have previously had breast cancer. This study aims to assess how different processing techniques used in fat grafting (1) impact aromatase gene expression, (2) affect breast cancer cell proliferation, and (3) affect the cellular composition of the engrafted lipoaspirate. Methods: Patients who underwent breast reconstruction for breast cancer treatment or for prophylactic measures, and were receiving autologous fat grafting, were enrolled in a prospective randomized controlled trial (NCT04891510). Patients were randomized to one of three processing techniques: standard decantation, active filtration, and low-pressure decantation. Conditioned media (CM) was created from each sample. Aromatase mRNA was measured in the lipoaspirate using qRT-PCR for aromatase (CYP19A1) and related to patient BMI or menopausal status. The effect of CM on the proliferation of MCF7 cells (estrogen receptor positive (ER+) breast cancer cell line) was measured using CyQUANT. Formalin-fixed lipoaspirate samples were embedded in HistoGel and paraffin. Adipocyte diameter was measured in hematoxylin and eosin (H&amp;E) stained sections using ImageJ. Results: Aromatase mRNA levels were correlated with BMI and were higher in postmenopausal women (p≤0.05), with the standard decantation group demonstrating a stronger correlation with BMI. Samples processed via active filtration were associated with weaker correlations between aromatase gene expression and BMI and menopausal status. CM induced MCF7 cell proliferation to a similar extent to cells plated in fetal bovine serum-containing media. There was no difference in proliferation patterns between treatment groups. Upon histological assessment, adipocytes were intact, and adipocyte diameter was significantly correlated with patient BMI. Conclusion: Lipoaspirate may contain factors that promote breast cancer cell proliferation, unaffected by processing technique. Caution should be used to ensure local control of the cancer has been achieved prior to reconstruction. Our data suggest that active filtration selects for a lower percentage of adipose stromal cells, which may be beneficial for patients who previously had ER+ breast cancer. Presentation: 6/1/2024

Analysis of the relationship between resistin with prognosis, cell migration, and p38 and ERK1/2 activation in breast cancer

Obesity increases the risk and mortality of breast cancer through dysregulated secretion of proinflammatory cytokines and tumor adipokines that induce an inflammatory breast microenvironment. Resistin is an adipokine secreted by adipocytes, immune cells, and predominantly macrophages, which contributes to cancer progression, but its molecular mechanism in cancer is not completely described. In this study, we analyzed the relationship of resistin on breast cancer prognosis and tumor progression and the effect in vitro of resistin on p38 and ERK1/2 activation in breast cancer cell lines. By bioinformatic analysis, we found that resistin is overexpressed in the basal subtype triple-negative breast cancer and is related to poor prognosis. In addition, we demonstrated a positive correlation between RETN and MAPK3 expression in basal triple-negative breast cancer. Importantly, we found amplifications of the RETN gene in at least 20 % of metastatic samples from patients with breast cancer. Most samples with RETN amplifications metastasized to bone and showed high expression of IL-8 (CXCL8) and IL-6 (IL6). Finally, resistin could be considered a prognostic marker for basal triple-negative breast cancer, and we also proposed the possibility that resistin-induced cell migration involves the activation of MAPK in breast cancer cells.

Oncostatin M: friend or foe in PCOS pathogenesis.

Polycystic ovary syndrome (PCOS) is a primary endocrinological disorder in women of reproductive age that is characterized by androgen excess and ovulatory irregularities. This syndrome is associated with adipose tissue dysfunction, an elevated risk of insulin resistance, hyperinsulinemia, obesity, and type 2 diabetes. Adipocyte dysfunction affects the secretion of adipokines and pro-inflammatory cytokines. Nevertheless, adipose tissue is not an exclusive source of adipokines as it can also be produced locally by reproductive tissues. Although adipokines have been recognized in the development of PCOS, the role of oncostatin M (OSM), a multifaceted adipokine, remains unclear. Current evidence suggests that this cytokine is associated with key aspects of the syndrome, including obesity, insulin resistance, hyperandrogenism, and inflammation. However, the data are often contradictory, likely due to variations in study designs, methodologies, and species differences. By investigating the link between OSM and PCOS-associated issues, this review identified the potential role of this adipokine in PCOS pathogenesis. This underscores the need for further research to clarify its predominant effects and assess its relevance as a therapeutic target.

Metabolic obesity phenotypes and thyroid cancer risk: A systematic exploration of the evidence.

Obesity is recognized as a risk factor for various cancers, including thyroid cancer. However, the association between different metabolic obesity phenotypes and thyroid cancer risk remains unclear. This systematic review aimed to comprehensively evaluate the existing literature to elucidate the association between metabolic obesity phenotypes and thyroid cancer risk. This systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Scopus, EMBASE, Web of Science, and Google Scholar were searched for relevant studies until April 2024. Studies examining the link between metabolic obesity phenotypes and thyroid cancer risk were included. Five cohort studies involving 831,510 participants met the inclusion criteria. Metabolically unhealthy obesity was consistently associated with an increased risk of thyroid cancer in both men and women. Central adiposity emerged as a significant predictor of thyroid cancer risk. Mechanistically, chronic inflammation, dysregulated adipokine secretion, hormonal imbalances, and altered signaling pathways may contribute to thyroid carcinogenesis. There is an ongoing debate regarding the risk associated with metabolically healthy obesity, with some suggesting potential protective effects due to favorable metabolic profiles. This systematic review highlights the complex relationship between metabolic obesity phenotypes and thyroid cancer risk. The findings highlighted the importance of considering metabolic status alongside obesity in thyroid cancer risk assessment and intervention strategies.