Obesity-related Dysfunction Research Articles

Obesity-induced PARIS (ZNF746) accumulation in adipose progenitor cells leads to attenuated mitochondrial biogenesis and impaired adipogenesis

White adipose tissue (WAT) is critical for whole-body energy metabolism, and its dysfunction leads to various metabolic disorders. In recent years, many studies have suggested that impaired mitochondria may contribute to obesity-related decline in adipose tissue function, but the detailed mechanisms remain unclear. To investigate these mechanisms, we carried out a comprehensive analysis of WAT from mice with diet-induced obesity. We discovered the transcription factor Parkin interactive substrate (PARIS or ZNF746), which suppresses the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key regulator of mitochondrial biogenesis, to be accumulated in adipose progenitor cells from obese mice. Furthermore, we demonstrated that 3T3-L1 preadipocytes with overexpression of PARIS protein exhibited decreased mitochondrial biogenesis and impaired adipogenesis. Our results suggest that the accumulation of PARIS protein may be a novel component in the pathogenesis of obesity-related dysfunction in WAT.

Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.

Estrogens in Adipose Tissue Physiology and Obesity-Related Dysfunction.

Menopause-related decline in estrogen levels is accompanied by a change in adipose tissue distribution from a gynoid to an android and an increased prevalence of obesity in women. These unfavorable phenomena can be partially restored by hormone replacement therapy, suggesting a significant role for estrogen in the regulation of adipocytes' function. Indeed, preclinical studies proved the involvement of these hormones in adipose tissue development, metabolism, and inflammatory activity. However, the relationship between estrogen and obesity is bidirectional. On the one hand-their deficiency leads to excessive fat accumulation and impairs adipocyte function, on the other-adipose tissue of obese individuals is characterized by altered expression of estrogen receptors and key enzymes involved in their synthesis. This narrative review aims to summarize the role of estrogen in adipose tissue development, physiology, and in obesity-related dysfunction. Firstly, the estrogen classification, synthesis, and modes of action are presented. Next, their role in regulating adipogenesis and adipose tissue activity in health and the course of obesity is described. Finally, the potential therapeutic applications of estrogen and its derivates in obesity treatment are discussed.

Integrated analysis of the microbiota-gut-brain axis in response to sleep deprivation and diet-induced obesity.

Sleep deprivation (SD) and obesity are common in modern societies. SD and obesity frequently coexist, but research on the combined consequences of SD and obesity has been limited. In this study, we investigated the gut microbiota and host responses to SD and high-fat diet (HFD)-induced obesity. In addition, we attempted to identify key mediators of the microbiota-gut-brain axis. C57BL/6J mice were divided into four groups based on whether they were sleep deprived and whether they were fed a standard chow diet (SCD) or HFD. We then performed fecal microbiome shotgun sequencing, gut transcriptome analysis using RNA sequencing, and brain mRNA expression analysis using the nanoString nCounter Mouse Neuroinflammation Panel. The gut microbiota was significantly altered by the HFD, whereas the gut transcriptome was primarily influenced by SD. Sleep and diet are both important in the inflammatory system of the brain. When SD and the HFD were combined, the inflammatory system of the brain was severely disrupted. In addition, inosine-5' phosphate may be the gut microbial metabolite that mediates microbiota-gut-brain interactions. To identify the major drivers of this interaction, we analyzed the multi-omics data. Integrative analysis revealed two driver factors that were mostly composed of the gut microbiota. We discovered that the gut microbiota may be the primary driver of microbiota-gut-brain interactions. These findings imply that healing gut dysbiosis may be a viable therapeutic target for enhancing sleep quality and curing obesity-related dysfunction.

Hyaluronan in Adipose Tissue, Metabolic Inflammation, and Diabetes: Innocent Bystander or Guilty Party?

Hyaluronic acid, or hyaluronan (HA), is a nonsulfated glucosaminoglycan that has long been recognized for its hydrophilic properties and is widely used as a dermal filler. Despite much attention given to the study of other extracellular matrix (ECM) components, in the field of ECM properties and their contribution to tissue fibroinflammation, little is known of HA's potential role in the extracellular milieu. However, recent studies suggest that it is involved in inflammatory response, diet-induced insulin resistance, adipogenesis, and autoimmunity in type 1 diabetes. Based on its unique physical property as a regulator of osmotic pressure, we emphasize underestimated implications in adipose tissue function, adipogenesis, and obesity-related dysfunction.

Edible and medicinal mushrooms (Pleurotus ostreatus, Ustilago maydis, Ganoderma lucidum) reduce endoplasmic reticulum stress and inflammation in adipose tissue of obese Wistar rats fed with a high fat plus saccharose diet.

Obesity is an increasing global public health problem. A strategy to treat obesity is the use of functional foods. Edible and medicinal mushrooms contain diverse bioactive compounds showing important antihyperlipidemic, antioxidant, and prebiotic properties. We analysed the effects of adding (10%) of Pleurotus ostreatus (Po, basidiomata), Ganoderma lucidum (Gl, basidiomata), or Ustilago maydis (Um, galls), milled, to a high fat plus saccharose diet (HFD + S) for 6 months in a model of obesity with Wistar rats. We assessed weight gain, body composition, lipid parameters, endoplasmic reticulum stress (proteins and inflammatory markers: BiP, XBP-1, JNK, p-JNK, TNF-α), and adiponectin in subcutaneous adipose tissue (SAT). The consumption of edible and medicinal mushrooms decreased weight gain (-17.2-30.1%) and fat mass (-23.7-43.1%), maintained fat-free mass, reduced levels of serum biochemical parameters (TC: -40.1-44.1%, TG: -37.7-51.6%, LDL-C: -64.5-71.1%), and prevented adipocyte hypertrophy (-30.9-36.9%) and collagen deposition (-70.9-73.7%) in SAT. Compared with the HFD + S group, mushroom consumption by Wistar rats significantly reduced the expression of proteins associated with endoplasmic reticulum stress and inflammation (BiP: -72.2-88.2%; XBP-1: -71.5-81.8%; JNK: -71.2-90.0%; p-JNK: -37.3-81.0%; TNF-α: -80.7-91.5%), whereas significantly increased adiponectin protein expression (246.4-654.2%) in SAT. These effects outperformed those obtained through the commercial lipid-lowering drug atorvastatin, contributing synergistically to prevent further obesity-related dysfunctions, such as insulin resistance derived from inflammation and ER stress in adipose tissue. Bioactive compounds from edible, functional and medicinal mushrooms represent new emerging therapies for obesity treatments using natural products.

Zinc Supplementation Partially Decreases the Harmful Effects of a Cafeteria Diet in Rats but Does Not Prevent Intestinal Dysbiosis.

Zinc (Zn) plays an important role in metabolic homeostasis and may modulate neurological impairment related to obesity. The present study aimed to evaluate the effect of Zn supplementation on the intestinal microbiota, fatty acid profile, and neurofunctional parameters in obese male Wistar rats. Rats were fed a cafeteria diet (CAF), composed of ultra-processed and highly caloric and palatable foods, for 20 weeks to induce obesity. From week 16, Zn supplementation was started (10 mg/kg/day). At the end of the experiment, we evaluated the colon morphology, composition of gut microbiota, intestinal fatty acids, integrity of the intestinal barrier and blood–brain barrier (BBB), and neuroplasticity markers in the cerebral cortex and hippocampus. Obese rats showed dysbiosis, morphological changes, short-chain fatty acid (SCFA) reduction, and increased saturated fatty acids in the colon. BBB may also be compromised in CAF-fed animals, as claudin-5 expression is reduced in the cerebral cortex. In addition, synaptophysin was decreased in the hippocampus, which may affect synaptic function. Our findings showed that Zn could not protect obese animals from intestinal dysbiosis. However, an increase in acetate levels was observed, which suggests a partial beneficial effect of Zn. Thus, Zn supplementation may not be sufficient to protect from obesity-related dysfunctions.

Abstract ES7-1: Harnessing Lifestyle Interventions via Diet and Exercise for Cancer Risk Reduction

Abstract A growing body of evidence indicates the importance of maintaining optimal metabolic health to reduce the risk of developing cancer and to improve outcomes after cancer diagnosis. Classical and normal weight obesity are states of metabolic dysfunction, and highly prevalent risk factors for the development and growth of several cancers. Classical obesity (defined as a body mass index (BMI) ≥ 30) is a risk factor for at least 13 different types of cancer. Recent data indicate that up to one third of normal weight individuals have metabolic obesity and, subsequently, increased risk for several cancers including breast and colon. Methods to risk-stratify metabolic health and subsequent cancer risk beyond traditional anthropometric metrics such as BMI could improve the efficacy of lifestyle interventions aimed at reducing cancer risk and improving cancer outcomes. In this educational session, the molecular mechanisms linking classical and normal weight obesity to cancer growth will be presented. Obesity-related dysfunction can contribute to cancer pathogenesis and treatment resistance through various mechanisms, including those mediated by insulin, leptin, adiponectin, pro-inflammatory mediators, and hormone signaling pathways, particularly in women. Furthermore, adiposity-related changes can influence tumor vascularity and inflammation in the tumor microenvironment, which can support tumor development and growth. Building upon these mechanistic findings, several clinical trials testing “precision lifestyle” interventions targeted at specific biologic pathways are ongoing. Several randomized control trials testing diet, exercise, and weight loss interventions in cancer populations have demonstrated the feasibility of such interventions. Here, the next generation of lifestyle interventions, such as digital interventions, that target specific pathway dysregulation will be presented. Additionally, pharmacologic interventions that target host metabolism are under study as adjuncts to standard cancer therapy. As rates of classical and normal weight obesity continue to increase, the development of individualized and biologically rational lifestyle interventions could represent an impactful strategy to reduce the worldwide cancer burden. Citation Format: NM Iyengar. Harnessing Lifestyle Interventions via Diet and Exercise for Cancer Risk Reduction [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 ES7-1.

Olfactory Stimulation by Fennel (Foeniculum vulgare Mill.) Essential Oil Improves Lipid Metabolism and Metabolic Disorders in High Fat-Induced Obese Rats.

In this study, odor components were analyzed using gas chromatography/mass spectrometry (GC/MS) and solid-phase microextraction (SPME), and odor-active compounds (OACs) were identified using GC-olfactometry (GC-O). Among the volatile compounds identified through GC-O, p-anisaldehyde, limonene, estragole, anethole, and trans-anethole elicit the fennel odor. In particular, trans-anethole showed the highest odor intensity and content. Changes in body weight during the experimental period showed decreasing values of fennel essential oil (FEO)-inhaled groups, with both body fat and visceral fat showing decreased levels. An improvement in the body’s lipid metabolism was observed, as indicated by the increased levels of cholesterol and triglycerides and decreased levels of insulin in the FEO-inhaled groups compared to group H. Furthermore, the reduction in systolic blood pressure and pulse through the inhalation of FEO was confirmed. Our results indicated that FEO inhalation affected certain lipid metabolisms and cardiovascular health, which are obesity-related dysfunction indicators. Accordingly, this study can provide basic research data for further research as to protective applications of FEO, as well as their volatile profiles.

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.

Heat shock response to exercise in pancreatic islets of obese mice

Chronic obesity imposes an organismal state of low-grade inflammation because the physiological resolution of inflammation is progressively repressed giving rise to cellular senescence and its accompanying Senescence-Associated Secretory Phenotype (SASP), which avoids apoptosis but perpetuates the relay of inflammatory signals from adipose tissue toward the rest of the body. Conversely, resolution of inflammation depends on the integrity of heat shock response (HSR) pathway that leads to the expression of cytoprotective and anti-inflammatory protein chaperones of the 70 kDa family (HSP70). However, chronic exposure to the aforementioned injuring factors leads to SASP, which, in turn, suppresses the HSR. A main metabolic tissue severely jeopardized by obesity-related dysfunctions is the endocrine pancreas, particularly β-cells of the islets of Langerhans. Because exercise is a powerful inducer of HSR and predicted to alleviate negative health outcomes of obesity, we sought whether obesity influence HSP70 expression in pancreatic islets and other metabolic tissues (adipose tissue and skeletal muscle) of adult B6.129SF2/J mice fed on a high-fat diet (HFD) for 13 weeks since the weaning and whether acute exercise as well as moderate-intensity exercise training (8 weeks) could interfere with this scenario. We showed that acute exercise of moderate intensity protects pancreatic islets against cytokine-induced cell death. In addition, acute exercise challenge time-dependently increased islet HSP70 that peaked at 12 h post-exercise in both trained and untrained mice fed on a control diet, suggesting an adequate HSR to exercise training. Unexpectedly, however, neither exercise training nor acute exercise challenges were able to increase islet HSP70 contents in trained mice submitted to HFD, but only in untrained HFD animals. In parallel, HFD disrupted glycemic status which is accompanied by loss of muscular mass resembling sarcopenic obesity that could not be rescued by exercise training. These results suggest that exercise influences HSR in pancreatic islets but obesity undermines islet, muscle and adipose tissue HSR, which is associated with metabolic abnormalities observed in such tissues.

Pistachio Consumption Prevents and Improves Lipid Dysmetabolism by Reducing the Lipid Metabolizing Gene Expression in Diet-Induced Obese Mice.

Pistachios contain beneficial substances such as unsaturated fatty acids, phytosterols, and polyphenols. In the present study, we investigated if pistachio consumption is able to prevent or to revert hyperglycemia, dyslipidemia, hepatic steatosis, and adipose tissue morphological alterations caused by high fat diet (HFD) in the mouse. Moreover, the impact of pistachio intake on the mRNA expression of peroxisome proliferator-activated receptor γ (PPAR-γ), fatty acid transport proteins (FAT-P), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD1), and sterol regulatory element-binding transcription factor-1c (SREBP-1c) in liver and adipose tissue was also analyzed. No change in body weight, food intake, and hyperglycemia was observed between mice consuming pistachios (HFD-P) and HFD mice. Pistachio intake was able to prevent but not to reverse HFD-induced hypertriglyceridemia. Cholesterol plasma levels, steatosis grading, body fat mass, and adipocyte size were significantly lower in HFD-P group compared to HFD in both prevention and reversal protocol. Pistachio-diet was able to prevent HFD-induced overexpression of PPAR-γ, FAS, and SCD1 in the liver and SREBP-1c, PPAR-γ, and FAT-P in adipose tissue. Similarly, HFD-P significantly ameliorated the expression levels of FAT-P and SCD1 in the liver and SREBP-1c, FAS, and SCD1 in adipose tissue of obese mice. The present study shows that pistachio consumption is able to prevent and to ameliorate obesity-related dysfunctions by positively modulating the expression of genes linked to lipid metabolism.

Obesity, energy balance and spermatogenesis.

Obesity has grown to pandemic proportions. It affects an increasing number of children, adolescents and young adults exposed to the silent comorbidities of this disorder for a longer period. Infertility has arisen as one important comorbidity associated with the energy dysfunction promoted by obesity. Spermatogenesis is a highly regulated process that is determined by specific energetic requirements. The reproductive potential of males relies on hormonal-dependent and -independent stimuli that control sperm quality. There are conflicting data concerning the impact of male overweight and obesity on sperm quality, as well as on the possible paternal-induced epigenetic trait inheritance of obesity. In addition, it remains a matter of debate whether massive weight loss induced by lifestyle interventions, drugs or bariatric surgery may or may not benefit obese men seeking fatherhood. Herein, we propose to discuss how energy balance may modulate hormonal signalling and sperm quality in overweight and obese men. We also discuss some molecular mechanisms that mediate obesity-related dysfunction in male reproductive system and how paternal obesity may lead to trait inheritance. Finally, we will discuss how lifestyle modifications and sustained weight loss, particularly the loss achieved by bariatric surgery, may revert some of the deleterious effects of obesity in men and their offspring.

Urine metabolomics of high-fat diet induced obesity using UHPLC-Q-TOF-MS

Obesity has become a global epidemic and public health challenge which associates with serious health issues including diabetes, cardiovascular disease, stroke, arthritis, and some types of cancer. To better understand obesity and obesity-related dysfunction, a high-fat diet (HFD) induced obese model was developed on Sprague-Dawley rats. Metabolomics based on ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was untilized to identify and analyze obesity related metabolites in rat urine samples. Multivariate analyses were applied to differentiate metabolite patterns between HFD group and normal group. The study successfully identified 20 altered urine metabolites that correlated with obesity. These metabolites are mainly involved in tryptophan metabolism, phenylalanine and tyrosine metabolism, gut microbiota metabolism and insulin resistance related metabolism. They could serve as potential biomarkers to diagnose the development of obesity.

Taste of Fat: A Sixth Taste Modality?

An attraction for palatable foods rich in lipids is shared by rodents and humans. Over the last decade, the mechanisms responsible for this specific eating behavior have been actively studied, and compelling evidence implicates a taste component in the orosensory detection of dietary lipids [i.e., long-chain fatty acids (LCFA)], in addition to textural, olfactory, and postingestive cues. The interactions between LCFA and specific receptors in taste bud cells (TBC) elicit physiological changes that affect both food intake and digestive functions. After a short overview of the gustatory pathway, this review brings together the key findings consistent with the existence of a sixth taste modality devoted to the perception of lipids. The main steps leading to this new paradigm (i.e., chemoreception of LCFA in TBC, cell signaling cascade, transfer of lipid signals throughout the gustatory nervous pathway, and their physiological consequences) will be critically analyzed. The limitations to this concept will also be discussed in the light of our current knowledge of the sense of taste. Finally, we will analyze the recent literature on obesity-related dysfunctions in the orosensory detection of lipids ("fatty" taste?), in relation to the overconsumption of fat-rich foods and the associated health risks.

Obesity Reduces Cognitive and Motor Functions across the Lifespan.

Due to a sedentary lifestyle, more and more people are becoming obese nowadays. In addition to health-related problems, obesity can also impair cognition and motor performance. Previous results have shown that obesity mainly affects cognition and motor behaviors through altering brain functions and musculoskeletal system, respectively. Many factors, such as insulin/leptin dysregulation and inflammation, mediate the effect of obesity and cognition and motor behaviors. Substantial evidence has suggested exercise to be an effective way to improve obesity and related cognitive and motor dysfunctions. This paper aims to discuss the association of obesity with cognition and motor behaviors and its underlying mechanisms. Following this, mechanisms of exercise to improve obesity-related dysfunctions are described. Finally, implications and future research direction are raised.

Enhancement of energy production by black ginger extract containing polymethoxy flavonoids in myocytes through improving glucose, lactic acid and lipid metabolism.

Enhancement of muscular energy production is thought to improve locomotive functions and prevent metabolic syndromes including diabetes and lipidemia. Black ginger (Kaempferia parviflora) has been cultivated for traditional medicine in Thailand. Recent studies have shown that black ginger extract (KPE) activated brown adipocytes and lipolysis in white adipose tissue, which may cure obesity-related dysfunction of lipid metabolism. However, the effect of KPE on glucose and lipid utilization in muscle cells has not been examined yet. Hence, we evaluated the effect of KPE and its constituents on energy metabolism in pre-differentiated (p) and differentiated (d) C2C12 myoblasts. KPE (0.1-10 μg/ml) was added to pC2C12 cells in the differentiation process for a week or used to treat dC2C12 cells for 24 h. After culturing, parameters of glucose and lipid metabolism and mitochondrial biogenesis were assessed. In terms of the results, KPE enhanced the uptake of 2-deoxyglucose and lactic acid as well as the mRNA expression of glucose transporter (GLUT) 4 and monocarboxylate transporter (MCT) 1 in both types of cells. The expression of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α was enhanced in pC2C12 cells. In addition, KPE enhanced the production of ATP and mitochondrial biogenesis. Polymethoxy flavonoids in KPE including 5-hydroxy-7-methoxyflavone, 5-hydroxy-3,7,4'-trimethoxyflavone and 5,7-dimethoxyflavone enhanced the expression of GLUT4 and PGC-1α. Moreover, KPE and 5,7-dimethoxyflavone enhanced the phosphorylation of 5'AMP-activated protein kinase (AMPK). In conclusion, KPE and its polymethoxy flavonoids were found to enhance energy metabolism in myocytes. KPE may improve the dysfunction of muscle metabolism that leads to metabolic syndrome and locomotive dysfunction.

Erectile Dysfunction in Diabetic Men - Current Diagnostics and Therapy

Sexual functional dysfunctions represent a multidimensional nosological entity. Apart from the directly measurable pathophysiological parameters, psychological and dynamic partnership aspects are almost always involved. These can exert a triggering and a potentiating influence. Similarly, sociocultural factors have to be taken into account. In men the problem most frequently has a physiological focus and the main symptom within the complex of sexual difficulties, especially for diabetic patients, is erectile dysfunction. Disorders of ejaculation and orgasm may also occur. Testosterone production in men may be impaired due to obesity-related dysfunctions of the hypothalamic-pituitary-gonadal axis and this can lead to a clinically significant androgen deficit and thus also to a decline of libido.

Abstract 1096: Investigating the role of the adipocyte-macrophage interaction in breast cancer metastasis

Abstract Obesity is linked with a higher incidence of hormone-receptor positive breast cancer in post-menopausal women. Obesity is also associated with a worse outcome after the diagnosis of breast cancer, including greater tumor burden and higher grade tumors. Although several theories exist to explain these relationships, the proposed mechanisms are still being investigated. Obesity and the resulting expansion of adipose tissue is associated with aberrant cytokine production and a chronic inflammatory state, characterized by the recruitment of macrophages. Macrophages have been shown elsewhere to promote breast cancer progression. Therefore, we hypothesize that the interaction between adipocytes and macrophages promotes metastasis of breast cancer. Our data suggest that oxidized lipids released from adipocytes may have a role in mediating this interaction. We used a co-culture system to determine whether adipocytes could promote a pro-tumor phenotype in the macrophages. THP-1 macrophages were co-cultured with primary human visceral adipocytes using a Transwell system for 8 hours, then macrophage mRNA was analyzed for changes in transcription of markers for increased metastatic potential. Vascular Endothelial Growth Factor A (VEGF-A) mRNA levels were significantly increased in macrophages after exposure to adipocytes in comparison to control macrophages that were cultured alone. Co-culture experiments were repeated using human breast adipocytes to more directly model the conditions in the breast microenvironment. Again VEGF-A mRNA levels were significantly increased in macrophages after co-culture with adipocytes. Obesity is associated with stressed and necrotic adipose tissue in the breast. Therefore, to mimic obesity related dysfunction and cell death, we treated breast adipocytes with Tumor Necrosis Factor-alpha and Interleukin 6 prior to co-culturing with macrophages. The cytokine treatment enhanced the effects of adipocyte co-culture on macrophage VEGF-A mRNA levels. The increased inflammation and adipocyte dysfunction seen in obesity has been proposed to favor the generation of biologically active oxidized lipid mediators such as 4-hydroxynonenal (4-HNE). We therefore treated THP-1 macrophages with 4-HNE as a model oxidized lipid, hypothesizing that 4-HNE may convey some of the effects on macrophage gene expression seen in co-culture. We found that transcription of VEGF-D and platelet derived growth factor (PGF), both members of the VEGF family of cytokines, were significantly enhanced in 4-HNE-treated THP-1 cells. Together, our data show that the interaction of adipocytes and macrophages in obese breast tissue can stimulate pro-angiogenic macrophage signaling. This is a novel mechanism whereby the obese microenvironment can promote breast cancer metastasis. Citation Format: Nalini V.S. Yadav, Aaron T. Jacobs, Linda Connelly. Investigating the role of the adipocyte-macrophage interaction in breast cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1096. doi:10.1158/1538-7445.AM2014-1096

Effect of long-term treatment with melatonin against obesity related dysfunctions in obese mice

The increasing incidence of obesity, leading to metabolic complications is now recognized as a major public health problem. The adipocytes are not merely energystoring cells, but they play crucial roles in the development of the so-called metabolic syndrome and cardiovascular diseases due to the adipocyte-derived bioactive factors, such adipokines, cytokines and growth factors [1]. Most of adipokines, which affect whole-body homeostasis, are pro-inflammatory, whereas a small number of anti-inflammatory adipokines, including adiponectin exert beneficial actions on obese complications. The dysregulated production and secretion of adipokines seen in obesity is linked to the pathogenesis of various disease processes [2]. New emerging data showed that melatonin, pineal gland indoleamine, play an important role in body weight regulation and energy metabolism [3]. Lean and obese mice (ob/ob) received melatonin (100 mg/kg/day) or vehicle in drinking water for 8 weeks. In obese mice we observed a significant increase in fat depots and a deregulation of adipokines and cytokines fat expressions. In particular, we observed a significant reduction of adiponectin and an increase of resistin and visfatin at adipose tissue level. Melatonin administration for 8 weeks reduced fat accumulation and restored the correct adipokines expression, modulating in turn the vascular tone and homeostasis. These results indicate that melatonin counteracts some of the disrupting effects of obesity.