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Purpose: Catecholamines (CA) play a major role in metabolism and immune response. Recent reports showing adipose tissue can synthetize CA enlighten new roles for these amines in obesity. This study aimed to evaluate the expression of both tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) and CA content along preadipocytes differentiation, under normal and obesigenic conditions., Methods: 8-9 week-old male C57BL/6 mice were divided in two groups: one fed with a high-fat diet (HFD) and other with a standard diet (SD) for 20 weeks. Afterwards, both TH and PNMT expression, localization, and CA content in adipocytes, were evaluated., Results: qPCR results showed no changes for TH and PNMT expression during the differentiation process for visceral and subcutaneous preadipocytes from mice fed with SD. Comparing to SD, HFD increased TH gene expression of subcutaneous preadipocytes and PNMT gene expression of both visceral preadipocytes and adipocytes. HPLC-ED analyses revealed HFD increased visceral adipocytes noradrenaline intracellular content comparing with preadipocytes (p = 0.037). When compared with SD, HFD raised and decreased noradrenaline content, respectively, in visceral adipocytes (p = 0.004) and subcutaneous preadipocytes (p = 0.001). Along the differentiation process, HFD increased visceral adrenaline intracellular content comparing with SD (p < 0.001). HFD increased visceral comparing to subcutaneous adrenaline content for both preadipocytes (p = 0.004) and adipocytes (p = 0.001)., Conclusions: TH and PNMT expression in adipose tissue is differently modulated in visceral and subcutaneous adipose depots, and seems to depend on diet. Differences observed in visceral adipose CA handling in HFD-fed mice might uncover novel pharmacological/nutritional strategies against obesity and cardiovascular risk.

Aims: Obesity is a complex health disorder and a trigger to many diseases like Diabetes mellitus (DM) and breast cancer (BrCa), both leading causes of morbidity and mortality worldwide. Also evidence demonstrates that abnormal glucose metabolism termed 'the Warburg effect' in cancer cell is closely associated with malignant phenotypes and promote the aggressiveness of several types of cancer, including BrCa. In this study, we evaluated the breast cancer cell metabolism in normoglycemia, hyperglycemia and in an obesity condition in order to clarify the potential underlined mechanisms that link these disorders., Materials and Methods: MCF-7 cells were exposed to low and high glucose levels, the latter either in the presence of 3T3-L1 adipocyte conditioned medium (CM), thus mimicking the adiposity observed in obese patients. Cell viability, migration, proliferation, cytotoxicity and cell death assays were performed under the different culture conditions. Hormonal and lipid profile were also characterized by biochemical assays and primary metabolism was determined by Nuclear Magnetic Resonance (NMR)-based metabolomics., Results: Our results show an increased aggressiveness in the condition mimicking diabetogenic obesity with an altered energy/lipid metabolism. Interestingly in the experimental obesity-mimicking status, lipids and amino acids were expended while glucose was produced by tumor cells from lactate. These findings reveal a shift on tumor cells metabolism that is opposite to 'the Warburg effect'., Conclusions: Overall, this experimentally obesity-mimicking condition not only revealed an increased tumor proliferation and aggressiveness but also disclosed a new mechanism of cancer metabolism, the 'Warburg Effect Inversion'., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Melanoma is an aggressive form of skin cancer refractory to conventional therapies. Obesity has reached epidemic dimensions acting as a risk factor for several cancer types, such as melanoma. Several reactive species of oxygen are also involved in melanoma initiation and progression. Low levels of antioxidant content and/or activity in lightly pigmented cells could expose them to an extremely oxidative environment and rise the susceptibility to oxidative damage and consequently loss of cell homeostasis. Despite the knowledge about melanoma biology, pathogenesis and developed therapies, is extremely important to understand the antioxidant modulation of melanoma under an environment of obesity, especially the effect of some natural compounds of the diet, such as antioxidant vitamins A, C and E and selenium in order to establish alternatives to conventional therapies, which are known to be ineffective against melanoma., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSC) in obesity is induced by tumor-associated neutrophils (TAN) recruited by adipocyte-secreted IL1β. PSCs further secrete IL1β, and inactivation of PSCs reduces IL1β expression and TAN recruitment. Furthermore, depletion of TANs, IL1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In patients with pancreatic cancer, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity., Significance: Considering the current obesity pandemic, unraveling the mechanisms underlying obesity-induced cancer progression is an urgent need. We found that the aggravation of desmoplasia is a key mechanism of obesity-promoted PDAC progression. Importantly, we discovered that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts. Cancer Discov; 6(8); 852-69. ©2016 AACR.See related commentary by Bronte and Tortora, p. 821This article is highlighted in the In This Issue feature, p. 803., (©2016 American Association for Cancer Research.)

Obesity, favored by the modern lifestyle, acquired epidemic proportions nowadays. Obesity has been associated with various major causes of death and morbidity including malignant neoplasms. This increased prevalence has been accompanied by a worldwide increase in cutaneous melanoma incidence rates during the last decades. Obesity involvement in melanoma aetiology has been recognized, but the implicated mechanisms remain unclear. In the present study, we address this relationship and investigate the influence of adipocytes secretome on B16-F10 and MeWo melanoma cell lines. Using the 3T3-L1 adipocyte cell line, as well as ex vivo subcutaneous (SAT) and visceral (VAT) adipose tissue conditioned medium, we were able to show that adipocyte-released factors play a dual role in increasing melanoma cell overall survival, both by enhancing proliferation and decreasing apoptosis. B16-F10 cell migration and cell-cell and cell-matrix adhesion capacity were predominantly enhanced in the presence of SAT and VAT released factors. Melanocytes morphology and melanin content were also altered by exposure to adipocyte conditioned medium disclosing a more dedifferentiated phenotype of melanocytes. In addition, exposure to adipocyte-secreted molecules induced melanocytes to rearrange, on 3D cultures, into vessel-like structures, and generate characteristic vasculogenic mimicry patterns. These findings are corroborated by the released factors profile of 3T3-L1, SAT, and VAT assessed by microarrays, and led us to highlight the mechanisms by which adipose secretome from sub-cutaneous or visceral depots promote melanoma progression. J. Cell. Biochem. 117: 1697-1706, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Purpose: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity., Experimental Design: We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples., Results: We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity., Conclusions: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993-3004. ©2016 AACR., (©2016 American Association for Cancer Research.)

Obesity remains nowadays one of the main threats to human health, being a problem of worldwide proportions. It is characterized by augmented storage of fatty acids in an enlarged adipose tissue. This process is possible thanks to a rich capillary network, supported by a mechanism that has also a crucial role on cancer: angiogenesis. Given that several studies point obesity as a risk factor for cancer development, angiogenesis may be approached as the missed link between these two pathologies. Understanding the different pathways behind angiogenesis becomes essential to break this link by developing new anti-angiogenic therapies or improving the actual ones. In the first phase, this paper will focus the structural and cellular changes that adipose tissue suffers in obesity. Then, the main pro-angiogenic players will be reviewed, taking into account the pathways that explain their putative role in obesity-cancer link. Finally, the clinical implications of the presented mechanisms will also be regarded, being the main focus on the anti-angiogenic therapies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Obesity and asthma are widely prevalent and associated disorders. Recent studies of our group revealed that Substance P (SP) is involved in pathophysiology of obese-asthma phenotype in mice through its selective NK1 receptor (NK1-R). Lymphangiogenesis is impaired in asthma and obesity, and SP activates contractile and inflammatory pathways in lymphatics. Our aim was to study whether NK1-R expression was involved in lymphangiogenesis on visceral (VAT) and subcutaneous (SAT) adipose tissues and in the lungs, in obese-allergen sensitized mice., Main Methods: Diet-induced obese and ovalbumin (OVA)-sensitized Balb/c mice were treated with a selective NK1-R antagonist (CJ 12,255, Pfizer Inc., USA) or placebo. Lymphatic structures (LYVE-1+) and NK1-R expression were analyzed by immunohistochemistry. A semi-quantitative score methodology was used for NK1-R expression., Key Findings: Obesity and allergen-sensitization together increased the number of LYVE-1+ lymphatics in VAT and decreased it in SAT and lungs. NK1-R was mainly expressed on adipocyte membranes of VAT, blood vessel areas of SAT, and in lung epithelium. Obesity and allergen-sensitization combined increased the expression of NK1-R in VAT, SAT and lungs. NK1-R antagonist treatment reversed the effects observed in lymphangiogenesis in those tissues., Significance: The obese-asthma phenotype in mice is accompanied by increased expression of NK1-R on adipose tissues and lung epithelium, reflecting that SP released during inflammation may act directly on these tissues. Blocking NK1-R affects lymphangiogenesis, implying a role of SP, with opposite physiological consequences in VAT, and in SAT and lungs. Our results provide a clue for a novel SP role in the obese-asthma phenotype., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aim: A number of studies have shown an association between obesity and asthma. Controversy remains on the mechanisms supporting this association. In this study we aimed to assess neurogenic inflammation in a model of diet-induced obesity and allergen-challenged mice., Methods: High fat diet-induced (HFD) obese Balb/c mice were sensitized and challenged with ovalbumin (OVA). Glucose, insulin, OVA-specific IgE and substance P (SP), and the main tachykinin involved in neurogenic inflammation, were quantified in sera. Cell counts were performed in bronchoalveolar lavage fluid (BALF). The extent of peribronchial infiltrates was estimated on lung tissue sections and inflammation was score based on inflammatory cell counts surrounding the bronchi., Results: Obesity per se and allergen-sensitization per se increased serum SP (P = .027, P = .004, respectively). Further increased was observed in obese-sensitized mice (P = .007). Obese-sensitized mice also showed higher insulin (P = .0016), OVA-specific IgE (P = .016), peribronchial inflammatory score (P = .045), and tendency for higher glycemia. The interaction of obesity and asthma on SP levels was confirmed (P = .005, R(2) = 0.710). SP was positively correlated with metabolic (glycemia, r = 0.539, P = .007) and allergic inflammation parameters (BALF eosinophils, r = 0.445, P = 0.033; BALF mast cells, r = 0.574, P = .004; peribronchial inflammation score, r = 0.661, P < .001; and OVA-specific IgE, r = 0.714, P < .001)., Conclusions: Our findings provide support to the neurogenic inflammation link between obesity and asthma in mice. These two conditions independently increased SP and the presence of both pathologies further increased this level. Neurogenic inflammation may be a previously unrecognized mechanism beyond the obese-asthma phenotype. Further studies are need to confirm this role of SP in human obesity-asthma association.