Adipocyte-secreted Adipokines Research Articles

Loss of chemerin prevents ovariectomy-induced osteoporosis in mice through intraosseous vascular remodeling.

Chemerin, an adipocyte-secreted adipokine, can regulate bone resorption and bone formation and is a promising therapy for postmenopausal osteoporosis. However, the effect of endogenous chemerin on intraosseous vascular remodeling in postmenopausal osteoporosis remains unclear. In this study, we investigated the effect of chemerin on osteogenesis formation and intraosseous vascular remodeling in ovariectomized Rarres2 knockout (Rarres2-/-) mice. The results showed that the bone mineral density (BMD) and volume score, trabecular thickness, cortical thickness, bone formation marker BALP and osteocalcin, and angiogenesis markers CD31 and EMCN significantly increased in ovariectomized Rarres2-/- mice. Furthermore, the expression of biomarkers to osteoblasts (β-catenin and Runx2) and angiogenesis markers (VEGF-A, Noggin, and Ang-1) significantly increased in the bone tissue of ovariectomized Rarres2-/- mice, as well as in bone marrow stromal cells and primary intraosseous vascular endothelial cells of Rarres2-/- mice. Conversely, treatment with chemerin significantly inhibited expression of biomarkers for osteoblasts and angiogenesis markers in bone marrow stromal cells and primary intraosseous vascular endothelial cells of Rarres2-/- mice. More importantly, the supernatants of the primary intraosseous vascular endothelial cells of the Rarres2-/- mice could promote the osteogenic differentiation effect of BMSCs, which could be blocked by treating with the chemerin recombinant protein. These data indicate that endogenous chemerin has an inhibitory effect on intraosseous vascular formation as well as osteoblast differentiation and proliferation in ovariectomy-induced osteoporosis mice. Chemerin effectively promoted postmenopausal osteoporosis development, which is associated with the involvement of chemerin in the reduction of microcirculation within the skeleton.

Estimation of Fibulin-1, Chemerin and Omentin-1 in Iraqi Women with Polycystic Ovary Syndrome-Associated Infertility

Background: Adipokines (fibulin-1, chemerin, and omentin-1) affect the hypothalamic-pituitary-gonadal axis and ovarian steroidogenesis. Adipocyte-secreted adipokines are dysregulated in females with polycystic ovarian syndrome (PCOS). Objective: To investigate the role of serum fibulin-1, chemerin, omentin-1, total cholesterol (TC), high-density lipoprotein (HDL), triglyceride (TG), progesterone (PROG), and prolactin (PRL) in PCOS and the development of infertility. Methods: 150 PCOS, infertile PCOS women and control women aged 20–40 years were enrolled in this observational study and divided into three groups: 40 women who were control, 60 women who had PCOS only, and 50 women who had infertility and PCOS. Analyses of fibulin-1, chemerin, omentin-1, lipid profile, PROG, and PRL were performed for all participants. Results: The results showed elevated levels of fibulin-1, chemerin, and PRL in both PCOS and infertile PCOS when compared with control, while omentine-1 and PROG decreased in both PCOS and infertile PCOS when compared with control. The levels of TC, HDL, and TG weren’t affected in PCOS alone, but in cases of infertility, TC and TG increased while HDL decreased. Conclusions: The increased level of fibulin-1 may be a new marker for PCOS and infertility. Chemerin shows a high level in both infertile PCOS and PCOS women, while omentin-1 shows a low level in both infertile PCOS and PCOS women.

Development of metabolic dysfunction in mice lacking chemerin

Chemerin, an adipocyte-secreted adipokine, is hypothesized to participate in energy homeostasis and glucoregulation. However, the physiologic effect of endogenous chemerin on glucose metabolism is unclear. The present studies tested the hypotheses that chemerin deficiency alters whole-body glucose homeostasis following switches to high-fat diet. Adult, male chemerin knockout and C57BL/6J control wild type mice were studied. During the following 4 weeks, chow- or high-fat diet maintained chemerin knockout mice showed elevated fasting glucose levels and glucose intolerance as well as insulin intolerance. Chemerin deficiency impaired adaptation to glucose and insulin challenge, leading to increased glucose levels. Moreover, the mRNA and protein levels of GLUT4 and PGC-1α expression in both skeletal muscle and adipose tissue were significantly decreased in chemerin knockout mice relative to the wild type, respectively. Taken together, the results support the hypotheses that chemerin helps adapt glucose metabolism to changes in dietary fat and modulates glucose consumption in mice by activation of PGC-1α/GLUT4 axis. Chemerin may play a significant role in elevation of glucose uptake and insulin sensitivity to promote glucose clearance.

Adiponectin-AdipoR1 axis in renal cell carcinoma plays a pivotal role in tumor progression and drug resistance.

634 Background: It is well established that renal cell carcinoma (RCC) is an obesity-associated cancer. Adiponectin, a major adipocyte-secreted adipokine, plays anti-tumor properties in many malignancies, but exerted paradoxical actions on RCC. Herein, we investigated the effects of adiponectin on RCC progression and resistance to sunitinib, and to exploit this molecular mechanism. Methods: Tissues were collected from 126 patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitor (TKI) therapy. Tumor Adiponectine receptor 1 (AdipoR1) and Adiponectine receptor 2 (AdipoR2) were detected by immunohistochemistry. Assays with RCC cell lines were used to examine the signal transduction pathways of adiponectin in RCC. Results: AdipoR2 was generally lower expressed than AdipoR1 in mRCC tumor (15.6% vs 89.1%, p < 0.001). AdipoR1 expression, but not AdipoR2, was a significant independent predictor of favorable responding to TKI and good survival outcomes. In cultured RCC cells adiponectin inhibited migration and invasion of RCC cells and sensitized cells to killing by sunitinib. Mechanistic investigations of ligand–receptor interactions revealed that AdipoR1 could hinder migration and invasion of RCC cells by blocking GSK3β and β-Catenin pathway and increase cells sensitivity to sunitinib through inhibiting AKT and NF-κB pathway. However, AdipoR2 was not associated with the tumor-limiting properties of adiponectin. Conclusions: These results show that AdipoR1 is a potential prognostic marker for favorable outcomes of mRCC patients. Adiponectin-AdipoR1 axis could be a plausible target to impede tumor progression and sensitize tumors to TKI therapy.

Leptin Signaling in the Control of Metabolism and Appetite: Lessons from Animal Models.

Obesity has become a major health concern in modern times, as it significantly increases the risk for the development of cardiovascular diseases, type 2 diabetes mellitus, and some types of cancer. The obesity epidemic has brought considerable attention to the molecular mechanisms through which adipocyte-secreted adipokines regulate physiological processes involved in metabolic and inflammatory diseases. Among them, leptin is considered as one of the principal regulators of a variety of physiological processes, including appetite and energy metabolism, through its binding to a variety of receptors and in particular by signaling through the long isoform receptor ObRb. Leptin signaling in the brain via ObRb plays an important role in the regulation of appetite and food intake, and involves several signaling pathways that either upregulate or attenuate leptin's anorexigenic response. This review describes ObRb-dependent, leptin-induced signaling pathways implicated in the control of appetite and energy metabolism in the organism, based on current information from animal models.

886P - Adiponectin-AdipoR1 axis in renal cell carcinoma plays a pivotal role in tumor progression and drug resistance

Background: It is well established that renal cell carcinoma (RCC) is an obesity-associated cancer. Adiponectin, a major adipocyte-secreted adipokine, plays anti-tumor properties in many malignancies, but exerted paradoxical actions on RCC. Herein, we investigated the effects of adiponectin on RCC progression and resistance to sunitinib, and to exploit this molecular mechanism. Methods: Tissues were collected from 126 patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitor (TKI) therapy. Tumor Adiponectine receptor 1 (AdipoR1) and Adiponectine receptor 2 (AdipoR2) were detected by immunohistochemistry. Assays with RCC cell lines were used to examine the signal transduction pathways of adiponectin in RCC. Results: AdipoR2 was generally lower expressed than AdipoR1 in mRCC tumor (15.6% vs 89.1%, p < 0.001). AdipoR1 expression, but not AdipoR2, was a significant independent predictor of favorable responding to TKI and good survival outcomes. In cultured RCC cells adiponectin inhibited migration and invasion of RCC cells and sensitized cells to killing by sunitinib. Mechanistic investigations of ligand–receptor interactions revealed that AdipoR1 could hinder migration and invasion of RCC cells by blocking GSK3β and β-Catenin pathway and increase cells sensitivity to sunitinib through inhibiting AKT and NF-κB pathway. However, AdipoR2 was not associated with the tumor-limiting properties of adiponectin. Conclusions: These results show that AdipoR1 is a potential prognostic marker for favorable outcomes of mRCC patients. Adiponectin-AdipoR1 axis could be a plausible target to impede tumor progression and sensitize tumors to TKI therapy. Legal entity responsible for the study: Guangxi Sun. Funding: National Natural Science Foundation of China (NSFC 81672547, 81402110), the Science and Technology Support Program of Sichuan Province (2015SZ0230-3) and 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University. Disclosure: All authors have declared no conflicts of interest.

Resistin induces multidrug resistance in myeloma by inhibiting cell death and upregulating ABC transporter expression.

Despite advances in therapy, multiple myeloma remains incurable, with a high frequency of relapse. This suggests the need to identify additional factors that contribute to drug resistance. Our previous studies revealed that bone marrow adipocytes promote resistance to chemotherapy in myeloma through adipocyte-secreted adipokines, but the mechanism underlying this effect and the specific adipokines involved are not well understood. We proposed to determine the role of resistin, an adipokine that is secreted by adipocytes, in chemotherapy resistance in myeloma. We found that resistin abrogated chemotherapy-induced apoptosis in established myeloma cell lines and primary myeloma samples. Resistin inhibited chemotherapy-induced caspase cleavage through the NF-κB and PI3K/Akt pathways. Resistin also increased the expression and drug efflux function of ATP-binding cassette (ABC) transporters in myeloma cells through decreasing the expression of both DNA methyltransferases DNMT1 and DNMT3a and the methylation levels of ABC gene promoters. In vivo studies further demonstrated the protective effect of resistin in chemotherapy-induced apoptosis. Our study thus reveals a new biological function of resistin in the pathogenesis of myeloma, with the implication that targeting resistin could be a potential strategy to prevent or overcome multidrug resistance in myeloma.

Resistin Induces Multidrug Resistance in Myeloma By Inhibiting Cell Death and Upregulating ABC Transporter Expression

Chemoresistance is a major hurdle in multiple myeloma. Most patients are prone to develop resistance to a wide spectrum of anticancer agents, significantly hampers the patients' long term outcome. Many studies point to bone marrow microenvironment as an important player in myeloma chemoresistance, in which marrow stromal cells and stromal-secreted soluble factors are shown to promote myeloma cell growth and survival. Our previous study has demonstrated that marrow-derived adipocytes protect myeloma cells against chemotherapy-induced apoptosis through adipocyte-secreted adipokines, one of such is leptin. However, the level of leptin expression in myeloma patients is not significantly changed, indicating the involvement of additional adipokines in this process. Interestingly, in a clinical study, an elevation of the adipokine resistin in the serum of myeloma patients after thalidomide treatment were observed as compared with that in patients before treatment, suggesting a potential role of this adipokine in response to chemotherapy. As a 12.5-kDa hormone that is mainly secreted by adipocytes and also secreted by other cells, resistin has a function in production of inflammatory cytokines that are important for cancer development. We thus hypothesized that resistin protects myeloma cells against chemotherapy. In our experiments, human myeloma cell lines and primary myeloma cells isolated from patient bone marrow aspirates were cultured in medium with addition of the recombinant human resistin and chemotherapy drugs melphalan or bortezomib for 24 hours. Cells without resistin served as a control. After cultures, an annexin-V binding assay for assessing apoptosis, western blot analysis for assessing cleavage of caspases and phosphorylation of signaling kinases, and the eFluxx-ID Gold uptake assay for examining ABC transporters activity were performed. In the animal study, myeloma-bearing SCID mice were treated with or without resistin and/or melphalan. Our results showed that resistin treatment reduced melphalan- or bortezomib-induced apoptosis both in vitro and in vivo. This protective effect has been further confirmed by the reduced cleavage of caspase-9, caspase-3, and poly (ADP-ribose) polymerase in myeloma cells. Mechanistic studies showed that culturing myeloma cells with resistin upregulated expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL and downregulated expression of the pro-apoptotic protein Bax via the NF-kB and the PI3K/Akt signaling pathways. Addition of resistin also reduced the intracellular accumulation of eFluxx-ID gold fluorescence in myeloma cells ARP-1 and MM.1S, when compared to that in cells without resistin. In addition, resistin significantly increased the mRNA and protein expression of ATP-binding cassette (ABC) transporters in myeloma cells by downregulating the expression of DNA methyltransferase 1 and 3a, and CpG methylation in the promoters of ABC transporters. Thus, our study demonstrates that resistin is a novel factor contributing to myeloma chemoresistance, and also implicates that disruption of its protective effect can be a potential strategy to improve current chemotherapy in patients and prolong survival. DisclosuresNo relevant conflicts of interest to declare.

The effect of local delivery of adiponectin from biodegradable microsphere-scaffold composites on new bone formation in adiponectin knockout mice.

Adiponectin (APN) is the most abundant adipocyte-secreted adipokine; it regulates energy homeostasis and exerts well-characterized insulin-sensitizing properties. Previous studies have verified that globular adiponectin (gAPN) is also involved in bone metabolism, although observations have been controversial. The purpose of the current study is to use an APN-knockout (APN-KO) mouse model to evaluate the local delivery of gAPN to new bone formation. Using chitosan microspheres (CMs), we found that following an initial burst at 1 week, the release behavior of gAPN from the scaffold was sustained in a linear manner for the first 4 weeks, followed by a slower, more stable release from week 5 onwards. Interestingly, PLGA/β-TCP/CM-loaded gAPN scaffolds implanted in APN-KO mice increased bone formation and mineralization, and enhanced osteogenic marker expression 28 days post-implantation. gAPN also promoted preosteoblast (MC3T3-E1) cellular proliferation in vitro. In MC3T3-E1 cells, adaptor protein-containing pleckstrin homology domain, phosphotyrosine domain, leucine zipper motif (APPL1) and phosphoinositide 3-kinase (PI3K) expression was upregulated in a time-dependent manner upon gAPN treatment, while APPL1 small interfering RNA (siRNA) pre-treatment reversed this enhanced expression. In conclusion, modified bone graft substitutes loaded with gAPN increase bone formation and mineralization in part by promoting osteoblast proliferation via the APPL1/PI3K pathway.

Globular adiponectin enhances invasion in human breast cancer cells

Every year, a large number of women succumb to metastatic breast cancer due to a lack of curative approaches for this disease. Adiponectin (AdipoQ) is the most abundant of the adipocyte-secreted adipokines. In recent years, there has been an interest in the use of AdipoQ and AdipoQ receptor agonists as therapeutic agents for the treatment of breast cancer. However, while multiple epidemiological studies have previously indicated that low levels of circulating plasma AdipoQ portend poor prognosis in patients with breast cancer, recent studies have reported that elevated expression levels of AdipoQ in breast tissue are correlated with advanced stages of the disease. Thus, the aim of the present study was to clarify the mechanism by which AdipoQ in breast tissue acts directly on tumor cells to regulate the early steps of breast cancer metastasis. In the present study, the effects of different AdipoQ isoforms on the metastatic potential of human breast cancer cells were investigated. The results revealed that globular adiponectin (gAd) promoted invasive cell morphology and significantly increased the migration and invasion abilities of breast cancer cells, whereas full-length adiponectin (fAd) had no effect on these cells. Additionally, gAd, but not fAd, increased the expression levels of microtubule-associated protein 1 light chain 3 beta (LC3B)-II and intracellular LC3B puncta, which are indicators of autophagosome formation, thus suggesting autophagic induction by gAd. Furthermore, the inhibition of autophagic function by autophagy-related protein 7 knockdown attenuated the gAd-induced increase in invasiveness in breast cancer cells. Therefore, the results of the present study suggested that a specific AdipoQ isoform may enhance breast cancer invasion, possibly via autophagic induction. Understanding the roles of the different AdipoQ isoforms as microenvironmental regulatory molecules may aid the development of effective AdipoQ-based treatments for breast cancer.

Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation.

A major problem in patients with multiple myeloma is chemotherapy resistance, which develops in myeloma cells upon interaction with bone marrow stromal cells. However, few studies have determined the role of bone marrow adipocytes, a major component of stromal cells in the bone marrow, in myeloma chemotherapy resistance. We reveal that mature human adipocytes activate autophagy and upregulate the expression of autophagic proteins, thereby suppressing chemotherapy-induced caspase cleavage and apoptosis in myeloma cells. We found that adipocytes secreted known and novel adipokines, such as leptin and adipsin. The addition of these adipokines enhanced the expression of autophagic proteins and reduced apoptosis in myeloma cells. In vivo studies further demonstrated the importance of bone marrow-derived adipocytes in the reduced response of myeloma cells to chemotherapy. Our findings suggest that adipocytes, adipocyte-secreted adipokines, and adipocyte-activated autophagy are novel targets for combatting chemotherapy resistance and enhancing treatment efficacy in myeloma patients.

Chemerin inhibition of myogenesis and induction of adipogenesis in C2C12 myoblasts

Chemerin is an adipocyte-secreted adipokine that regulates the differentiation and metabolism of adipose through auto-/paracrine signaling. Its function in the differentiation of multipotent myoblast cells has thus far received little attention. In this study, C2C12 myoblast cells were cultured in the medium with Chemerin, and the differentiation potential of C2C12 myoblasts was analyzed. The results showed that Chemerin increased ROS levels and TG content of C2C12 cells. At the same time, the mRNA expressions and protein concentrations of the adipogenic factors PPARγ, C/EBPα and UCP1 were up-regulated, while the muscle specific transcription factors MyoD, Myogenin and MyHC were decreased in cultured C2C12 cells. In conclusion, the adipokine Chemerin promoted the adipogenic differentiation potential and altered the fate of myoblast cells from myogenesis to adipogenesis, which contributed in part to the up-regulated adipocyte genes. Our study reveals the importance of functional Chemerin signaling in adipogenesis and in directing the differentiation of multipotent myoblast cells.

Adiponectin regulates bone marrow mesenchymal stem cell niche through a unique signal transduction pathway: an approach for treating bone disease in diabetes.

Adiponectin (APN) is an adipocyte-secreted adipokine that exerts well-characterized antidiabetic properties. Patients with type 2 diabetes (T2D) are characterized by reduced APN levels in circulation and impaired stem cell and progenitor cell mobilization from the bone marrow for tissue repair and remodeling. In this study, we found that APN regulates the mobilization and recruitment of bone marrow-derived mesenchymal stem cells (BMSCs) to participate in tissue repair and regeneration. APN facilitated BMSCs migrating from the bone marrow into the circulation to regenerate bone by regulating stromal cell-derived factor (SDF)-1 in a mouse bone defect model. More importantly, we found that systemic APN infusion ameliorated diabetic mobilopathy of BMSCs, lowered glucose concentration, and promoted bone regeneration in diet-induced obesity mice. In vitro studies allowed us to identify Smad1/5/8 as a novel signaling mediator of APN receptor (AdipoR)-1 in BMSCs and osteoblasts. APN stimulation of MC3T3-E1 osteoblastic cells led to Smad1/5/8 phosphorylation and nuclear localization and increased SDF-1 mRNA expression. Although APN-mediated phosphorylation of Smad1/5/8 occurred independently from adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1, it correlated with the disassembly of protein kinase casein kinase 2 and AdipoR1 in immunoprecipitation experiments. Taken together, this study identified APN as a regulator of BMSCs migration in response to bone injury. Therefore, our findings suggest APN signaling could be a potential therapeutic target to improve bone regeneration and homeostasis, especially in obese and T2D patients.

Abstract 3927: Obesity induces changes in adipokines profile and activates Akt/mTOR signaling accelerating breast carcinogenesis and tumor growth

Abstract Obesity increases the risk of cancer death among postmenopausal women with estrogen receptor-positive (ER+) breast cancer (BC), but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiological phenomenon. Transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ BC patients were analyzed. Transgenic and an orthotopic/syngeneic obese mouse models were created to phenocopy obese patients and evaluate the effect of obesity on breast carcinogenesis and tumor progression, and to explore further direct mechanisms. We used co-culture system to examine the impact of adipocytes and adipokines on BC cell proliferation. Functional transcriptomic analysis of patients revealed the association of obesity with many of the functional changes linked to cancer hallmarks. Our transgenic and orthotopic/syngeneic obese-mouse models recapitulated the functional transcriptomic landscape of obesity-associated changes seen in human patients and demonstrated the role of the Akt/mTOR pathway in obesity-induced breast carcinogenesis and tumor progression. Metformin and everolimus can suppress obesity-induced adipokines secretion and breast tumor formation and growth. An in vitro co-culture model revealed that adipocyte-secreted adipokines (e.g., TIMP-1) regulate adipocyte-induced BC cell proliferation and invasion. Metformin suppress adipocytes-induced cell proliferation and adipocytes-secreted adipokines in vitro. In conclusion, the patients' data provided evidence for the mechanistic involvement of adipokines in addition to estrogen, insulin and IGF-1 signaling in the link between obesity and ER+ BC. Our animal experiments provide strong evidence for the role of obesity on the accelerated breast carcinogenesis and obesity-induced tumor growth by activation of the Akt/mTOR signaling. Metformin and everolimus may be use as alternatives therapeutic interventions for BC patients with obesity. Citation Format: Enrique Fuentes-Mattei, Guermarie Velazquez-Torres, Liem Phan, Fanmao Zhang, Ping-Chieh Chou, Ji-Hyun Shin, Hyun-Ho Choi, Jiun-Sheng Chen, Ruiying Zhao, Jian Chen, Chris Gully, Colin Carlock, Yuan Qi, Ya Zhang, Yun Wu, Francisco Esteva, Yongde Luo, Wallace L. McKeehan, Joe E. Ensor, Gabriel N. Hortobagyi, Lajos Pusztai Pusztai, W. Fraser Symmans, Mong-Hong Lee, Sai-Ching J. Yeung. Obesity induces changes in adipokines profile and activates Akt/mTOR signaling accelerating breast carcinogenesis and tumor growth. [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 3927. doi:10.1158/1538-7445.AM2014-3927

Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer.

BackgroundObesity increases the risk of cancer death among postmenopausal women with estrogen receptor–positive (ER+) breast cancer, but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiologic phenomenon.MethodsWe analyzed transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ breast cancer patients. We generated transgenic (MMTV-TGFα;A y /a) and orthotopic/syngeneic (A y /a) obese mouse models to investigate the effect of obesity on tumorigenesis and tumor progression and to determine biological mechanisms using whole-genome transcriptome microarrays and protein analyses. We used a coculture system to examine the impact of adipocytes/adipokines on breast cancer cell proliferation. All statistical tests were two-sided.ResultsFunctional transcriptomic analysis of patients revealed the association of obesity with 59 biological functional changes (P < .05) linked to cancer hallmarks. Gene enrichment analysis revealed enrichment of AKT-target genes (P = .04) and epithelial–mesenchymal transition genes (P = .03) in patients. Our obese mouse models demonstrated activation of the AKT/mTOR pathway in obesity-accelerated mammary tumor growth (3.7- to 7.0-fold; P < .001; n = 6–7 mice per group). Metformin or everolimus can suppress obesity-induced secretion of adipokines and breast tumor formation and growth (0.5-fold, P = .04; 0.3-fold, P < .001, respectively; n = 6–8 mice per group). The coculture model revealed that adipocyte-secreted adipokines (eg, TIMP-1) regulate adipocyte-induced breast cancer cell proliferation and invasion. Metformin suppress adipocyte-induced cell proliferation and adipocyte-secreted adipokines in vitro.ConclusionsAdipokine secretion and AKT/mTOR activation play important roles in obesity-accelerated breast cancer aggressiveness in addition to hyperinsulinemia, estrogen signaling, and inflammation. Metformin and everolimus have potential for therapeutic interventions of ER+ breast cancer patients with obesity.

Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice

Acetaminophen (APAP) overdose causes hepatic necrosis and acute liver injury by inducing mitochondrial dysfunction and damage. Although the biochemical pathways that mediate APAP-induced hepatotoxicity have been well studied, the body's defense mechanism to attenuate this disease remains elusive. This study investigated the roles of adiponectin, an adipocyte-secreted adipokine with pleiotropic protective effects against obesity-related metabolic dysfunction, in the pathogenesis of APAP-induced liver injury in mice. Adiponectin knockout (ADN KO) and C57 wild type mice were treated with an overdose of APAP, followed by histological and biochemical evaluation of liver injury and activation of autophagy. The mechanism of adiponectin in APAP-induced hepatocytic toxicity was also explored in primary cultured hepatocytes. APAP overdose triggers a marked accumulation of adiponectin in injured liver tissues. ADN KO mice exhibit severely exacerbated mitochondrial dysfunction and damage, oxidative stress and necrosis and much higher mortality in response to APAP overdose, whereas these changes are reversed by a single injection of adiponectin. Mechanistically, adiponectin induces autophagosome formation by AMP-activated protein kinase (AMPK)-dependent activation of the Unc-51-like kinase 1, consequently leading to the removal of damaged mitochondria from hepatocytes. The protective effects of adiponectin against APAP-induced mitochondrial damage, oxidative stress and necrosis are abrogated by blockage of AMPK or pharmacological inhibition of autophagy. Our findings suggest that the APAP-induced accumulation of adiponectin in liver tissues serves as an adaptive mechanism to ameliorate hepatotoxicity by promoting autophagy-mediated clearance of damaged mitochondria. Adiponectin agonists may represent a promising therapy for the drug-induced acute liver failure.

Adiponectin promotes pancreatic cancer progression by inhibiting apoptosis via the activation of AMPK/Sirt1/PGC-1α signaling.

Adiponectin is an adipocyte-secreted adipokine with pleiotropic actions. Clinical evidence has shown that serum adiponectin levels are increased and that adiponectin can protect pancreatic beta cells against apoptosis, which suggests that adiponectin may play an anti-apoptotic role in pancreatic cancer (PC). Here, we investigated the effects of adiponectin on PC development and elucidated the underlying molecular mechanisms. Adiponectin deficiency markedly attenuated pancreatic tumorigenesis in vivo. We found that adiponectin significantly inhibited the apoptosis of both human and mouse pancreatic cancer cells via adipoR1, but not adipoR2. Furthermore, adiponectin can increase AMP-activated protein kinase (AMPK) phosphorylation and NAD-dependent deacetylase sirtuin-1 (Sirt1) of PC cells. Knockdown of AMPK or Sirt1 can increase the apoptosis in PC cells. AMPK up-regulated Sirt1, and Sirt1 can inversely phosphorylate AMPK. Further studies have shown that Sirt1 can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which can increase the expression levels of mitochondrial genes. Thus, adiponectin exerts potent anti-apoptotic effects on PC cells via the activation of AMPK/Sirt1/PGC1α signaling. Finally, adiponectin can elevate β-catenin levels. Taken together, these novel findings reveal an unconventional role of adiponectin in promoting pancreatic cancers, and suggest that the effects of adiponectin on tumorigenesis are highly tissue-dependent.

Abstract P3-01-04: Obesity induces functional transcriptomic changes enhancing the cancer hallmarks of estrogen receptor-positive breast cancer

Abstract Obesity increases the risk of cancer death among postmenopausal women with estrogen receptor-positive (ER+) breast cancer, but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiologic phenomenon. Transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ breast cancer patients were analyzed. A transgenic and an orthotopic/syngeneic obese mouse models were created to phenocopy obese patients and evaluate the effect of obesity on breast carcinogenesis and tumor progression, and to explore further direct mechanisms. Functional transcriptomic analysis of untreated human ER+ breast cancer revealed that obesity was associated with increased insulin signaling among others. Many of the functional changes in obese patients were linked to cancer hallmarks. Obese mouse models recapitulated the functional transcriptomic landscape of obesity-associated changes seen in human ER+ breast cancer and demonstrated the role of the Akt/mTOR pathway in obesity-induced breast carcinogenesis and tumor progression. Functional transcriptomic analysis identified 85 biological functions common to humans and mice. An in vitro co-culture model revealed that adipocyte-secreted adipokines (e.g., TIMP-1) regulate adipocyte-induced breast cancer cell proliferation and invasion. The human transcriptomic data provided direct evidence for the roles of hyperinsulinemia, estrogen signaling, adipokine secretion, and inflammation in the link between obesity and ER+ breast cancer. Our animal experiments provide strong evidence for the causal relationship between obesity and accelerated carcinogenesis and cancer progression and for potential therapeutic interventions by blocking these signaling pathways. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-01-04.

Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention

Adiponectin is a major adipocyte-secreted adipokine abundantly present in the circulation as three distinct oligomeric complexes. In addition to its role as an insulin sensitizer, mounting evidence suggests that adiponectin is an important player in maintaining vascular homoeostasis. Numerous epidemiological studies based on different ethnic groups have identified adiponectin deficiency (hypoadiponectinaemia) as an independent risk factor for endothelial dysfunction, hypertension, coronary heart disease, myocardial infarction and other cardiovascular complications. Conversely, elevation of circulating adiponectin concentrations by either genetic or pharmacological approaches can alleviate various vascular dysfunctions in animal models. Adiponectin exerts its vasculoprotective effects through its direct actions in the vascular system, such as increasing endothelial NO production, inhibiting endothelial cell activation and endothelium-leucocyte interaction, enhancing phagocytosis, and suppressing macrophage activation, macrophage-to-foam cell transformation and platelet aggregation. In addition, adiponectin reduces neointima formation through an oligomerization-dependent inhibition of smooth muscle proliferation. The present review highlights recent research advances in unveiling the molecular mechanisms that underpin the vascular actions of adiponectin and discusses the potential strategies of using adiponectin or its signalling pathways as therapeutic targets to combat obesity-related metabolic and vascular diseases.