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1.  Gene expression changes in adipose tissue with diet- and/or exercise-induced weight loss 
Adipose tissue plays a role in obesity-related cancers via increased production of inflammatory factors, steroid hormones, and altered adipokines. The impact of weight loss on adipose-tissue gene expression may provide insights into pathways linking obesity with cancer risk. We conducted an ancillary study within a randomized trial of diet, exercise, or combined diet+exercise vs. control among overweight/obese postmenopausal women. In 45 women, subcutaneous adipose-tissue biopsies were performed at baseline and after 6 months and changes in adipose-tissue gene expression were determined by microarray with an emphasis on pre-specified candidate pathways, as well as by unsupervised clustering of >37,000 transcripts (Illumina). Analyses were conducted first by randomization group, and then by degree of weight change at 6-months in all women combined. At 6 months, diet, exercise and diet+exercise participants lost a mean of 8.8 kg, 2.5 kg, and 7.9 kg (all p<0.05 vs. no change in controls). There was no significant change in candidate-gene expression by intervention group. In analysis by weight-change category, greater weight loss was associated a decrease in 17β-hydroxysteroid dehydrogenase-1 (HSD17B1, p-trend<0.01) and leptin (LEP, p-trend<0.01) expression, and marginally significant increased expression of estrogen receptor-1 (ESR1, p-trend=0.08) and insulin-like growth factor binding protein-3 (IGFBP3, p-trend=0.08). Unsupervised clustering revealed 83 transcripts with statistically significant changes. Multiple gene-expression changes correlated with changes in associated serum biomarkers. Weight-loss was associated with changes in adipose-tissue gene expression after 6 months, particularly in two pathways postulated to link obesity and cancer, i.e., steroid-hormone metabolism and IGF signaling.
doi:10.1158/1940-6207.CAPR-12-0212
PMCID: PMC3738189  PMID: 23341572
Adiposity; gene expression; obesity; weight-loss; exercise; diet; leptin; sex hormones; inflammation; adipokines; human; randomized-controlled trial
2.  Adipokines Mediate Inflammation and Insulin Resistance 
For many years, adipose tissue was considered as an inert energy storage organ that accumulates and stores triacylglycerols during energy excess and releases fatty acids in times of systemic energy need. However, over the last two decades adipose tissue depots have been established as highly active endocrine and metabolically important organs that modulate energy expenditure and glucose homeostasis. In rodents, brown adipose tissue plays an essential role in non-shivering thermogenesis and in energy dissipation that can serve to protect against diet-induced obesity. White adipose tissue collectively referred too as either subcutaneous or visceral adipose tissue is responsible for the secretion of an array of signaling molecules, termed adipokines. These adipokines function as classic circulating hormones to communicate with other organs including brain, liver, muscle, the immune system, and adipose tissue itself. The dysregulation of adipokines has been implicated in obesity, type 2 diabetes, and cardiovascular disease. Recently, inflammatory responses in adipose tissue have been shown as a major mechanism to induce peripheral tissue insulin resistance. Although leptin and adiponectin regulate feeding behavior and energy expenditure, these adipokines are also involved in the regulation of inflammatory responses. Adipose tissue secretes various pro- and anti-inflammatory adipokines to modulate inflammation and insulin resistance. In obese humans and rodent models, the expression of pro-inflammatory adipokines is enhanced to induce insulin resistance. Collectively, these findings have suggested that obesity-induced insulin resistance may result, at least in part, from an imbalance in the expression of pro- and anti-inflammatory adipokines. Thus we will review the recent progress regarding the physiological and molecular functions of adipokines in the obesity-induced inflammation and insulin resistance with perspectives on future directions.
doi:10.3389/fendo.2013.00071
PMCID: PMC3679475  PMID: 23781214
adipokine; adipocyte; inflammation; insulin; macrophages and metabolism
3.  Sarcopenia, obesity, and natural killer cell immune senescence in aging: Altered cytokine levels as a common mechanism 
Aging (Albany NY)  2012;4(8):535-546.
Human aging is characterized by both physical and physiological frailty. A key feature of frailty, sarcopenia is the age-associated decline in skeletal muscle mass, strength, and endurance that characterize even the healthy elderly. Increases in adiposity, particularly in visceral adipose tissue, are almost universal in aging individuals and can contribute to sarcopenia and insulin resistance by increasing levels of inflammatory cytokines known collectively as adipokines. Aging also is associated with declines in adaptive and innate immunity, known as immune senescence, which are risk factors for cancer and all-cause mortality. The cytokine interleukin-15 (IL-15) is highly expressed in skeletal muscle tissue and declines in aging rodent models. IL-15 inhibits fat deposition and insulin resistance, is anabolic for skeletal muscle in certain situations, and is required for the development and survival of natural killer (NK) lymphocytes. We review the effect that adipokines and myokines have on NK cells, with special emphasis on IL-15. We posit that increased adipokine and decreased IL-15 levels during aging constitute a common mechanism for sarcopenia, obesity, and immune senescence.
PMCID: PMC3461341  PMID: 22935594
Skeletal muscle; adipose tissue; Sarcopenia; obesity; immunity; natural killer lymphocytes; aging
4.  Obesity, insulin resistance, adipocytokines and breast cancer: New biomarkers and attractive therapeutic targets 
Worldwide, breast cancer (BC) represents the most common type of non-skin human malignancy and the second leading cause of cancer-related deaths amid women in Western countries. Obesity and its metabolic complications have rapidly become major global health issues and are associated with increased risk for cancer, especially BC in postmenopausal women. Adipose tissue is considered as a genuine endocrine organ secreting a variety of bioactive adipokines, such as leptin, adiponectin, resistin and nicotinamide phosphoribosyl-transferase/visfatin. Recent evidence has indicated that the constellation of obesity, insulin resistance and adipokines is associated with the risk and prognosis of postmenopausal BC. Direct evidence is growing rapidly supporting the stimulating and/or inhibiting role of adipokines in the process of development and progression of BC. Adipokines could exert their effects on the normal and neoplastic mammary tissue by endocrine, paracrine and autocrine mechanisms. Recent studies support a role of adipokines as novel risk factors and potential diagnostic and prognostic biomarkers in BC. This editorial aims at providing important insights into the potential pathophysiological mechanisms linking adipokines to the etiopathogenesis of BC in the context of a dysfunctional adipose tissue and insulin resistance in obesity. A better understanding of these mechanisms may be important for the development of attractive preventive and therapeutic strategies against obesity-related breast malignancy.
doi:10.5493/wjem.v3.i3.34
PMCID: PMC3905595  PMID: 24520544
Breast cancer; Obesity; Insulin resistance; Adipokines; Adiponectin; Resistin; Leptin; Nicotinamide phosphoribosyl-transferase; Visfatin
5.  Retinol Binding Protein 4 Expression in Humans: Relationship to Insulin Resistance, Inflammation, and Response to Pioglitazone 
Context
Retinol binding protein 4 (RBP4) was recently found to be expressed and secreted by adipose tissue, and was strongly associated with insulin resistance.
Objective
The aim was to determine the relationship between RBP4 and obesity, insulin resistance, and other markers of insulin resistance in humans.
Design and Patients
RBP4 mRNA levels in adipose tissue and muscle of nondiabetic human subjects with either normal or impaired glucose tolerance (IGT) were studied, along with plasma RBP4. RBP4 gene expression was also measured in adipose tissue fractions, and from visceral and sc adipose tissue (SAT) from surgical patients.
Setting
The study was conducted at University Hospital and General Clinical Research Center.
Intervention
Insulin sensitivity (SI) was measured, and fat and muscle biopsies were performed. In IGT subjects, these procedures were performed before and after treatment with metformin or pioglitazone.
Main Outcome Measures
The relationship between RBP4 expression and obesity, SI, adipose tissue inflammation, and intramyocellular lipid level, and response to insulin sensitizers was measured.
Results
RBP4 was expressed predominantly from the adipocyte fraction of SAT. Although SAT RBP4 expression and the plasma RBP4 level demonstrated no significant relationship with body mass index or SI, there was a strong positive correlation between RBP4 mRNA and adipose inflammation (monocyte chemoattractant protein-1 and CD68), and glucose transporter 4 mRNA. Treatment of IGT subjects with pioglitazone resulted in an increase in SI and an increaseinRBP4gene expression in both adipose tissue and muscle, but not in plasma RBP4 level, and the in vitro treatment of cultured adipocytes with pioglitazone yielded a similar increase in RBP4 mRNA.
Conclusions
RBP4 gene expression in humans is associated with inflammatory markers, but not with insulin resistance. The increase in RBP4 mRNA after pioglitazone treatment is unusual, suggesting a complex regulation of this novel adipokine.
doi:10.1210/jc.2006-0816
PMCID: PMC2893415  PMID: 17595259
6.  Tissue-Specific Increases in 11β-Hydroxysteroid Dehydrogenase Type 1 in Normal Weight Postmenopausal Women 
PLoS ONE  2009;4(12):e8475.
With age and menopause there is a shift in adipose distribution from gluteo-femoral to abdominal depots in women. Associated with this redistribution of fat are increased risks of type 2 diabetes and cardiovascular disease. Glucocorticoids influence body composition, and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11βHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11βHSD1 gene expression and activity are up-regulated in the older, postmenopausal women compared to young, premenopausal women. Twenty-three pre- and 23 postmenopausal, healthy, normal weight women were recruited. The participants underwent a urine collection, a subcutaneous adipose tissue biopsy and the hepatic 11βHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5α-tetrahydrocortisol+5β-tetrahydrocortisol)/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05), indicating an increased whole-body 11βHSD1 activity. Postmenopausal women had higher 11βHSD1 gene expression in subcutaneous fat (P<0.05). Hepatic first pass conversion of oral cortisone to cortisol was also increased in postmenopausal women versus premenopausal women in follicular phase of the menstrual cycle (P<0.01, at 30 min post cortisone ingestion), suggesting higher hepatic 11βHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11βHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women.
doi:10.1371/journal.pone.0008475
PMCID: PMC2795198  PMID: 20041117
7.  Mineralocorticoid Receptor Blockade Reverses Obesity-Related Changes in Expression of Adiponectin, PPARγ and Pro-inflammatory Adipokines 
Circulation  2008;117(17):2253-2261.
Background
In obesity, decreases in adiponectin and increases in pro-inflammatory adipokines are associated with heart disease. Since adipocytes express mineralocorticoid receptor (MR) and MR blockade reduces cardiovascular inflammation and injury, we tested the hypothesis that MR blockade reduces inflammation and expression of pro-inflammatory cytokines in adipose tissue and increases adiponectin expression in adipose tissue and hearts of obese mice.
Methods and Results
We determined the effect of MR blockade (eplerenone, 100 mg/kg/day for 16 weeks) on gene expression in retroperitoneal adipose and heart tissue from obese, diabetic db/db mice (n=8) as compared with untreated obese, diabetic db/db mice (n=10) and lean, non-diabetic db/+ littermates (n=11). There was increased expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor type-1 (PAI-1) and macrophage protein CD68 and decreased expression of adiponectin and peroxisome proliferator-activated receptor-γ (PPARγ) in retroperitoneal adipose tissue from obese versus lean mice. Also, adiponectin expression in heart was reduced in obese versus lean mice. MR blockade prevented these obesity-related changes in gene expression. Further, treatment of undifferentiated preadipocytes with aldosterone (10−8 M for 24 h) increased mRNA levels of TNF-α and MCP-1, and reduced mRNA and protein levels of PPARγ and adiponectin, supporting a direct aldosterone effect on gene expression.
Conclusions
MR blockade reduced expression of pro-inflammatory and pro-thrombotic factors in adipose tissue and increased expression of adiponectin in heart and adipose tissue of obese, diabetic mice. These effects on adiponectin and adipokine gene expression may represent a novel mechanism for the cardioprotective effects of MR blockade.
doi:10.1161/CIRCULATIONAHA.107.748640
PMCID: PMC2746647  PMID: 18427128
Obesity; Inflammation; aldosterone antagonist; adipose tissue; mineralocorticoid receptor
8.  Could there be a fine-tuning role for brain-derived adipokines in the regulation of bodyweight and prevention of obesity? 
McGill Journal of Medicine : MJM  2008;11(2):177-184.
Obesity is one of the most prevalent medical conditions, often associated with several negative stereotypes. Although it is true that weight gain occurs when food intake exceeds energy expenditure, it is important to note that even a 1% mismatch between the two can lead to a substantial weight gain after only a few years. Further, the body appears to balance energy metabolism via an endogenous lipostatic loop in which adipose stores send hormonal signals (e.g. adipokines such as leptin) to the hypothalamus in order to reduce appetite and increase energy expenditure. However, the brain is also a novel site of expression of many of these adipokine genes. This led to the hypothesis that hypothalamic-derived adipokines might also be involved in bodyweight regulation by exerting some effect on the control of appetite or hypothalamic function. When RNA interference (RNAi) was used to specifically silence adipokine gene expression in various in vitro models, this led to increases in cell death, modification of the expression of key signaling genes (i.e. suppressor of cytokine signaling-3; SOCS-3), and modulation of the activation of cellular energy sensors (i.e. adenosine monophosphate-activated protein kinase; AMPK). Subsequently, when RNAi was used to inhibit the expression of brain-derived leptin in adult rats this resulted in minor increases in weight gain in addition to modifying the expression of other adipokine genes (eg. resistin). In summary, although adipokines secreted by adipose tissue appear to the main regulator of lipostatic loop, this review shows that the fine tuning that is required to maintain a stable bodyweight by this system might be accomplished by hypothalamic-derived adipokines. Perturbations in this central adipokine system could lead to alterations in normal hypothalamic function which leads to unintended weight gain.
PMCID: PMC2582659  PMID: 19148319
9.  Weight Cycling Enhances Adipose Tissue Inflammatory Responses in Male Mice 
PLoS ONE  2012;7(7):e39837.
Background
Obesity is associated with low-grade chronic inflammation attributed to dysregulated production, release of cytokines and adipokines and to dysregulated glucose-insulin homeostasis and dyslipidemia. Nutritional interventions such as dieting are often accompanied by repeated bouts of weight loss and regain, a phenomenon known as weight cycling (WC).
Methods
In this work we studied the effects of WC on the feed efficiency, blood lipids, carbohydrate metabolism, adiposity and inflammatory markers in C57BL/6 male mice that WC two or three consecutive times by alternation of a high-fat (HF) diet with standard chow (SC).
Results
The body mass (BM) grew up in each cycle of HF feeding, and decreased after each cycle of SC feeding. The alterations observed in the animals feeding HF diet in the oral glucose tolerance test, in blood lipids, and in serum and adipose tissue expression of adipokines were not recuperated after WC. Moreover, the longer the HF feeding was (two, four and six months), more severe the adiposity was. After three consecutive WC, less marked was the BM reduction during SC feeding, while more severe was the BM increase during HF feeding.
Conclusion
In conclusion, the results of the present study showed that both the HF diet and WC are relevant to BM evolution and fat pad remodeling in mice, with repercussion in blood lipids, homeostasis of glucose-insulin and adipokine levels. The simple reduction of the BM during a WC is not able to recover the high levels of adipokines in the serum and adipose tissue as well as the pro-inflammatory cytokines enhanced during a cycle of HF diet. These findings are significant because a milieu with altered adipokines in association with WC potentially aggravates the chronic inflammation attributed to dysregulated production and release of adipokines in mice.
doi:10.1371/journal.pone.0039837
PMCID: PMC3405086  PMID: 22848362
10.  Angiotensinogen Gene Silencing Reduces Markers of Lipid Accumulation and Inflammation in Cultured Adipocytes 
Inflammatory adipokines secreted from adipose tissue are major contributors to obesity-associated inflammation and other metabolic dysfunctions. We and others have recently documented the contribution of adipose tissue renin-angiotensin system to the pathogenesis of obesity, inflammation, and insulin resistance. We hypothesized that adipocyte-derived angiotensinogen (Agt) plays a critical role in adipogenesis and/or lipogenesis as well as inflammation. This was tested using 3T3-L1 adipocytes, stably transfected with Agt-shRNA or scrambled Sc-shRNA as a control. Transfected preadipocytes were differentiated and used to investigate the role of adipose Agt through microarray and PCR analyses and adipokine profiling. As expected, Agt gene silencing significantly reduced the expression of Agt and its hormone product angiotensin II (Ang II), as well as lipid accumulation in 3T3-L1 adipocytes. Microarray studies identified several genes involved in lipid metabolism and inflammatory pathways which were down-regulated by Agt gene inactivation, such as glycerol-3-phosphate dehydrogenase 1 (Gpd1), serum amyloid A 3 (Saa3), nucleotide-binding oligomerization domain containing 1 (Nod1), and signal transducer and activator of transcription 1 (Stat1). Mouse adipogenesis PCR arrays revealed lower expression levels of adipogenic/lipogenic genes such as peroxisome proliferator activated receptor gamma (PPARγ), sterol regulatory element binding transcription factor 1 (Srebf1), adipogenin (Adig), and fatty acid binding protein 4 (Fabp4). Further, silencing of Agt gene significantly lowered expression of pro-inflammatory adipokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and monocyte chemotactic protein-1 (MCP-1). In conclusion, this study directly demonstrates critical effects of Agt in adipocyte metabolism and inflammation and further support a potential role for adipose Agt in the pathogenesis of obesity-associated metabolic alterations.
doi:10.3389/fendo.2013.00010
PMCID: PMC3593681  PMID: 23483012
angiotensinogen; gene silencing; inflammation; adipocytes; adipokines; adipogenesis
11.  Adipose tissue dysregulation and reduced insulin sensitivity in non-obese individuals with enlarged abdominal adipose cells 
Background
Obesity contributes to Type 2 diabetes by promoting systemic insulin resistance. Obesity causes features of metabolic dysfunction in the adipose tissue that may contribute to later impairments of insulin action in skeletal muscle and liver; these include reduced insulin-stimulated glucose transport, reduced expression of GLUT4, altered expression of adipokines, and adipocyte hypertrophy. Animal studies have shown that expansion of adipose tissue alone is not sufficient to cause systemic insulin resistance in the absence of adipose tissue metabolic dysfunction. To determine if this holds true for humans, we studied the relationship between insulin resistance and markers of adipose tissue dysfunction in non-obese individuals.
Method
32 non-obese first-degree relatives of Type 2 diabetic patients were recruited. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was measured with the hyperinsulinaemic-euglycaemic clamp. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene/protein expression and adipocyte cell size measurements.
Results
Our findings show that also in non-obese individuals low insulin sensitivity is associated with signs of adipose tissue metabolic dysfunction characterized by low expression of GLUT4, altered adipokine profile and enlarged adipocyte cell size. In this group, insulin sensitivity is positively correlated to GLUT4 mRNA (R = 0.49, p = 0.011) and protein (R = 0.51, p = 0.004) expression, as well as with circulating adiponectin levels (R = 0.46, 0 = 0.009). In addition, insulin sensitivity is inversely correlated to circulating RBP4 (R = −0.61, 0 = 0.003) and adipocyte cell size (R = −0.40, p = 0.022). Furthermore, these features are inter-correlated and also associated with other clinical features of the metabolic syndrome in the absence of obesity. No association could be found between the hypertrophy-associated adipocyte dysregulation and HIF-1alpha in this group of non-obese individuals.
Conclusions
In conclusion, these findings support the concept that it is not obesity per se, but rather metabolic dysfunction of adipose tissue that is associated with systemic insulin resistance and the metabolic syndrome.
doi:10.1186/1758-5996-4-42
PMCID: PMC3523053  PMID: 22992414
Adipocyte cell size; BMI; Insulin sensitivity; GLUT4; Adiponectin; RBP4
12.  Allograft inflammatory factor 1 (AIF-1) is a new human adipokine involved in adipose inflammation in obese women 
Background
Allograft inflammatory factor 1 (AIF-1) is a putative obesity gene. Our aim was to examine the expression of AIF-1 in human white adipose tissue (WAT) in relation to obesity and metabolic phenotypes in women.
Methods
WAT secretion of AIF-1 was determined in subcutaneous adipose tissue pieces in vitro by ELISA from 5 subjects. mRNA expression of AIF-1 was determined by RT-qPCR in the isolated cell fractions of adipose tissue (n = 5-6 per group), in subcutaneous and visceral WAT pieces from non-obese (n = 12) and obese women (n = 23), and in some subcutaneous WAT also before and after weight reduction (n = 10). Finally, adipose AIF-1 mRNA was related to metabolic phenotypes in 96 subjects with a wide range of BMI.
Results
AIF-1 was secreted in a time dependent fashion from WAT. The major source of AIF-1 was WAT resident macrophages. Expression of AIF-1 was similar in visceral and subcutaneous WAT and was two-fold increased in obese women (P < 0.01). AIF-1 mRNA expression levels were normalized after weight reduction (P < 0.01). Expression of AIF-1 was inversely correlated with insulin sensitivity as assessed by insulin tolerance test (KITT), and circulating levels of adiponectin (P = 0.02), and positively correlated with insulin resistance as estimated by HOMA (=0.0042).
Conclusions
AIF-1 is a novel adipokine produced mainly by macrophages within human WAT. Its expression is increased in obese women and associates with unfavourable metabolic phenotypes. AIF-1 may play a paracrine role in the regulation of WAT function through cross-talk between macrophages and other cell types within the adipose tissue.
doi:10.1186/1472-6823-13-54
PMCID: PMC4175115  PMID: 24267103
AIF-1; Adipokines; Obesity; Adipose tissue
13.  Interplay of adipokines and myokines in cancer pathophysiology: Emerging therapeutic implications 
Excess body weight constitutes a worldwide health problem with epidemic proportions impacting on the risk and prognosis of several disease states including malignancies. It is believed that the metabolic changes associated with weight gain, particularly visceral obesity, and physical inactivity could lead to dysfunctional adipose and muscle tissues causing insulin resistance, low-grade chronic inflammation and abnormal secretion of adipokines and myokines. The complex paracrine and endocrine interconnection between adipokines and myokines reflects a yin-yang balance with important implications in processes such as lipolysis control, insulin sensitivity and prevention from obesity-driven chronic low-grade inflammation and cancer promotion through anti-inflammatory adipokines and myokines. Furthermore, the complex pathophysiology of cancer cachexia is based on the interplay between muscle and adipose tissue mediated by free fatty acids, various adipokines and myokines. The purpose of this editorial is to explore the role of the adipose and muscle tissue interplay in carcinogenesis, cancer progression and cachexia, and to examine the mechanisms underpinning their association with malignancy. Understanding of the mechanisms connecting the interplay of adipokines and myokines with cancer pathophysiology is expected to be of importance in the development of therapeutic strategies against cancer cachexia. Advances in the field of translational investigation may lead to tangible benefits to obese and inactive persons who are at increased risk of cancer as well as to cancer patients with cachexia.
doi:10.5493/wjem.v3.i3.26
PMCID: PMC3905596  PMID: 24520543
Adipokine; Myokine; Cancer; Cachexia; Interleukin-15; Interleukin-6; Obesity; Myostatin
14.  Emerging role of adipokines as mediators in atherosclerosis 
World Journal of Cardiology  2010;2(11):370-376.
Atherosclerotic cardiovascular disease is a major health problem around the world. Obesity is a primary risk factor for atherosclerosis and is associated with increased morbidity and mortality of cardiovascular diseases. However, the precise molecular pathways underlying this close association remain poorly understood. Adipokines are cytokines, chemokines and hormones secreted by adipose tissue that couple the regulation of lipid accumulation, inflammation, and atherogenesis, and therefore serve to link obesity with cardiovascular disorders. Obesity-related disorders including metabolic syndrome, diabetes, atherosclerosis, hypertension, and coronary artery disease are associated with dysregulated adipokine(s) expression. Recent studies demonstrate the proinflammatory effects as well as atherogenic properties of adipokines. Adipokines also participate in the regulation of endothelial function, which is an early event in atherosclerosis. By contrast, adiponectin, an adipocyte-derived hormone, exerts anti-inflammatory, anti-atherogenic and vascular protective effects. Furthermore, there is an interactive association among adipokines, by which adipokines reciprocally regulate each other’s expression. Understanding this interplay may reveal plausible mechanisms for treating atherosclerosis and coronary heart disease by modulating adipokine(s) expression. In this review, we discuss insights into the role and the therapeutic potential of adipokines as mediators of atherosclerosis.
doi:10.4330/wjc.v2.i11.370
PMCID: PMC3006473  PMID: 21179304
Obesity; Inflammation; Adipokines; Endothelial function; Atherosclerosis
15.  Adipokine resistin predicts anti-inflammatory effect of glucocorticoids in asthma 
Background
Adipokines are protein mediators secreted by adipose tissue. Recently, adipokines have also been involved in the regulation of inflammation and allergic responses, and suggested to affect the risk of asthma especially in obese female patients. We assessed if adipokines predict responsiveness to glucocorticoids and if plasma adipokine levels are associated with lung function or inflammatory activity also in non-obese (body mass index (BMI) ≤ 30 kg/m2) women with newly-diagnosed steroid-naïve asthma.
Methods
Lung function, exhaled NO, plasma levels of adipokines leptin, resistin, adiponectin and adipsin, and inflammatory markers were measured in 35 steroid-naïve female asthmatics and in healthy controls. The measurements were repeated in a subgroup of asthmatics after 8 weeks of treatment with inhaled fluticasone. Adipokine concentrations in plasma were adjusted for BMI.
Results
High baseline resistin concentrations were associated with a more pronounced decrease in serum levels of eosinophil cationic protein (ECP) (r = -0.745, p = 0.013), eosinophil protein X (EPX) (r = -0.733, p = 0.016) and myeloperoxidase (MPO) (r = -0.721, p = 0.019) during fluticasone treatment. In asthmatics, leptin correlated positively with asthma symptom score and negatively with lung function. However, no significant differences in plasma adipokine levels between non-obese asthmatics and healthy controls were found. The effects of resistin were also investigated in human macrophages in cell culture. Interestingly, resistin increased the production of proinflammatory factors IL-6 and TNF-α and that was inhibited by fluticasone.
Conclusions
High resistin levels predicted favourable anti-inflammatory effect of inhaled glucocorticoids suggesting that resistin may be a marker of steroid-sensitive phenotype in asthma. High leptin levels were associated with a more severe disease suggesting that the link between leptin and asthma is not restricted to obesity.
doi:10.1186/1476-9255-8-12
PMCID: PMC3117675  PMID: 21615949
16.  Gene expression in subcutaneous adipose tissue differs in women with polycystic ovary syndrome and controls matched pair-wise for age, body weight, and body mass index 
Adipocyte  2014;3(3):190-196.
Adipose tissue dysfunction may be a central factor in the pathogenesis of insulin resistance in women with polycystic ovary syndrome (PCOS). Gene expression in subcutaneous adipose tissue in PCOS and its relation to metabolic and endocrine features of the syndrome have been fragmentarily investigated. The aim was to assess in subcutaneous adipose tissue the expression of genes potentially associated with adipose tissue dysfunction and to explore their relation to features of the syndrome. Twenty-one women with PCOS (body mass index [BMI] 18.2–33.4 kg/m2) and 21 controls (BMI 19.2–31.7 kg/m2) were matched pair-wise for age, body weight, and BMI. Tissue biopsies were obtained to measure mRNA expression of 44 genes (TaqMan Low Density Array). Differential expression levels were correlated with BMI, glucose infusion rate (GIR), sex hormone binding globulin (SHBG), and sex steroids. In PCOS, expression of adiponectin receptor 2 (ADIPOR2), LPL, and twist-related protein 1 (TWIST1) was decreased, while expression of chemokine (C-C motif) ligand 2 (CCL2) and heme oxygenase (decycling 1) (HMOX1) was increased. TWIST1 and HMOX1, both novel adipokines, correlated with BMI and GIR. After BMI adjustment, LPL and ADIPOR2 expression correlated with plasma estradiol, and CCL2 expression correlated with GIR, in all women. We conclude that adipose tissue mRNA expression differed in PCOS women and controls and that two novel adipokines, TWIST1 and HMOX1, together with adiponectin, LPL, and CCL2, and their downstream pathways merit further investigation.
doi:10.4161/adip.28731
PMCID: PMC4110095  PMID: 25068085
adiponectin receptor 2 (ADIPOR2); adipose tissue; chemokine (C-C motif) ligand 2 (CCL2); gene expression; heme oxygenase (decycling 1) (HMOX1); insulin sensitivity; lipoprotein lipase (LPL); PCOS; twist-related protein 1 (TWIST1)
17.  Genome Wide Meta-analysis Highlights the Role of Genetic Variation in RARRES2 in the Regulation of Circulating Serum Chemerin 
PLoS Genetics  2014;10(12):e1004854.
Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p<5.0×10−8) in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8×10−14, beta = −0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p<0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.
Author Summary
Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. In the present study we show that circulating chemerin is a heritable trait. In a meta-analysis of genome-wide association studies (GWAS) of 2,791 individuals from Germany and Finland, we identified common genetic variants which associate with serum chemerin levels. The variants map within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) at chromosome 7. To better understand the potential functionality of the identified variants, we also provide insights into the mRNA expression of RARRES2 (encoding chemerin) in blood and adipose tissue. Our results highlight the role and function of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.
doi:10.1371/journal.pgen.1004854
PMCID: PMC4270463  PMID: 25521368
18.  Ceruloplasmin Is a Novel Adipokine Which Is Overexpressed in Adipose Tissue of Obese Subjects and in Obesity-Associated Cancer Cells 
PLoS ONE  2014;9(3):e80274.
Obesity confers an increased risk of developing specific cancer forms. Although the mechanisms are unclear, increased fat cell secretion of specific proteins (adipokines) may promote/facilitate development of malignant tumors in obesity via cross-talk between adipose tissue(s) and the tissues prone to develop cancer among obese. We searched for novel adipokines that were overexpressed in adipose tissue of obese subjects as well as in tumor cells derived from cancers commonly associated with obesity. For this purpose expression data from human adipose tissue of obese and non-obese as well as from a large panel of human cancer cell lines and corresponding primary cells and tissues were explored. We found expression of ceruloplasmin to be the most enriched in obesity-associated cancer cells. This gene was also significantly up-regulated in adipose tissue of obese subjects. Ceruloplasmin is the body's main copper carrier and is involved in angiogenesis. We demonstrate that ceruloplasmin is a novel adipokine, which is produced and secreted at increased rates in obesity. In the obese state, adipose tissue contributed markedly (up to 22%) to the total circulating protein level. In summary, we have through bioinformatic screening identified ceruloplasmin as a novel adipokine with increased expression in adipose tissue of obese subjects as well as in cells from obesity-associated cancers. Whether there is a causal relationship between adipose overexpression of ceruloplasmin and cancer development in obesity cannot be answered by these cross-sectional comparisons.
doi:10.1371/journal.pone.0080274
PMCID: PMC3968011  PMID: 24676332
19.  Time-course microarrays reveal early activation of the immune transcriptome and adipokine dysregulation leads to fibrosis in visceral adipose depots during diet-induced obesity 
BMC Genomics  2012;13:450.
Background
Visceral white adipose tissue (WAT) hypertrophy, adipokine production, inflammation and fibrosis are strongly associated with obesity, but the time-course of these changes in-vivo are not fully understood. Therefore, the aim of this study was to establish the time-course of changes in adipocyte morphology, adipokines and the global transcriptional landscape in visceral WAT during the development of diet-induced obesity.
Results
C57BL/6 J mice were fed a high-fat diet (HFD) or normal diet (ND) and sacrificed at 8 time-points over 24 weeks. Excessive fat accumulation was evident in visceral WAT depots (Epidydimal, Perirenal, Retroperitoneum, Mesentery) after 2–4 weeks. Fibrillar collagen accumulation was evident in epidydimal adipocytes at 24 weeks. Plasma adipokines, leptin, resistin and adipsin, increased early and time-dependently, while adiponectin decreased late after 20 weeks. Only plasma leptin and adiponectin levels were associated with their respective mRNA levels in visceral WAT. Time-course microarrays revealed early and sustained activation of the immune transcriptome in epididymal and mesenteric depots. Up-regulated inflammatory genes included pro-inflammatory cytokines, chemokines (Tnf, Il1rn, Saa3, Emr1, Adam8, Itgam, Ccl2, 3, 4, 6, 7 and 9) and their upstream signalling pathway genes (multiple Toll-like receptors, Irf5 and Cd14). Early changes also occurred in fibrosis, extracellular matrix, collagen and cathepsin related-genes, but histological fibrosis was only visible in the later stages.
Conclusions
In diet-induced obesity, early activation of TLR-mediated inflammatory signalling cascades by CD antigen genes, leads to increased expression of pro-inflammatory cytokines and chemokines, resulting in chronic low-grade inflammation. Early changes in collagen genes may trigger the accumulation of ECM components, promoting fibrosis in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes altered early by HFD feeding may help ameliorate the deleterious effects of diet-induced obesity.
doi:10.1186/1471-2164-13-450
PMCID: PMC3447724  PMID: 22947075
Adipocytokine dysregulation; Transcriptional response; Adipose tissue; Extracellular matrix; Cathepsin; Fibrosis
20.  Resistin, but not Adiponectin and Leptin, is Associated with the Risk of Ischemic Stroke Among Postmenopausal Women: Results from the Women’s Health Initiative 
Background
Adipose tissue is considered an endocrine organ that secretes adipokines which possibly mediate the effects of obesity on risk of cardiovascular disease. However, there are yet limited prospective data on the association between circulating adipokine levels and risk of ischemic stroke. We aimed to examine the associations of three adipokines (adiponectin, leptin and resistin) with risk of ischemic stroke.
Methods and Results
We conducted a prospective nested case-control study (972 stroke cases and 972 matched controls) within the Women’s Health Initiative Observational Study cohort. The controls were matched to cases on age, race/ethnicity, date of study enrollment and follow-up time. Adipokine levels were associated with established stroke risk factors, such as obesity and systolic blood pressure. Adjusted for body mass index, the odds ratios (OR) for incident ischemic stroke comparing the highest (Q4) to the lowest quartile (Q1) were 0.81 (95% confidence intervals [CI]: 0.61–1.08; p-trend: 0.068) for adiponectin, 1.15 (95% CI: 0.83–1.59; p-trend: 0.523) for leptin, and 1.57 (95% CI: 1.18–2.08; p-trend: 0.002) for resistin. The association for resistin remained significant even after accounting for established stroke risk factors (OR: 1.39; 95% CI: 1.01–1.90; p-trend: 0.036). Further adjustment for markers for inflammation, angiogenesis, and endothelial function also did not affect our results.
Conclusions
Circulating levels of resistin, but not those of adiponectin or leptin, are associated with an increased risk of incident ischemic stroke in postmenopausal women, independent of obesity and other CVD risk factors.
doi:10.1161/STROKEAHA.110.607853
PMCID: PMC4059356  PMID: 21546486
stroke; adipokines; women
21.  The contribution of visceral fat to improved insulin signaling in Ames dwarf mice 
Aging Cell  2014;13(3):497-506.
Ames dwarf (Prop1df, df/df) mice are characterized by growth hormone (GH), prolactin, and thyrotropin deficiency, remarkable extension of longevity and increased insulin sensitivity with low levels of fasting insulin and glucose. Plasma levels of anti-inflammatory adiponectin are increased in df/df mice, while pro-inflammatory IL-6 is decreased in plasma and epididymal fat. This represents an important shift in the balance between pro- and anti-inflammatory adipokines in adipose tissue, which was not exposed to GH signals during development or adult life. To determine the role of adipose tissue in the control of insulin signaling in these long-living mutants, we examined the effects of surgical removal of visceral (epididymal and perinephric) adipose tissue. Comparison of the results obtained in df/df mice and their normal (N) siblings indicated different effects of visceral fat removal (VFR) on insulin sensitivity and glucose tolerance. The analysis of the expression of genes related to insulin signaling indicated that VFR improved insulin action in skeletal muscle in N mice. Interestingly, this surgical intervention did not improve insulin signaling in df/df mice skeletal muscle but caused suppression of the signal in subcutaneous fat. We conclude that altered profile of adipokines secreted by visceral fat of Ames dwarf mice may act as a key contributor to increased insulin sensitivity and extended longevity of these animals.
doi:10.1111/acel.12201
PMCID: PMC4032618  PMID: 24690289
adiponectin; adipose tissue; Ames dwarf; insulin; obesity
22.  Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice 
Cancer Biology & Therapy  2011;11(10):910-917.
Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n = 6) or a high-fat (60%, HF, n = 6) diet for 12 weeks. In the eighth week of the dietary program, 106 E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3 ± 1.7 vs. 41.5 ± 1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062 ± 0.005 vs. 0.032 ± 0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62 ± 0.63 vs. 1.98 ± 0.27 g; p < 0.01) and IMD (173 ± 3.7 vs. 139 ± 4.3 IM#/mm2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3 ± 3.8 vs. 49.5 ± 4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69 ± 7.1 vs. 48 ± 3.5 pg/ml) and visceral fat VEGF levels (424.4 ± 39.5 vs. 208.5 ± 22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n = 6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77 ± 1.14 vs. 0.94 ± 0.16 pg/mg tissue; n = 6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer progression, possibly through increased adipose tissue mass and adipokines such as VEGF that could systemically and locally affect breast cancer progression.
doi:10.4161/cbt.11.10.15473
PMCID: PMC3230297  PMID: 21451264
postmenopausal obesity; breast cancer; vascular endothelial growth factor (VEGF); adipose tissue; visceral fat; subcutaneous fat; mice
23.  Over expression of resistin in adipose tissue of the obese induces insulin resistance 
World Journal of Diabetes  2012;3(7):135-141.
AIM: To compare resistin mRNA expression in subcutaneous adipose tissue (SAT) and its correlation with insulin resistance (IR) in postmenopausal obese women.
METHODS: A total of 68 postmenopausal women (non obese = 34 and obese = 34) were enrolled for the study. The women of the two groups were age matched (49-70 years). Fasting blood samples were collected at admission and abdominal SAT was obtained during surgery for gall bladder stones or hysterectomy. Physical parameters [age, height, weight, body mass index (BMI)] were measured. Biochemical (plasma insulin and plasma glucose) parameters were estimated by enzymatic methods. RNA was isolated by the Trizol method. SAT resistin mRNA expression was done by real time- reverse transcription polymerase chain reaction (RT-PCR) by using Quanti Tect SYBR Green RT-PCR master mix. Data was analyzed using independent Student’s t test, correlation and simple linear regression analysis.
RESULTS: The mean weight (52.81 ± 8.04 kg vs 79.56 ± 9.91 kg; P < 0.001), BMI (20.23 ± 3.05 kg/m2 vs 32.19 ± 4.86 kg/m2; P < 0.001), insulin (8.47 ± 3.24 μU/mL vs 14.67 ± 2.18 μU/mL; P < 0.001), glucose (97.44 ± 11.31 mg/dL vs 109.67 ± 8.02 mg/dL; P < 0.001) and homeostasis model assessment index (2.01 ± 0.73 vs 3.96 ± 0.61; P < 0.001) were significantly higher in postmenopausal obese women compared to postmenopausal non obese women. The mean serum resistin level was also significantly higher in postmenopausal obese women compared to postmenopausal non obese women (9.05 ± 5.15 vs 13.92 ± 6.32, P < 0.001). Furthermore, the mean SAT resistin mRNA expression was also significantly (0.023 ± 0.008 vs 0.036 ± 0.009; P < 0.001) higher and over expressed 1.62 fold (up-regulated) in postmenopausal obese women compared to postmenopausal non obese women. In postmenopausal obese women, the relative SAT resistin mRNA expression showed positive (direct) and significant correlation with BMI (r = 0.78, P < 0.001) and serum resistin (r = 0.76, P < 0.001). Furthermore, the SAT resistin mRNA expression in postmenopausal obese women also showed significant and direct association (r = 0.45, P < 0.01) with IR, while in postmenopausal non obese women it did not show any association (r = -0.04, P > 0.05).
CONCLUSION: Increased SAT resistin mRNA expression probably leads to inducing insulin resistance and thus may be associated with obesity-related disorders in postmenopausal obese women.
doi:10.4239/wjd.v3.i7.135
PMCID: PMC3399912  PMID: 22816026
Resistin; Subcutaneous adipose tissue; Insulin resistance; Obesity; Body mass index
24.  Microarray Evidences the Role of Pathologic Adipose Tissue in Insulin Resistance and Their Clinical Implications 
Journal of Obesity  2011;2011:587495.
Clustering of insulin resistance and dysmetabolism with obesity is attributed to pathologic adipose tissue. The morphologic hallmarks of this pathology are adipocye hypertrophy and heightened inflammation. However, it's underlying molecular mechanisms remains unknown. Study of gene function in metabolically active tissues like adipose tissue, skeletal muscle and liver is a promising strategy. Microarray is a powerful technique of assessment of gene function by measuring transcription of large number of genes in an array. This technique has several potential applications in understanding pathologic adipose tissue. They are: (1) transcriptomic differences between various depots of adipose tissue, adipose tissue from obese versus lean individuals, high insulin resistant versus low insulin resistance, brown versus white adipose tissue, (2) transcriptomic profiles of various stages of adipogenesis, (3) effect of diet, cytokines, adipokines, hormones, environmental toxins and drugs on transcriptomic profiles, (4) influence of adipokines on transcriptomic profiles in skeletal muscle, hepatocyte, adipose tissue etc., and (5) genetics of gene expression. The microarray evidences of molecular basis of obesity and insulin resistance are presented here. Despite the limitations, microarray has potential clinical applications in finding new molecular targets for treatment of insulin resistance and classification of adipose tissue based on future risk of insulin resistance syndrome.
doi:10.1155/2011/587495
PMCID: PMC3092611  PMID: 21603273
25.  Sepsis-Induced Adipokine Change with regard to Insulin Resistance 
Background. Assessment of white adipose tissue has changed in recent years, with WAT now being considered as an active endocrine organ, secreting a large number of bioactive mediators, so-called adipokines. Besides other functions, these adipokines are involved in inflammatory response thereby exhibiting predominantly proinflammatory or anti-inflammatory properties and contribute to insulin resistance. Methods. Comprehensive review of the literature of the role of adipokines relevant to critical care medicine using PubMed search. Results. Adiponectin—the prototype of an anti-inflammatory and insulin-sensitizing adipokine—is diminished in sepsis, while resistin—a protein with proinflammatory properties—is elevated. Plasminogen activator inhibitor-1, interleukin (IL)-1, IL-6, IL-8, and IL-10, and tumor-necrosis-factor-alpha mediate insulin resistance and are elevated in sepsis, while retinol-binding protein-4 concentrations are significantly reduced in sepsis. Chemerin displays potent anti-inflammatory and insulin-resistance properties, while monocyte chemotactic protein-1—increased in sepsis—contributes to macrophage infiltration in adipose tissue and insulin resistance. Conclusions. The expression of adipokines in humans is altered as well in obese as in septic patients with elevated levels of proinflammatory adipokines. Changes in adipokine levels in acute sepsis could contribute to insulin resistance. Consequently, in critically ill patients, these alterations underline a possible contribution of adipokines in the development of hyperglycemia.
doi:10.1155/2012/972368
PMCID: PMC3261472  PMID: 22272381

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