Obesity Triggers Enhanced MDSC Accumulation in Murine Renal Tumors via Elevated Local Production of CCL2

Obesity is one of the leading risk factors for developing renal cell carcinoma, an immunogenic tumor that is treated clinically with immunostimulatory therapies. Currently, however, the mechanisms linking obesity with renal cancer incidence are unclear. Using a model of diet-induced obesity, we found that obese BALB/c mice with orthotopic renal tumors had increased total frequencies of myeloid-derived suppressor cells (MDSC) in renal tumors and spleens by d14 post-tumor challenge, relative to lean counterparts. Renal tumors from obese mice had elevated concentrations of the known myeloid cell chemoattractant CCL2, which was produced locally by increased percentages of dendritic cells, macrophages, B cells, and CD45^- cells in tumors. MDSC expression of the CCL2 receptor, CCR2, was unaltered by obesity but greater percentages of CCR2⁺ MDSCs were present in renal tumors from obese mice. Of note, the intracellular arginase levels and per-cell suppressive capacities of tumor-infiltrating and splenic MDSCs were unchanged in obese mice relative to lean controls. Thus, our findings suggest that obesity promotes renal tumor progression via development of a robust immunosuppressive environment that is characterized by heightened local and systemic MDSC prevalence. Targeted intervention of the CCL2/CCR2 pathway may facilitate immune-mediated renal tumor clearance in the obese.     

Obesity is a common soil for premature cardiac aging and heart diseases - Role of autophagy

The advance in medical technology and healthcare has dramatically improved the average human lifespan. One of the consequences for longevity is the high prevalence of aging-related chronic disorders such as cardiovascular diseases, cancer and metabolic abnormalities. As the composition of aging population is raising in western countries, heart failure remains the number one cause of death with a more severe impact in the elderly. Obesity and aging are the most critical risk factors for increased susceptibility to heart failure in developing and developed countries. Numerous population-based and experimental data have depicted a close relationship between the age-related diseases and obesity. There is an overall agreement that obesity is causally linked to the development of cardiovascular disorders and severe premature cardiac aging. Accumulating evidence indicates that autophagy plays an important role in obesity, cardiac aging and diseases. In this review, we will focus on the role of autophagy in obesity-related cardiac aging and diseases, and how it regulates age-dependent changes in the heart.     

Protective properties of n-3 fatty acids and implications in obesity-associated breast cancer

Obesity is well documented as a risk factor for developing breast cancer, especially in postmenopausal women. Adipose tissue in the breast under obese conditions induces inflammation by increasing macrophage infiltration and pro-inflammatory cytokines that in turn up-regulates genes and signaling pathways, resulting in increased inflammation, cell proliferation and tumor growth in the breast. Due to their potent anti-inflammatory effects, n-3 polyunsaturated fatty acids (n-3 PUFA) are a promising and safe dietary intervention in reducing breast cancer risk. Here, we briefly review current status of breast cancer and its relationship with obesity. We then review in depth, current research and knowledge on the role of n-3 PUFA in reducing/preventing breast cancer cell growth in vitro, in vivo and in human studies, and how n-3 PUFA may modulate signaling pathways mitigating their effects on breast cancer development.     

New aspects in the management of obesity: operation and the impact of lipase inhibitors

Obesity is an increasing health problem in most developed countries and its prevalence is also increasing in developing countries. There has been no great success with dietary means and life style modification for permanent weight loss. Various surgical treatment methods for obesity are now available. They are aimed at limiting oral energy intake with or without causing dumping or inducing selective maldigestion and malabsorption. Based on current literature, up to 75% of excess weight is lost by surgical treatment with concomitant disappearance of hyperlipidaemias, type 2 diabetes, hypertension or sleep apnoea. The main indication for operative treatment is morbid obesity (body mass index greater than 40 kg/m2) or severe obesity (body mass index > 35 kg/m2) with comorbidities of obesity. Orlistat is a new inhibitor of pancreatic lipase enzyme. At doses of 120 mg three times per day with meals it results in a 30% reduction in dietary fat absorption, which equals approximately 200 kcal daily energy deficit. In the long term, orlistat has been shown to be more effective than placebo in reducing body weight and serum total and low-density lipoprotein cholesterol levels. Orlistat has a lowering effect on serum cholesterol independent of weight loss. Along with weight loss, orlistat also favourably affects blood pressure and glucose and insulin levels in obese individuals and in obese type 2 diabetic patients.     

Effects of adipokines and obesity on uterine contractility

Obesity is a major public health problem. The prevalence of obesity has significantly increased in developed countries, particularly in France with an overall increase of 76% over the last 15 years. In pregnant women, obesity is associated with alterations in the quality of labor, such as delayed onset of labor, a higher rate of prolonged pregnancies, prolonged labor, and higher oxytocin requirements. There is also an increased prevalence of Cesarean sections, particularly during the active phase of labor, and perinatal complications (postpartum hemorrhage).It seems that some of these functional changes and their consequences can be attributed to a disruption of hormonal balance encountered in obese women and involving adipokines (apelin, ghrelin, visfatin, leptin), but also to the interactions between adipose tissue and the “oxytocin (OT) – oxytocin receptor (OTR)”.In this review, we detailed mechanisms to understand the impact of specific metabolic alterations in obesity on uterine contractility.Better knowledge of the impact of obesity on labor and delivery pathophysiology should strengthen the prevention of obesity in women of childbearing age and provide a suitable and effective management. The beneficial effect of weight loss and exercise in non-pregnant women on the correction of metabolic disorders secondary to obesity should be studied in populations of overweight women to demonstrate its effectiveness.     

National Economic Development Status May Affect the Association between Central Adiposity and Cognition in Older Adults

Background

Obesity is becoming a global problem, rather than one found only in developed countries. Although recent studies have suggested a detrimental effect of obesity on cognition, studies of the relationship between obesity and cognition among older adults have been limited to developed countries. We aimed to examine the associations between central obesity, as measured by waist circumference, and cognition level in adults aged 50 years and older in England and Indonesia.

Methods

We used linear regression models to analyse these associations and multiple imputation to manage missing data. The 2006 English Longitudinal Study of Ageing Wave 3 is the source of data from England, while data from Indonesia is sourced from the 2007 Indonesian Family Life Survey Wave 4.

Findings

Centrally obese respondents had lower cognition levels than non-centrally obese respondents in England. In contrast, central adiposity had a statistically significant positive association with cognition in Indonesia. Higher levels of education and higher economic status were associated with higher cognitive ability, while age was associated with lower cognition in both countries. Elevated C-reactive protein (CRP) concentrations and smoking behaviour, both linked to higher risk of obesity, were negatively associated with cognitive ability among older adults in England, but they had no statistically significant association with cognition among Indonesians.

Interpretation

The contradictory findings on obesity and cognition in England and Indonesia not only create a puzzle, but they may also have different policy implications in these countries. Reducing the prevalence of obesity may be the main focus in England and other developed countries to maintain older adults’ cognition. However, Indonesia and other developing countries should place more emphasis on education, in addition to continued efforts to tackle the double burden of malnutrition, in order to prevent cognitive impairment among older adults.     

Anti-obesity effects of gut microbiota are associated with lactic acid bacteria

The prevalence of obesity is rapidly becoming endemic in industrialized countries and continues to increase in developing countries worldwide. Obesity predisposes people to an increased risk of developing metabolic syndrome. Recent studies have described an association between obesity and certain gut microbiota, suggesting that gut microbiota might play a critical role in the development of obesity. Although probiotics have many beneficial health effects in humans and animals, attention has only recently been drawn to manipulating the gut microbiota, such as lactic acid bacteria (LAB), to influence the development of obesity. In this review, we first describe the causes of obesity, including the genetic and environmental factors. We then describe the relationship between the gut microbiota and obesity, and the mechanisms by which the gut microbiota influence energy metabolism and inflammation in obesity. Lastly, we focus on the potential role of LAB in mediating the effects of the gut microbiota in the development of obesity.     

Tissue‐Specificity and Ethnic Diversity in Obesity‐Related Risk of Cancer May Be Explained by Variability in Insulin Response and Insulin Signaling Pathways

Obesity is a predisposing risk factor for several chronic diseases. The link between obesity and cancer appears to be particularly complex. Notably only the risk for development of specific cancers appear to be affected. Moreover, the obesity‐related risk of cancer is very different across ethnic groups. African‐Americans appear particularly prone, whereas Hispanics appear to be relatively protected. Obesity is associated with increased levels of circulating insulin. These levels of elevated insulin may serve to promote proliferation of fat cells to accommodate the elevated nutrient flux. However, elevated levels of insulin may be a major mediating factor influencing cancer risk. This hypothesis alone cannot explain the complexity of the phenomenon. We suggest here that the different insulin responses to obesity of different ethnic groups may explain their different risk profiles. Moreover, we speculate that tissue‐specific variations in the insulin signaling pathways may underlie their differential susceptibility to tumorigenesis in the face of elevated obesity. Elevated cancer risk may be an unwanted side effect of insulin responding to elevated nutrient flux in the obese which it serves to proliferate fat cells that provide a location for storage of ingested fat, which consequently prevents ectopic fat storage. Hence, while Hispanics may be protected from cancer risk in obesity because of their lower insulin response, they have an elevated risk of fatty liver disease. Reduction of insulin levels in obesity as a strategy to reduce cancer risk may pose additional problems unless it is combined also with interventions that aim to limit nutrient influx.     

Measured parental weight status and familial socio-economic status correlates with childhood overweight and obesity at age 9

Background

Parental obesity is a predominant risk factor for childhood obesity. Family factors including socio-economic status (SES) play a role in determining parent weight. It is essential to unpick how shared family factors impact on child weight. This study aims to investigate the association between measured parent weight status, familial socio-economic factors and the risk of childhood obesity at age 9.

Methodology/Principal Findings

Cross sectional analysis of the first wave (2008) of the Growing Up in Ireland (GUI) study. GUI is a nationally representative study of 9-year-old children (N = 8,568). Schools were selected from the national total (response rate 82%) and age eligible children (response rate 57%) were invited to participate. Children and their parents had height and weight measurements taken using standard methods. Data were reweighted to account for the sampling design. Childhood overweight and obesity prevalence were calculated using International Obesity Taskforce definitions. Multinomial logistic regression examined the association between parent weight status, indicators of SES and child weight. Overall, 25% of children were either overweight (19.3%) or obese (6.6%). Parental obesity was a significant predictor of child obesity. Of children with normal weight parents, 14.4% were overweight or obese whereas 46.2% of children with obese parents were overweight or obese. Maternal education and household class were more consistently associated with a child being in a higher body mass index category than household income. Adjusted regression indicated that female gender, one parent family type, lower maternal education, lower household class and a heavier parent weight status significantly increased the odds of childhood obesity.

Conclusions/Significance

Parental weight appears to be the most influential factor driving the childhood obesity epidemic in Ireland and is an independent predictor of child obesity across SES groups. Due to the high prevalence of obesity in parents and children, population based interventions are required.     

Socioeconomic inequality and obesity prevalence trends in luxembourg, 1995¿2007

ABSTRACT: BACKGROUND: Overweight and obesity are becoming increasingly critical problems in most developed countries. Approximately 20% of adults in most European countries are obese. This study examines the prevalence of overweight and obesity in Luxembourg and their association with different demographic, socioeconomic (SES), and behavioural factors. METHODS: The data used in this study were taken from 2 surveys on household income and living conditions conducted in 1995 and 2007. The target population was household residents aged 16 years and older, and body mass index (BMI) data were self-reported. Average BMI, overweight, and obesity prevalence rates were calculated according to each demographic (gender, nationality, marital status), SES (educational level, profession, and place of residence), and behavioural (physical activity and diet) factors. A multivariate logistic regression analysis was conducted to measure the relationship between obesity and demographic, SES, and behavioural factors. All analyses were conducted according to gender, and data used were weighted. RESULTS: Between 1995 and 2007, the average BMI remained nearly constant among men and women in the entire study population. Obesity prevalence increased by 24.5% through the study period (14.3% in 1995 to 17.8% in 2007). Obesity prevalence increased by 18.5% for men (15.1% in 1995 to 17.9% in 2007) and by 30% for women (13.6% in 1995 to 17.7% in 2007). Between 1995 and 2007, obesity increased sharply by 48.2% (from 11% to 16.3%) in Portuguese men, 76.7% (from 13.3% to 23.5%) in Portuguese women, 79.7% (from 17.2% to 30.9%) in widowed men, and 84.3% (from 12.1% to 22.3%) in divorced women. Multivariate logistic regression analysis showed that the relationship between the educational level and obesity was not statistically significant for men, but was significant for women. CONCLUSIONS: The prevalence of overweight and obesity is high in Luxembourg and has changed slightly in recent years. SES inequalities in obesity exist and are most compelling among women. The fight against obesity should focus on education, with emphasis on the socially disadvantaged segment of the population.     

Leptin and cancer

The prevalence of obesity has markedly increased over the past two decades, especially in the industrialized countries. While the impact of excess body weight on the development of cardiac disease and diabetes has been well documented, the link between obesity and carcinogenesis is just being recognized. This review will focus on the link between leptin, a cytokine that is elevated in obese individuals, and cancer development. First, we briefly discuss the biological functions of leptin and its signaling pathways. Then, we summarize the effects of leptin on different cancer types in experimental cellular and animal models. Next, we analyze epidemiological data on the relationship between obesity and the presence of cancer or cancer risk in patients. Finally, leptin as a target for cancer treatment and prevention will be discussed.     

Obesity and post-prandial lipid metabolism. Feast or famine?

Both in Western countries and in third world countries there is an increasing incidence of obesity. Obesity per se or insulin resistance associated with obesity may increase cardiovascular risk factors including dyslipidemia, hypertension and Type 2 diabetes. Over the past decade the understanding has increased of specific mediators in the hypothalamus that are involved in regulating food intake and body weight. In obese humans fasting plasma lipids can be normal but postprandial lipid metabolism is abnormal with an accumulation of triglyceride-rich remnant lipoproteins. In viscerally obese men chylomicron remnant catabolism was markedly decreased when compared with lean individuals. The decreased clearance of chylomicron remnants in viscerally obese subjects may be explained by competition between chylomicron remnants and the increased hepatic production of VLDL for clearance by low density lipoprotein receptors. Increased food intake in rodent models of obesity was shown to be associated with a delay in the catabolism of remnant lipoprotein particles. Prevention of hyperphagia was found to correct the impairment in the metabolism of remnant lipoproteins. Under fasting and food restricted conditions the improvement of remnant metabolism was associated with an increased oxidation of remnant lipids as determined by a novel stable isotope breath test. Anti-obesity and lipid lowering drugs have been used for the treatment of obesity. Inhibitors of cholesterol synthesis inhibitors (statins) have been shown to be effective in treating dyslipidemia. Inhibition of cholesterol synthesis with Atorvastatin was shown to improve chylomicron metabolism by increasing chylomicron remnant catabolism in obese subjects as assessed by the newly developed stable isotope breath test.     

Prevalencia de obesidad y riesgo cardiovascular asociado en la población general de un área de salud de Extremadura. Estudio Hermex

Introduction and objectivesTo estimate the prevalence of obesity and its associated cardiovascular risk in the general population of a health area in Extremadura.Materials and methodsA cross-sectional study on a random population sample aged 25-79 years from the Don Benito-Villanueva (Badajoz) health area. Risk factors and cardiovascular disease were examined. Anthropometric and blood pressure measurements were collected, and a blood sample was taken. Obese subjects were categorized into different risk levels as proposed by the Spanish Society for the Study of Obesity, and the influence of obesity on estimation of the risk of ischemic heart disease was studied using the Framingham function, as adapted for Spain.ResultsA total of 2833 of the 3521 subjects screened (80.5%) participated in the study. Mean age was 51.2 years (SD 14.7), and 46.5% were males. Male subjects had a greater prevalence of overweight and obesity (46.2% and 37.7% respectively) as compared to females (37.7% and 32.6%) (p<0.005 and p<0.05 respectively). Only 10% of obese subjects had no increased cardiovascular risk. Obesity was associated to an 8-fold increase in the presence of a high risk for ischemic heart disease in females (p<0.001), as compared to a 1.4-fold increase in males (p=0.095).ConclusionsObesity is highly prevalent and affects, together with overweight, 74.1% of the population in an Extremadura health area. A vast majority of obese subjects have an increased cardiovascular risk, which is very marked for ischemic heart disease in females.     

Determinants of Obesity and Associated Population Attributability,South Africa: Empirical Evidence from a National Panel Survey, 2008-2012

Background

Obesity is a major risk factor for emerging non-communicable diseases (NCDS) in middle income countries including South Africa (SA). Understanding the multiple and complex determinants of obesity and their true population attributable impact is critical for informing and developing effective prevention efforts using scientific based evidence. This study identified contextualised high impact factors associated with obesity in South Africa.

Methods

Analysis of three national cross sectional (repeated panel) surveys, using a multilevel logistic regression and population attributable fraction estimation allowed for identification of contextualised high impact factors associated with obesity (BMI>30 kg/m²) among adults (15years+).

Results

Obesity prevalence increased significantly from 23.5% in 2008 to 27.2% in 2012, with a significantly (p-value<0.001) higher prevalence among females (37.9% in 2012) compared to males (13.3% in 2012). Living in formal urban areas, white ethnicity, being married, not exercising and/or in higher socio-economic category were significantly associated with male obesity. Females living in formal or informal urban areas, higher crime areas, African/White ethnicity, married, not exercising, in a higher socio-economic category and/or living in households with proportionate higher spending on food (and unhealthy food options) were significantly more likely to be obese. The identified determinants appeared to account for 75% and 43% of male and female obesity respectively. White males had the highest relative gain in obesity from 2008 to 2012.

Conclusions

The rising prevalence of obesity in South Africa is significant and over the past 5 years the rising prevalence of Type-2 diabetes has mirrored this pattern, especially among females. Targeting young adolescent girls should be a priority. Addressing determinants of obesity will involve a multifaceted strategy and requires at individual and population levels. With rising costs in the private and public sector to combat obesity related NCDS, this analysis can inform culturally sensitive mass communications and wellness campaigns. Knowledge of social determinants is critical to develop “best buys”.     

Modulation of the Leptin Receptor Mediates Tumor Growth and Migration of Pancreatic Cancer Cells

Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration.     

Obesity in Europe

Obesity, defined as a body mass index > 30 kg/m² is relatively common in Europe, particularly among women, and especially in Southern and Eastern European countries. Among men the distribution of body mass index values is surprisingly similar in most countries of Europe. Educational level is strongly inversely associated with the prevalence of obesity. Although differences in body mass index cannot entirely explain the large variation in risk factors and mortality from coronary heart disease, it can be shown that within populations an increased body mass index is associated with less favorable risk patterns. More research is needed to elucidate the reasons for the large variation in the prevalence of obesity among European women and to the health risks associated with obesity in different European countries.     

Preventing a surgical complication during cesarean delivery in a morbidly obese patient: a simple apparatus to retract the abdominal panniculus

Obesity is no longer just a "Western" problem, as evidenced by an increase in prevalence of up to 75% in parts of the developing world. It is important to transfer experience from the developed world to developing countries in an attempt to prepare for the inevitable health and economic problems. This case report highlights an unusual intraoperative complication that has medical and medico-legal implications. A simple apparatus designed to retract the panniculus of an obese patient might reduce complications when performing abdominal surgery in such cases.     

Stromal Cells Derived from Visceral and Obese Adipose Tissue Promote Growth of Ovarian Cancers

Obesity, and in particular visceral obesity, has been associated with an increased risk of developing cancers as well as higher rates of mortality following diagnosis. The impact of obesity on adipose-derived stromal cells (ASC), which contribute to the formation of tumor stroma, is unknown. Here we hypothesized that visceral source and diet-induced obesity (DIO) changes the ASC phenotype, contributing to the tumor promoting effects of obesity. We found that ASC isolated from subcutaneous (SC-ASC) and visceral (V-ASC) white adipose tissue(WAT) of lean(Le) and obese(Ob) mice exhibited similar mesenchymal cell surface markers expression, and had comparable effects on ovarian cancer cell proliferation and migration. Obese and visceral derived ASC proliferated slower and exhibited impaired differentiation into adipocytes and osteocytes in vitro as compared to ASC derived from subcutaneous WAT of lean mice. Intraperitoneal co-injection of ovarian cancer cells with obese or visceral derived ASC, but not lean SC-ASC, increased growth of intraperitoneal ID8 tumors as compared to controls. Obese and V-ASC increased stromal infiltration of inflammatory cells, including CD3+ T cells and F4/80+ macrophages. Obese and visceral derived ASC, but not lean SC-ASC, increased expression of chemotactic factors IL-6, MIP-2, and MCP-1 when cultured with tumor cells. Overall, these results demonstrate that obese and V-ASC have a unique phenotype, with more limited proliferation and differentiation capacity but enhanced expression of chemotactic factors in response to malignant cells which support infiltration of inflammatory cells and support tumor growth and dissemination.     

Obesity-related changes in high-density lipoprotein metabolism

Obesity is associated with a 3-or-more-fold increase in the risk of fatal and nonfatal myocardial infarction (1,2,3,4,5,6). The American Heart Association has reclassified obesity as a major, modifiable risk factor for coronary heart disease (7). The increased prevalence of premature coronary heart disease in obesity is attributed to multiple factors (8,9,10). A principal contributor to this serious morbidity is the alterations in plasma lipid and lipoprotein levels. The dyslipidemia of obesity is commonly manifested as high plasma triglyceride levels, low high-density lipoprotein cholesterol (HDLc), and normal low-density lipoprotein cholesterol (LDLc) with preponderance of small dense LDL particles (7,8,9,10). However, there is a considerable heterogeneity of plasma lipid profile in overweight and obese people. The precise cause of this heterogeneity is not entirely clear but has been partly attributed to the degree of visceral adiposity and insulin resistance. The emergence of glucose intolerance or a genetic predisposition to familial combined hyperlipidemia will further modify the plasma lipid phenotype in obese people (11,12,13,14,15).     

Decreased energy levels can cause and sustain obesity

Obesity has reached epidemic proportions and has become one of the major health problems in developed countries. Current theories consider obesity a result of overeating and sedentary life style and most efforts to treat or prevent weight gain concentrate on exercise and food intake. This approach does not improve the situation as may be seen from the steep increase in the prevalence of obesity. This encouraged us to reanalyse existing information and look for biochemical basis of obesity. Our approach was to ignore current theories and concentrate on experimental data which are described in scientific journals and are available from several databases. We developed and applied a Knowledge Discovery in Databases procedure to analyse metabolic data. We began with the contradictory information: in obesity, more calories are consumed than used up, suggesting that obese people should have excess energy. On the other side, obese people experience fatigue and decreased physical endurance that indicates diminished energy supply in the body. The result of our work is a chain of metabolic events leading to obesity. The crucial event is the inhibition of the TCA cycle at the step of aconitase. It disturbs energy metabolism and results in ATP deficiency with simultaneous fat accumulation. Further steps in obesity development are the consequences of diminished energy supply: inhibition of beta-oxidation, leptin resistance, increase in appetite and food intake and a decrease in physical activity. Thus, our theory shows that obesity does not have to be caused by overeating and sedentary life-style but may be the result of the "obese" change in metabolism which is forcing people to overeat and save energy to sustain metabolic functions of cells. This "obese" change is caused by environmental factors that activate chronic low-grade inflammatory process in the body linking obesity with the environment of developed countries.