Increased Adipose Tissue Mass Research Articles

Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice

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, 10^6 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#/mm^2; 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.

Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression

Obese postmenopausal women have 50% higher risk of breast cancer than non-obese women. There is no animal model that mimics postmenopausal obesity related to breast cancer progression. This study used age-relevant C57BL/6 mice for determing 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 8th wk of the dietary program, 10^6 E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland, and tumor size was monitored for 4 wk. OVX/HF mice significantly increased body weight (55.3±1.7 vs. 41.5±1.5 g), visceral fat/BW ratio (0.062±0.005 vs. 0.032±0.003), tumor weight (4.62±0.63 vs. 1.98±0.27 g), plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml), visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein), tumor VEGF levels (73.3±3.8 vs. 49.5±4.3 pg/mg protein), and intratumoral microvessel density (173±3.7 vs. 139±4.3 IM#/mm^2), compared to OVX/LF group, respectively (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.

Role of AMP-activated Protein Kinase and Adiponectin during Development of Hepatic Steatosis in High-fat Diet-induced Obesity in Rats

Obesity, an abnormal condition of adipose tissue, has recently been recognized as a major cause of metabolic syndromes, especially non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to examine the possible involvement of adipokines in the development of fatty liver. Sprague-Dawley (SD) rats fed a high-fat (HF) diet for 15 weeks developed increased hepatocellular vacuolation, hepatic triglyceride (TG) content and serum TG, total cholesterol and free fatty acid levels, with increases in adipose tissue mass. The serum concentration of adiponectin decreased slightly in these animals. Western blotting analysis demonstrated a decrease in the levels of AMP-activated protein kinase (AMPK) and phosphorylated-AMPK in the livers of these rats. These results indicate similarities between the diet-induced obesity rat model of NAFLD and human NAFLD, thus making the rat a useful model for the further study of NAFLD, including the interactions between adipokines and hepatic fat metabolism.

The Influence of a High‐Fat Dietary Environment in the Fetal Period on Postnatal Metabolic and Immune Function

Few reports show whether a high-fat (HF) dietary environment in the fetal period affects immune function or the development of lifestyle-related disease at maturity. We examined the influence of an HF dietary environment in the fetal period on postnatal metabolic and immune function. A total of 16 pregnant mice were given control (CON) diet and 16 were given HF diet in the gestational period, from mating to delivery. After delivery lactating mice were given either CON or HF diet, resulting in four groups. After weaning, the offspring mice were given the same diet that their mothers received during lactation. HF dietary intake in the postnatal period increased fat pad weights, serum glucose, and leptin levels. An HF diet in the fetal period resulted in fewer splenic lymphocytes, a thinner thymic cortex, and impaired antigen-specific immune reactions. Furthermore, tumor necrosis factor (TNF)-alpha production and serum triglyceride levels were elevated in the fetal HF group. In addition, the HF-HF group showed a consistent decrease in ovalbumin (OVA)-specific IgG and elevation of IgE, associated with advanced fatty changes in the liver. Results from this study suggest that HF environment during the fetal period induces epigenetic propensity toward obesity and immunological burden in part due to increased adipose tissue mass, significant reduction in the number of immune cells and decreased activities of immune cells.

Twelve-Week Aerobic Training Decreases Chemerin Level and Improves Cardiometabolic Risk Factors in Overweight and Obese Men

The inflammatory state of adipose tissue in obese subjects may be the most important factor linking increased adipose tissue mass to insulin resistance. Chemerin is a newly discovered adipokine that plays an important role in macrophage infiltration into adipose tissue and may contribute to the development of inflammation and insulin resistance. We examined the effects of 12 weeks of aerobic training on serum chemerin levels in association with cardiovascular risk factors in overweight and obese males. Twenty-one overweight and obese subjects [44.3 (±4.1 yrs, body mass index (BMI) ≥25 kg/m(2)) were assigned to exercise training (obese EX, n= 11) and control (obese CON, n= 10) groups. The obese EX group participated in 12 weeks of progressive aerobic training 5 days a week. Serum chemerin, insulin resistance, lipid profiles, blood pressure, and body composition were all measured before and after the training. After the aerobic training, waist circumference (P=0.009), fat percent (P=0.03), visceral fat (P=0.03), subcutaneous fat (P=0.01), fasting glucose (P=0.01), insulin resistance (P=0.03), triglyceride (P=0.05), total cholesterol (P=0.04), low-density lipoprotein cholesterol (P=0.05) and systolic blood pressure (P=0.04) of participates were significantly decreased. Concurrently, serum chemerin concentrations were significantly decreased after aerobic program (P=0.02). Aerobic training caused an improvement in cardiometabolic risk factors in obese subjects, and this improvement was accompanied by decreased chemerin levels.

ChemInform Abstract: Pharmacological Treatment of Obesity: Therapeutic Strategies

Obesity is now a common disorder in the industrialized world.1 Much has been reported during the past several years in the popular press about the increasing incidence of obesity and the comorbidity of associated conditions. In addition, there have recently been fundamental advances in our understanding of factors which mediate hunger and satiety and those involved with energy utilization and storage. In this Perspective, we summarize the present state of research in the field of therapeutics targeted for obesity, including promising new approaches for the future. Obesity is a chronic condition characterized by an overabundance of adipose tissue and can be measured in a variety of different ways.2 Excess energy is stored in the form of triglycerides in adipose tissue, and increased adipose tissue mass can occur through increases in cell size, cell number, or both. Increased adipose cell size alone results in hypertrophic obesity which is relatively mild. Increased fat cell number, however, causes hyperplastic obesity characteristic of a more severe condition. While the volume of lipid an individual adipocyte can accumulate is finite, the capacity of adipose tissue to expand is virtually limitless. The most common obesity measure is the body mass index or BMI, defined as weight in kilograms divided by (height in meters)2. BMI values are easy to calculate and correlate well with rankings obtained from more sophisticated techniques and the cormorbidities associated with obesity. It is difficult to set a definitive BMI level threshold to define obesity, particularly for women in which excess weight is often found in the pelvis and not in the abdomen. For example, the BMI scale does not take the distribution of body fat or lean muscle mass into account. Nevertheless, obesity is defined by the World Health Organization as a BMI of 30.0 kg/m2 and above, with a BMI of 25.0-29.9 kg/m2 classified as overweight or preobese.3 A large body of epidemiological data correlates increased body weight with risks such as high blood pressure, coronary heart disease, diabetes, altered steroid metabolism, gallstones, and certain forms of cancer.4 In one study, involving a cohort of >115 000 female nurses over a period of 14-16 years, increased risks of cardiovascular disease and cancer were observed with increasing BMI. Excluding smokers from all groups, there was a 100% greater risk of death from all causes for a BMI of >29.0 kg/m2 relative to the risk of death for slender women (BMI of <19.0 kg/m2) during the course of the study.5 On the basis of an increasing awareness of the public health risks associated with excess weight, the American Heart Association has recently reclassified obesity as a “major, modifiable risk factor for coronary heart disease”.6 Second only to smoking, obesity is a major threat to the public health with ca. 300 000 deaths attributed annually in the United States.1,7 Our understanding of the prevalence of obesity in the U.S. population has come largely from the four cycles of the National Health and Nutrition Examination Surveys, conducted by the National Center for Health Statistics.8 In 1994, 55% of the population was considered overweight and 22.5% were obese. These alarmingly high levels represent a marked increase from previous years and are accompanied by a worldwide * Address correspondence to either author. A. B. Reitz: tel, 215628-5615; fax, 215-628-4985; e-mail, areitz@prius.jnj.com. C. P. Kordik: tel, 215-628-7986; fax, 215-628-4985; e-mail, ckordik@prius.jnj.com. © Copyright 1999 by the American Chemical Society

Obesity, overweight, and weight gain over adult life are main determinants of elevated hs-CRP in a cohort of Mediterranean women

Body mass index (BMI), waist circumference (WC), body weight modification, and rate of weight increase over 10 years were evaluated in relation to high-sensitive C-reactive protein (hs-CRP) to assess the association of cross-sectional or longitudinal estimates of obesity/overweight with levels of circulating CRP, a well established and standardized marker of low-grade inflammation, in relation to cardiovascular risk. This study included a subgroup of 390 menopausal women participating in a large currently ongoing epidemiological study (Progetto Atena; N=5062). At the final visit, women in the third tertile of BMI, compared with those in the first tertile, showed the following odds ratio (OR) of having high hs-CRP values: III vs I tertile OR, 3.55; 95% confidence interval, 1.94-6.49, P<0.001, adjusted for age, and metabolic syndrome. Similar results were obtained when we evaluated women in the third tertile of WC, or those in the highest group of estimated weight increase, relative to their weight at age 20 years or in the group of highest rate of weight increase over 10 years of observation (weight at the final visit-weight at the baseline visit divided by time in months between visits). The independent relations between different markers of overweight/obesity and elevated hs-CRP consistently indicate that high (above 1.5 mg l(-1), median) hs-CRP is a major biochemical counterpart of cross-sectional or longitudinal estimates of increased adipose tissue mass.

White adipose tissue genome wide-expression profiling and adipocyte metabolic functions after soy protein consumption in rats

Obesity is associated with an increase in adipose tissue mass due to an imbalance between high dietary energy intake and low physical activity; however, the type of dietary protein may contribute to its development. The aim of the present work was to study the effect of soy protein versus casein on white adipose tissue genome profiling, and the metabolic functions of adipocytes in rats with diet-induced obesity. The results showed that rats fed a Soy Protein High-Fat (Soy HF) diet gained less weight and had lower serum leptin concentration than rats fed a Casein High-Fat (Cas HF) diet, despite similar energy intake. Histological studies indicated that rats fed the Soy HF diet had significantly smaller adipocytes than those fed the Cas HF diet, and this was associated with a lower triglyceride/DNA content. Fatty acid synthesis in isolated adipocytes was reduced by the amount of fat consumed but not by the type of protein ingested. Expression of genes of fatty acid oxidation increased in adipose tissue of rats fed Soy diets; microarray analysis revealed that Soy protein consumption modified the expression of 90 genes involved in metabolic functions and inflammatory response in adipose tissue. Network analysis showed that the expression of leptin was regulated by the type of dietary protein and it was identified as a central regulator of the expression of lipid metabolism genes in adipose tissue. Thus, soy maintains the size and metabolic functions of adipose tissue through biochemical adaptations, adipokine secretion, and global changes in gene expression.

Hyperinsulinemia and ectopic fat deposition can develop in the face of hyperadiponectinemia in young obese rats

Serum adiponectin has been reported to inversely correlate with the degree of adiposity in children. However, the relative contribution of adiponectin-dependent signaling to the development of metabolic syndrome in childhood obesity is unclear. We overfed prepubertal, male Sprague–Dawley rats a high-fat diet via total enteral nutrition. Excessive caloric intake led to obesity, increased body weight and fat mass; dyslipidemia; ectopic fat deposition; and hyperinsulinemia ( P<.05). Expression of fatty acid transporter FAT/CD36 was elevated in both liver and skeletal muscle ( P<.05). Hepatic Akt phosphorylation was elevated ( P<.05) and FoxO1 protein in hepatic nuclear extracts was reduced ( P<.05) in the face of hyperinsulinemia, whereas no increase in Akt phosphorylation or decrease in nuclear FoxO1 was observed in skeletal muscle. Overfeeding increased serum adiponectin concentration from 24.6±1.9 μg/ml to 46.3±5.9 μg/ml ( P<.004), and positively correlated with increased adipose tissue mass. The expression of the inflammatory cytokine tumor necrosis factor α in the adipose tissue was unchanged. Adiponectin-mediated adenosine monophosphate (AMP) kinase phosphorylation, peroxisome proliferator-activator receptor-α expression and the expression of genes involved in fatty acid oxidation were elevated in both liver and muscle ( P<.05). These data (1) demonstrate that excessive intake of a high-fat diet in young rats results in “adiponectin-independent” increases in ectopic fat deposition and hyperinsulinemia, (2) suggest that fatty acid transport is a major mechanism underlying ectopic fat deposition, (3) demonstrate tissue-specific differences in the response of Akt-FoxO signaling to hyperinsulinemia following the development of pediatric obesity and (4) suggest age-related differences in the role of adiponectin in pathological responses associated with obesity.

The role of nonesterified fatty acids in pathogenesis of cardiovascular diseases

The paper reviews publications concerned the role of nonesterifi ed fatty acids (NEFA) in pathogenesis of cardiovascular diseases. NEFAs are four and more carbons chain length carbonic acids and they are presented in free form (nonesterifi ed) in human body. Plasma NEFAs are produced by the adipose tissue triglyceride lipolysis, another source are lipoproteins such as chylomicrons, very low density lipoproteins and intermediate density lipoproteins. Elevated NEFA concentrations in plasma are the risk factor of cardiovascular diseases and type 2 diabetes mellitus and the independent risk factor of hypertension and sudden death. NEFA plasma concentration is elevated in atherosclerosis, acute myocardial infarction, diabetes mellitus, obesity, hypertension, and often in metabolic syndrome. A probable cause of NEFAs accumulation in plasma may be overeating and low physical activity, which result in increase of adipose tissue mass, lipolysis intensifi cation and elevation of NEFAs concentration in plasma. The role of elevated plasma NEFA concentration in a number of conditions (abdominal obesity, atherogenic dyslipidemia, insulin resistance, type 2 diabetes mellitus, endothelial dysfunction, vascular infl ammation, atherosclerosis, hypertension, ischemic heart disease, rhythm disturbances, sudden death) and possible ways of their correction are discussed.

Insulin-stimulated Interaction with 14-3-3 Promotes Cytoplasmic Localization of Lipin-1 in Adipocytes

Lipin-1 is a bifunctional protein involved in lipid metabolism and adipogenesis. Lipin-1 plays a role in the biosynthesis of triacylglycerol through its phosphatidate phosphatase activity and also acts as a transcriptional co-activator of genes involved in oxidative metabolism. Lipin-1 resides in the cytoplasm and translocates to the endoplasmic reticulum membrane to catalyze the phosphatidate phosphatase reaction. It also possesses a nuclear localization signal, which is required for its translocation to the nucleus and may therefore be important for lipin-1 co-activator function. Thus, subcellular localization may be an important factor in the regulation of this protein. Here, we show that the nuclear localization signal alone is not sufficient for lipin-1 nuclear localization, and identify lipin-1 interaction with 14-3-3 as a determinant of its subcellular localization. We demonstrate that lipin-1 interacts with 14-3-3 proteins and that overexpression of 14-3-3 promotes the cytoplasmic localization of lipin-1 in 3T3-L1 adipocytes. The effect of 14-3-3 is mediated through a serine-rich domain in lipin-1. Functional mapping of the 14-3-3-interacting region within the serine-rich domain indicates redundancy and cooperativity among several sites, including five phosphorylated serine and threonine residues. Insulin stimulation of 3T3-L1 adipocytes results in increased lipin-1 phosphorylation, enhanced interaction with 14-3-3, and predominantly cytoplasmic localization. In summary, our studies suggest that insulin may modulate the cellular function of lipin-1 by regulating its subcellular localization through interactions with 14-3-3 proteins.

Rye, Oats, and Weight Management

iets high in dietary fiber and whole grain foods are associated with re-duced risk of chronic disease. One of the main risk factors of many diseases is obe-sity, the prevalence of which is increasing at a high speed throughout the world. While the clear reason for weight gain and the increase of adipose tissue mass is an imbalance between energy intake and expenditure, the current sedentary life-style and the daily tempting food offerings are both significant contributors. This has led to a large-scale research interest in the role of food properties on satiation, i.e., the feeling of fullness after a meal, and also in other regulatory mechanisms sug-gested to be involved in the control of food intake.

Obesity and Cancer

Epidemiological studies have suggested that obesity is associated with increased risk of several cancer types including colon, esophagus, breast (in postmenopausal women), endometrium, kidney, liver, gallbladder and pancreas. Suggested mechanisms include increased intake of potentially carcinogenic food ingredients along with excessive amount of calories, loss of cancer protective effects due to reduced physical activity, carcinogenic factors released from increased adipose tissue mass and "secondary" associations via "precursor" condition such as gallstones. The increased cancer risk in patients with obesity is a neglected topic which deserves more scientific attention. Because of its extreme chronicity and co-association with numerous other conditions true causality and underlying mechanisms are difficult to study. Nevertheless, a large body of literature is already available which provides concepts for future research.

Obesity and lung inflammation

The prevalence of obesity has increased dramatically worldwide, predisposing individuals to an increased risk of morbidity and mortality due to cardiovascular disease and type 2 diabetes. Less recognized is the fact that obesity may play a significant role in the pathogenesis of pulmonary diseases through mechanisms that may involve proinflammatory mediators produced in adipose tissue that contribute to a low-grade state of systemic inflammation. In animal models, inflammatory responses in the lung have been shown to influence the production of the adipocytokines, leptin and adiponectin, cytokines, acute phase proteins, and other mediators produced by adipose tissue that may participate in immune responses of the lung. An increased adipose tissue mass may also influence susceptibility to pulmonary infections, enhance pulmonary inflammation associated with environmental exposures, and exacerbate airway obstruction in preexisting lung disease. An increased understanding of the mechanisms by which obesity influences pulmonary inflammation may facilitate the development of novel therapeutic interventions for the treatment of lung disease.

Neurogenin 3-Specific Dipeptidyl Peptidase-2 Deficiency Causes Impaired Glucose Tolerance, Insulin Resistance, and Visceral Obesity

The control of glucose metabolism is a complex process, and dysregulation at any level can cause impaired glucose tolerance and insulin resistance. These two defects are well-known characteristics associated with obesity and onset of type 2 diabetes. Here we introduce the N-terminal dipeptidase, DPP2, as a novel regulator of the glucose metabolism. We generated mice with a neurogenin 3 (NGN3)-specific DPP2 knockdown (kd) to explore a possible role of DPP2 in maintaining metabolic homeostasis. These mice spontaneously developed hyperinsulinemia, glucose intolerance, and insulin resistance by 4 months of age. In addition, we observed an increase in food intake in DPP2 kd mice, which was associated with a significant increase in adipose tissue mass and enhanced liver steatosis but no difference in body weight. In accordance with these findings, the mutant mice had a higher rate of respiratory exchange than the control littermates. This phenotype was exacerbated with age and when challenged with a high-fat diet. We report, for the first time, that DPP2 enzyme activity is essential for preventing hyperinsulinemia and maintaining glucose homeostasis. Interestingly, the phenotype of NGN3-DPP2 kd mice is opposite that of DPP4 knockout mice with regard to glucose metabolism, namely the former have normal glucagon-like peptide 1 levels but present with glucose intolerance, whereas the latter have increased glucagon-like peptide 1, which is accompanied by augmented glucose tolerance.

MCP-1 (Monocyte Chemotactic Protein-1)-induced Protein, a Recently Identified Zinc Finger Protein, Induces Adipogenesis in 3T3-L1 Pre-adipocytes without Peroxisome Proliferator-activated Receptor γ

Adipogenesis is a key differentiation process relevant to obesity and associated diseases such as type 2 diabetes. This process involves temporally regulated genes controlled by a set of transcription factors, CCAAT/enhancer-binding proteins (C/EBP) beta, C/EBPdelta, and C/EBPalpha and peroxisome proliferator-activated receptor gamma (PPARgamma). Currently, PPARgamma is universally accepted as the master regulator that is necessary and sufficient to induce adipogenesis as no known factor can induce adipogenesis without PPARgamma. We present evidence that a novel zinc finger protein, MCP-1-induced protein (MCPIP), can induce adipogenesis without PPARgamma. Classical adipogenesis-inducing medium induces MCP-1 production and expression of MCPIP in 3T3-L1 cells before the induction of the C/EBP family of transcription factors and PPARgamma. Knockdown of MCPIP prevents their expression and adipogenesis as measured by expression of adipocyte markers and lipid droplet accumulation. Treatment of 3T3-L1 cells with MCP-1 or forced expression of MCPIP induces expression of C/EBPbeta, C/EBPdelta, C/EBPalpha, and PPARgamma and adipogenesis without any other inducer. Forced expression of MCPIP induces expression of the C/EBP family of transcription factors and adipogenesis in PPARgamma(-/-) mouse embryonic fibroblasts. Thus, MCPIP is a newly identified protein that can induce adipogenesis without PPARgamma.

Aliskiren reduces body‐weight gain, adiposity and plasma leptin during diet‐induced obesity

Overfeeding increases adipose tissue mass and leptin production and up-regulates the renin-angiotensin system in adipose tissue in rodents. Here, we determined the effect of chronic treatment with the renin inhibitor, aliskiren, in a model of diet-induced obesity in mice, on: (i) body weight, adipose tissue weight and plasma leptin; (ii) food intake and caloric efficiency; and (iii) angiotensin II (Ang II) in adipose tissue. Four-week-old C57BL/6J mice (n= 40) received aliskiren (50 mg.kg(-1).day(-1); 6 weeks) by means of a subcutaneous osmotic Alzet minipump. Animals were given either a low-fat (10% kcal from fat) or a high-fat diet (45% kcal from fat) during this period. Food-intake and body-weight variation were monitored during treatment. In addition to a decrease of plasma renin activity, aliskiren reduced body-weight gain, adipose pads and plasma leptin concentration, independent of the diet. In adipose tissue, local concentrations of Ang II were also reduced by aliskiren. Aliskiren limited the gain of adiposity in young mice. This effect was not due to changes in food intake or caloric efficiency and might be related to a down-regulation of the local renin-angiotensin system in adipose tissue. These effects were accompanied by reduced plasma leptin levels. As Ang II favours differentiation of adipocytes, it is possible that the decreased adipose tissue was linked to changes in adipocyte size and number.

A high-fat diet increases adiposity but maintains mitochondrial oxidative enzymes without affecting development of heart failure with pressure overload

A high-fat diet can increase adiposity, leptin secretion, and plasma fatty acid concentration. In hypertension, this scenario may accelerate cardiac hypertrophy and development of heart failure but could be protective by activating peroxisome proliferator-activated receptors and expression of mitochondrial oxidative enzymes. We assessed the effects of a high-fat diet on the development of left ventricular hypertrophy, remodeling, contractile dysfunction, and the activity of mitochondrial oxidative enzymes. Mice (n = 10-12/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either a low-fat diet (10% of energy intake as fat) or a high-fat diet (45% fat) for 6 wk. The high-fat diet increased adipose tissue mass and plasma leptin and insulin. Left ventricular mass and chamber size were unaffected by diet in sham animals. TAC increased left ventricular mass (approximately 70%) and end-systolic and end-diastolic areas (approximately 100% and approximately 45%, respectively) to the same extent in both dietary groups. The high-fat diet increased plasma free fatty acid concentration and prevented the decline in the activity of the mitochondrial enzymes medium chain acyl-coenzyme A dehydrogenase (MCAD) and citrate synthase that was observed with TAC animals on a low-fat diet. In conclusion, a high-fat diet did not worsen cardiac hypertrophy or left ventricular chamber enlargement despite increases in fat mass and insulin and leptin concentrations. Furthermore, a high-fat diet preserved MCAD and citrate synthase activities during pressure overload, suggesting that it may help maintain mitochondrial oxidative capacity in failing myocardium.

Role of adipose tissue in haemostasis, coagulation and fibrinolysis

Obesity is associated with an increased incidence of insulin resistance (IR), type 2 diabetes mellitus and cardiovascular diseases. The increased risk for cardiovascular diseases could partly be caused by a prothrombotic state that exists because of abdominal obesity. Adipose tissue induces thrombocyte activation by the production of adipose tissue-derived hormones, often called adipokines, of which some such as leptin and adiponectin have been shown to directly interfere with platelet function. Increased adipose tissue mass induces IR and systemic low-grade inflammation, also affecting platelet function. It has been demonstrated that adipose tissue directly impairs fibrinolysis by the production of plasminogen activator inhibitor-1 and possibly thrombin-activatable fibrinolysis inhibitor. Adipose tissue may contribute to enhanced coagulation by direct tissue factor production, but hypercoagulability is likely to be primarily caused by affecting hepatic synthesis of the coagulation factors fibrinogen, factor VII, factor VIII and tissue factor, by releasing free fatty acids and pro-inflammatory cytokines (tumour necrosis factor-alpha, interleukin-1beta and interleukin-6) into the portal circulation and by inducing hepatic IR. Adipose tissue dysfunction could thus play a causal role in the prothrombotic state observed in obesity, by directly and indirectly affecting haemostasis, coagulation and fibrinolysis.

Chemotactic cytokines, obesity and type 2 diabetes:in vivoandin vitroevidence for a possible causal correlation?

A strong causal link between increased adipose tissue mass and insulin resistance in tissues such as liver and skeletal muscle exists in obesity-related disorders such as type 2 diabetes. Increased adipose tissue mass in obese patients and patients with diabetes is associated with altered secretion of adipokines, which also includes chemotactic proteins. Adipose tissue releases a wide range of chemotactic proteins including many chemokines and chemerin, which are interesting targets for adipose tissue biology and for biomedical research in obesity and obesity-related diseases. This class of adipokines may be directly linked to a chronic state of low-grade inflammation and macrophage infiltration in adipose tissue, a concept intensively studied in adipose tissue biology in recent years. The inflammatory state of adipose tissue in obese patients may be the most important factor linking increased adipose tissue mass to insulin resistance. Furthermore, chemoattractant adipokines may play an important role in this situation, as many of these proteins possess biological activity beyond the recruitment of immune cells including effects on adipogenesis and glucose homeostasis in insulin-sensitive tissues. The present review provides a summary of experimental evidence of the role of adipose tissue-derived chemotactic cytokines and their function in insulin resistance in vivo and in vitro.