Adipose tissue as an endocrine organ

Adipose tissue is a highly active endocrine organ secreting a range of soluble products with both local and distant actions. These hormones have important roles in metabolism, reproduction, cardiovascular function and immunity. It is now evident that adipose endocrine function directly influences other organ systems, including the brain, liver and skeletal muscle. The endocrine function of adipose tissue is significantly regulated by nutritional status, and both are inextricably linked to the energy storage role of adipose tissue. This chapter highlights the endocrinology of adipose tissue by concentrating on functional aspects of the secreted products. The data of particular relevance to humans are highlighted, and areas in need of future research are suggested.     

LEP as a potential biomarker in prognosis of breast cancer: Systemic review and meta analyses (PRISMA)

PurposeObesity strongly affects the prognosis of various malignancies, including breast cancer. Leptin (LEP) may be associated with obesity and breast cancer prognosis. The purpose of our study was to determine the prognostic value of LEP in breast cancer.MethodWe conducted a multi-omic analysis to determine the prognostic role of LEP. Different public bioinformatics platforms (Oncomine, Gene Expression Profiling Interactive Analysis, University of California Santa Cruz Xena, bc-GenExMiner, PrognoScan database, R2-Kaplan–Meier Scanner, UALCAN, Search Tool for the Retrieval of Interacting Genes/Proteins database , and The Database for Annotation, Visualization and Integrated Discovery) were used to evaluate the roles of LEP. Clinicopathological variables were evaluated.ResultsLEP was downregulated in breast cancer tissues compared to levels in normal tissues. By co-expressed gene analysis, a positive correlation between LEP and SLC19A3 was observed. Based on the clinicopathological analysis, low LEP expression was associated with older age, higher stage, lymph node status, human epidermal growth factor receptor 2 (HER2) status, estrogen receptor (ER+) positivity, and progesterone receptor (PR+) positivity. Kaplan–Meier survival analysis showed that low LEP expression indicated a poorer prognosis. LEP is hypermethylated in breast cancer tissues in PrognoScan and R2-Kaplan Meier Scanner, and low LEP expression was correlated with poor prognosis. LEP protein–protein interactions were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins database. Gene ontology analysis results showed that cellular component is mainly associated with the endosome lumen, cytosol, and secretory granules and is upregulated. For the biological process energy reserve, metabolic processes exhibited the greatest regulation compared to the others. In molecular function, it was mainly enriched in a variety of combinations, but hormone activity showed the highest regulation.ConclusionOur study provides evidence for the prognostic role of LEP in breast cancer and as a novel potential therapeutic target in such malignancies. Nevertheless, further validation is required.     

Adipose tissue dysfunction and hypertriglyceridemia: mechanisms and management

Elevated plasma triglyceride levels, as often seen in obese subjects, are independently associated with an increased risk of cardiovascular diseases. By secreting adipokines (such as adiponectin and leptin) and other proteins (such as lipoprotein lipase and cholesteryl ester transferase protein), adipose tissue affects triglyceride metabolism. In obesity, adipocyte hypertrophy leads to many changes in adipocyte function and production of anti‐ and pro‐inflammatory cytokines. Furthermore, free fatty acids are released into the circulation contributing to insulin resistance. Adipose tissue dysfunction will eventually lead to abnormalities in lipid metabolism, such as hypertriglyceridemia (due to increased hepatic very‐low‐density lipoprotein production and decreased triglyceride hydrolysis), small dense low‐density lipoprotein particles, remnant lipoproteins and low high‐density lipoprotein cholesterol levels, all associated with a higher risk for the development of cardiovascular diseases. The clinical implications of elevated plasma triglycerides are still a matter of debate. Understanding the pathophysiology of adipose tissue dysfunction in obesity, which is becoming a pandemic condition, is essential for designing appropriate therapeutic interventions. Lifestyle changes are important to improve adipose tissue function in obese patients. Pharmacological interventions to improve adipose tissue function need further evaluation. Although statins are not very potent in reducing plasma triglycerides, they remain the mainstay of therapy for cardiovascular risk reduction in high‐risk patients.     

Adipose tissue fatty acid metabolism in insulin-resistant men

AIMS/HYPOTHESIS: Increased NEFA production and concentrations may underlie insulin resistance. We examined systemic and adipose tissue NEFA metabolism in insulin-resistant overweight men (BMI 25-35 kg/m2). METHODS: In a cohort study we examined NEFA concentrations in men in the upper quartile of fasting insulin (n = 124) and in men with fasting insulin below the median (n = 159). In a metabolic study we examined NEFA metabolism in the fasting and postprandial states, in ten insulin-resistant men and ten controls. RESULTS: In the cohort study, fasting NEFA concentrations were not significantly different between the two groups (median values: insulin-resistant men, 410 micromol/l; controls, 445 micromol/l). However, triacylglycerol concentrations differed markedly (1.84 vs 1.18 mmol/l respectively, p < 0.001). In the metabolic study, arterial NEFA concentrations again did not differ between groups, whereas triacylglycerol concentrations were significantly higher in insulin-resistant men. Systemic NEFA production and the release of NEFA from subcutaneous adipose tissue, expressed per unit of fat mass, were both reduced in insulin-resistant men compared with controls (fasting values by 32%, p = 0.02, and 44%, p = 0.04 respectively). 3-Hydroxybutyrate concentrations, an index of hepatic fat oxidation and ketogenesis, were lower (p = 0.03). CONCLUSIONS/INTERPRETATION: Adipose tissue NEFA output is not increased (per unit weight of tissue) in insulin resistance. On the contrary, it appears to be suppressed by high fasting insulin concentrations. Alterations in triacylglycerol metabolism are more marked than those in NEFA metabolism and are indicative of altered metabolic partitioning of fatty acids (decreased oxidation, increased esterification) in the liver.     

结缔组织生长因子:糖尿病肾病治疗的新靶点

结缔组织生长因子(CTGF)作为转化生长因子(TGF)-β下游的调节因子参与了糖尿病肾病(DN)的发生发展,成为DN治疗研究的新靶点.其中高血糖、糖基化终末产物(AGEs)、肾素血管紧张素醛固酮系统(RAAS)等均可刺激.肾组织产生CTGF,引起肾纤维化.因此,通过控制上述因素抑制CT-GF的表达及特异地阻断CTGF将延缓DN的发展.     

Energy balance adiposity and breast cancer – energy restriction strategies for breast cancer prevention

Excess adiposity over the pre- and postmenopausal years is linked to risk of postmenopausal breast cancer. Weight loss could potentially reduce risk amongst those with excess weight via beneficial effects on the hormonal (decreased circulating levels of oestradiol, testosterone, insulin) and secretory profiles of adipocytes (decreased production of leptin, tumour necrosis factor-alpha, interleukin 6 and increased production of adiponectin). Only modest reductions in adipose tissue are achieved and sustained with current weight loss programmes, which makes strategies to mitigate the adverse metabolic effect of adiposity a priority for cancer prevention. The adverse hormonal and secretory effects of adipose tissue are influenced substantially by acute changes in energy balance prior to changes in adiposity. Human and animal studies have shown dietary energy restriction to bring about favourable changes in circulating levels of insulin, leptin, sex hormone binding globulin, insulin-like growth factor-1, oestradiol, testosterone, reactive oxygen species, and the production and secretion of locally acting adipokines and inflammatory cytokines, that is, increased adiponectin and decreased interleukin-6. Achieving and sustaining energy restriction remains a difficult challenge. Intermittent energy restriction is a potential strategy for promoting periods of energy restriction on a long-term basis. Animal and human data suggest that intermittent energy restriction may have cancer preventative effects beyond that of chronic energy restriction and weight loss. Intermittent energy restriction may be a potential strategy for the primary prevention of breast cancer.     

From neutrophils to macrophages: differences in regional adipose tissue depots

Currently, we do not fully understand the underlying mechanisms of how regional adiposity promotes metabolic dysregulation. As adipose tissue expands, there is an increase in chronic systemic low‐grade inflammation due to greater infiltration of immune cells and production of cytokines. This chronic inflammation is thought to play a major role in the development of metabolic complications and disease such as insulin resistance and diabetes. We know that different adipose tissue depots contribute differently to the risk of metabolic disease. People who have an upper body fat distribution around the abdomen are at greater risk of disease than those who tend to store fat in their lower body around the hips and thighs. Thus, it is conceivable that adipose tissue depots contribute differently to the inflammatory milieu as a result of varied infiltration of immune cell types. In this review, we describe the role and function of major resident immune cells in the development of adipose tissue inflammation and discuss their regional differences in the context of metabolic disease risk. We find that although initial studies have found regional differences, a more comprehensive understanding of how immune cells interrupt adipose tissue homeostasis is needed.     

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-α, interleukin-1β 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.     

Adipose tissue dysfunction and the pathogenesis of metabolic syndrome

Metabolic syndrome is a growing research area. The underlying mechanisms of metabolic syndrome are still not very clear. Insulin resistance, obesity, inflammation and oxidative stress may play an important role in the pathogenesis of metabolic syndrome. The role of adipose tissue dysfunction is emphasized during the development of obesity. Adipose tissue is identified as a complex endocrine organ and its metabolic functions extend well beyond the classical actions of thermoregulation and of storage and release of fatty acids. Chronic low-grade inflammation activated by the immune system in adipose tissue is a key contributing factor to type 2 diabetes mellitus and cardiovascular diseases. Visceral obesity results in cell autonomous impairment in insulin signaling that leads to insulin resistance. Chronic inflammation in adipose tissue has gained acceptance as a lead promoter of insulin resistance in obesity. Furthermore, obesity creates oxidative stress conditions in adipose tissue that not only correlates with insulin resistance but is also causative in its development. Oxidative stress may be a mechanistic link between several components of metabolic syndrome and cardiovascular diseases, through its role in inflammation and its ability to disrupt insulin-signaling. The study around adipose tissue dysfunction will help to understand the pathogenesis of metabolic syndrome and may bring effective therapy in treatment of metabolic syndrome related diseases. Therefore, this review mainly focuses on the roles of adipose tissue dysfunction in inflammation, insulin resistance, and oxidative stress in the pathogenesis of metabolic syndrome.     

Obesity and breast cancer screening

BACKGROUND: Compared to normal weight women, women with obesity have higher mortality from breast cancer but are less often screened. OBJECTIVES: To examine the relation between mammography use and weight category and to examine the influence of race, illness burden, and other factors on this relationship. DESIGN AND SETTING: The 1998 National Health Interview Survey, a U.S. civilian population-based survey. PARTICIPANTS: Five thousand, two hundred, and seventy-seven women ages 50 to 75 years who responded to the Sample Adult and Prevention questionnaires. MEASUREMENTS: Mammogram use in the preceding 2 years. RESULTS: Among 5277 eligible women, 72% reported mammography use. The rate was 74% among white women and 70% among black women. Among white women, mammogram use was lowest in women with a body mass index (BMI) greater than 35 kg/m(2) (64% to 67%). After adjusting for sociodemographic factors, health care access, medical conditions, hospitalizations, and mobility status, higher BMI was associated with lower screening among white women, P =.02 for trend; the relative risk (RR) for screening in moderately obese white women (BMI, 35 to 40 kg/m(2)) was 0.83 (95% confidence interval [CI], 0.68 to 0.96) compared to normal weight white women. Compared to normal weight black women, mammography use was similar or higher in overweight (BMI, 25 to 30 kg/m(2); RR, 1.19; 95% CI, 1.01 to 1.32), mildly obese (BMI, 30 to 35 kg/m(2); RR, 1.22; 95% CI, 0.98 to 1.39), and moderately obese black women (RR, 1.37; 95% CI, 1.37 to 1.50) after adjustment. The P value for the race-BMI interaction was.001. Results for white and black women were unchanged after additional adjustment for psychological functioning and health habits. CONCLUSION: Among white women, those with higher BMI were less likely to undergo breast cancer screening than normal weight women. This relationship was not seen in black women. Our findings were not explained by differences in sociodemographic factors, health care access, illness burden, or health habits. More research is needed to determine the reasons for these disparities so that appropriate efforts can be made to improve screening.     

Failure of mitomycin-vindesine combination chemotherapy as salvage treatment for metastatic breast cancer

Summary Mitomycin plus vindesine have been utilized as salvage therapy in metastatic breast cancer patients refractory to first line chemotherapy. No response was observed in 15 consecutively evaluable patients; according to the Gehan test a lack of effectiveness of this regimen is suggested at least in heavily pretreated patients.     

Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer

Pancreatic cancer is one of the most aggressive and difficult cancers to treat. Despite numerous research efforts, limited success has been achieved in the therapeutic management of patients with this disease. In the current review, we focus on one component of morphogenesis signaling, Hedgehog (Hh), with the aim of developing novel, effective therapies for the treatment of pancreatic cancer. Hh signaling contributes to the induction of a malignant phenotype in pancreatic cancer and is responsible for maintaining pancreatic cancer stem cells. In addition, we propose a novel concept linking Hh signaling and tumor hypoxic conditions, and discuss the effects of Hh inhibitors in clinical trials. The Hh signaling pathway may represent a potential therapeutic target for patients with refractory pancreatic cancer.     

Obesity, adipocytokines, and insulin resistance in breast cancer

The adipocytokines are biologically active polypeptides that are produced either exclusively or substantially by the adipocytes, and act by endocrine, paracrine, and autocrine mechanisms. Most have been associated with obesity, hyperinsulinaemia, type 2 diabetes, and chronic vascular disease; in addition, six adipocytokines--vascular endothelial growth factor, hepatocyte growth factor, leptin, tumour necrosis factor-alpha, heparin-binding epidermal growth factor-like growth factor, and interleukin-6--promote angiogenesis while one, adiponectin, is inhibitory. Obesity and insulin resistance have both been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis. Angiogenesis is essential for breast cancer development and progression, and so it is plausible that obesity-related increases in adipocytokine production and a reduction in adiponectin may adversely affect breast cancer outcome by their angiogenesis-related activities. There is also experimental evidence that some adipocytokines can act directly on breast cancer cells to stimulate their proliferation and invasive capacity. Thus, adipocytokines may provide a biological mechanism by which obesity and insulin resistance are causally associated with breast cancer risk and poor prognosis. Both experimental and clinical studies are needed to develop this concept, and particularly in oestrogen-independent breast cancers where preventive and therapeutic options are limited.     

Telomerase as a new target for pancreatic cancer treatment

Over the past several years, tremendous efforts have been made to understand the role of telomerase in the development and progression of human cancers. It has become clear that: (1) telomerase activity has been found in a majority of human cancers, whereas most benign diseases and normal tissues do not express this enzyme; (2) telomerase prevents cells from undergoing replicative senescence and contributes to their unlimited proliferation; (3) telomerase can protect cells from DNA damage and subsequent apoptosis; and (4) telomerase activity may correlate with the aggressive behavior (e.g., migration and invasion) of tumor cells. Based on these findings, telomerase has been proposed as a potential target not only for cancer diagnosis but also for anticancer therapies. A growing number of telomerase inhibitors have been developed and, in some cases, have been shown to suppress the growth of tumor cells in vitro and in vivo. On the other hand, several issues still need to be addressed before these drugs are moved into clinical trials. This review focuses on the recent progress in telomerase research and its implications in pancreatic cancer treatment.     

Diet and breast cancer

Abstract. Willett WC (Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA). Diet and Breast Cancer. J Intern Med 2001; 249: 395–411.     

Central obesity and breast cancer risk: a systematic review

The specific effect of central rather than general obesity on breast cancer risk is not clear. This review examines the relationship between waist and waist–hip ratio (WHR) and risk of breast cancer in pre‐ and post‐menopausal women using all available cohort and case‐control data. The databases of the Cochrane Library, Medline, Cancer Lit and Embase were searched until October 2002. Relevant cohort and case‐control studies with separate analyses in pre‐ and/or post‐menopausal women were included. Random effects meta‐analyses were carried out, subgrouped by pre‐ or post‐menopausal status and cohort or case‐control design. Sensitivity analyses were also performed. Five cohort studies with 72 1705 person years of observation (453 pre‐menopausal and 2684 post‐menopausal cases), and three case‐control studies comprising 276 pre‐menopausal cases with 758 pre‐menopausal controls and 390 post‐menopausal cases with 1071 post‐menopausal controls were included. Pooled results from cohort studies using the most adjusted data [but without adjustment for weight or body mass index (BMI)] suggest a 39% lower risk of breast cancer in post‐menopausal women with the smallest waist (compared with the largest) and a 24% lower risk in women with the smallest WHR. In pre‐menopausal women, however, pooled results suggest that measurement of waist or WHR have little effect on risk of breast cancer. Adjustment for BMI abolished the relationship between waist or WHR and risk of post‐menopausal breast cancer, but introduced such a relationship amongst pre‐menopausal women. The relationship between a smaller measurement of waist or WHR and lower risk of post‐menopausal breast cancer appears to result from the associated correlation with BMI. Amongst pre‐menopausal women, central (not general) obesity may be specifically associated with an increased risk of breast cancer.     

Peripheral targets in obesity treatment: a comprehensive update

Obesity is a major epidemic of our time and is associated with diseases such as metabolic syndrome, type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Although weight loss drugs, when accompanied by diet and exercise, could be a very helpful medical tool in treating obese or overweight patients, their usefulness has been questioned due to the complexity of this type of medication, which regards a plethora of issues such as efficacy and safety of the drug and also risks and benefits among different patients. In general, obesity drugs that target peripheral pathophysiological mechanisms can be divided into two main categories. The first category includes anti‐obesity agents able to reduce or limit energy absorption, such as pancreatic lipase and microsomal triglyceride transfer protein inhibitors. The second category consists of a heterogeneous group of compounds aiming to decrease fat mass by increasing energy expenditure or by redistributing adipose tissue. Angiogenesis inhibitors, beta‐3 receptor agonists, sirtuin‐I activators, diazoxide and other molecules belong to this group. The glucagon‐like peptide‐1 receptor agonists consist the third category of peripheral anti‐obesity agents discussed therein. This review aims to provide a general overview of the molecules and substances that are already or could potentially be used as peripheral anti‐obesity drugs, the molecular mechanisms by which they act, as well as their current stage of development, production and/or availability.     

Dissecting the Contributing Role of Divergent Adipose Tissue to Multidimensional Frailty in Cirrhosis

Background and AimsEmerging evidence has demonstrated that abnormal body composition may potentiate the development of frailty, whereas little work focuses on the role of divergent adipose tissue. Therefore, we aimed to determine the potential contribution of adipose tissue distribution to multidimensional frailty in decompensated cirrhosis.MethodsWe conducted a retrospective cohort study. Divergent adipose tissues were assessed by computed tomography-derived subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI) and total adipose tissue index (TATI), respectively. Frailty was identified by our validated self-reported Frailty Index. Multiple binary logistic models incorporating different covariates were established to assess the relationship between adipose tissue distribution and frailty.ResultsThe study cohort comprised 245 cirrhotic patients with 45.3% being male. The median Frailty Index, body mass index (BMI) and model for end-stage liver disease (MELD) score were 0.11, 24.3 kg/m² and 8.9 points, respectively. In both men and women, patients who were frail exhibited lower levels of SATI in comparison with nonfrail patients. SATI inversely correlated with Frailty Index in the entire cohort (r_s=−0.1361, p=0.0332). Furthermore, SATI or TATI was independently associated with frail phenotype in several multiple logistic regression models adjusting for age, BMI, presence of ascites, sodium, Child-Pugh class or MELD score in isolation.ConclusionsIn the context of decompensated cirrhosis, low SATI and concomitant TATI were associated with higher risk of being frail. These findings highlight the importance to further apply tissue-specific tools of body composition in place of crude metric like BMI.     

Angiogenesis as a therapeutic target in arthritis: learning the lessons of the colorectal cancer experience

The idea of a therapeutic modality aimed at ‘starving’ a tissue of blood vessels, and consequentially of oxygen and nutrients, was born from the concept that blood vessel formation (angiogenesis) is central to the progression and maintenance of diseases which involve tissue expansion/invasion. In the first instance, solid malignancies were the target for anti-angiogenic treatments, with colorectal cancer being the first disease for which an angiogenesis inhibitor—anti-vascular endothelial growth factor antibody bevacizumab—was approved in 2004. Our understanding of the pathogenesis of rheumatoid arthritis (RA) has lead to many parallels being drawn between this chronic inflammatory disease and solid tumours, in that both involve tissue expansion, invasion, expression of cytokines and growth factors and areas of hypoxia/hypoperfusion. As a result, angiogenesis blockade has been touted as a possible treatment for RA. The lessons learnt during the progression of eventually successful therapies such as bevacizumab should undoubtedly guide us in the future development of comparable treatments for RA.