Angiotensin II regulates adipocyte apolipoprotein E expression

CONTEXT: Obesity is increasing in prevalence and it is important to understand factors that regulate adipose tissue lipid metabolism. Recently, endogenous expression of apolipoprotein E (apoE) in adipose tissue has been shown to have important effects on adipocyte lipid flux and gene expression. Adipose tissue is also a physiological target of angiotensin II (AII). OBJECTIVE: The aim of the current study was to evaluate a potential regulatory effect for AII on adipose tissue apoE expression. RESULTS: Infusion of AII into mice for 3 d significantly reduced apoE expression in adipocytes from freshly isolated adipose tissue. ApoE expression was unchanged by the AII infusion in the stromovascular fraction. In isolated human adipocytes, treatment with AII significantly reduced cellular and secreted apoprotein E (by 20-60%). Suppression of apoE expression was observed in sc adipocytes obtained from nonobese (body mass index < 30 kg/m(2)) donors, and in sc and omental adipocytes obtained from obese (body mass index > 30 kg/m(2)) donors. Evaluation of the effect of AII in matched sets of sc and omental adipocytes from three separate donors showed lower overall apoE expression in omental adipocytes in two of the donors, and a concordant down-regulation of apoE expression in sc and omental adipocytes from all three subjects. The specific AT(1) receptor blocker, valsartan, eliminated the effect of AII on adipocyte apoE expression. CONCLUSION: Both apoE and components of the renin-angiotensin system are expressed in adipose tissue, and each has important effects on adipocyte lipid metabolism and gene expression. The regulatory interaction we have identified between these two pathways has important implications for a complete understanding of adipose tissue lipid homeostasis.     

Adipose tissue and adipocyte dysregulation

Obesity-associated insulin resistance is a complex disorder involving a number of candidate molecules, pathways and transduction systems possessing potential causal actions. Inflammation in adipose tissue (AT) is one mechanism proposed to explain the development of insulin resistance, while identification of factors that lead to or cause AT dysfunction when it reaches its limit of expansion represents an important challenge. Pathological expansion of AT is characterized by changes in its blood flow, and the presence of enlarged and dysfunctional adipocytes that begin an inflammatory campaign of altered adipokine and cytokine secretions. Adipocyte senescence, necrosis and death are associated with increased immune cell and macrophage infiltration of AT in obesity. This can boost inflammation and reinforce fat cell dysfunction and death. In addition, pathological fat mass expansion is also related to limited recruitment of fat cell progenitors able to proliferate and differentiate into healthy small fat cells to compensate for cell death and preserve adipocyte numbers. Limiting vascular development and enhancing fibrotic processes worsen inflammation towards chronic irreversibility. The AT expandability hypothesis states that failure of AT expansion is one of the key factors linking positive energy balance and cardiometabolic risks, not obesity per se. Besides the usual treatment of obesity based on behavioral approaches (specific dietary/nutritional approaches together with increased physical activity), a number of questions remain concerning the possible recovery of metabolic health after inflammation-preventing interventions.     

Adipose tissue compartments and the kinetics of very-low-density lipoprotein apolipoprotein B-100 in non-obese men

We examined the association between the kinetics of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB) and intraperitoneal, retroperitoneal, subcutaneous abdominal, and total adipose tissue masses (IPATM, RPATM, SAATM, TATM, respectively) in 14 healthy, non-obese men (body mass index [BMI] < 30 kg/m(2)). Hepatic secretion of VLDL-apoB was measured using an intravenous infusion of 1-[(13)C]-leucine. Isotopic enrichment of VLDL-apoB was measured using gas chromatography-mass-spectrometry and a multicompartmental model (Simulation, Analysis, and Modeling Software [SAAM II]) used to estimate the fractional catabolic rate (FCR) of VLDL-apoB. IPATM, RPATM, and SAATM (kg) were quantified between T11 and S1 using magnetic resonance imaging (MRI); TATM (kg) was determined using bioelectrical impedance. Insulin resistance was estimated by homeostasis model assessment (HOMA) score. In stepwise regression analysis, IPATM was the best predictor of the hepatic secretion of VLDL-apoB (r =.58, P <.05) and TATM the best predictor of the FCR of VLDL-apoB (r = -.56, P <.05). After adjusting for TATM, IPATM explained 59% of the variance in VLDL apoB secretion (P =.03). None of the fat compartments were significantly associated with VLDL-apoB kinetics after adjusting for HOMA score. The findings suggest that in non-obese men the quantity of both intraperitoneal and total fat are significant predictors for the kinetics of VLDL-apoB, which in turn, determines plasma triglyceride concentrations; these associations may, in part, be mediated by variations in insulin resistance, particularly among individual who are not ostensibly obese. Our preliminary results need confirmation in a larger study.     

Adipose tissue expression of IL-18 and HIV-associated lipodystrophy

IL-18 is an inducer of apoptosis/tissue injury. IL-18 messenger RNA expression was examined in adipose tissue (AT) obtained from HIV patients with lipodystrophy, without lipodystrophy and healthy controls. IL-18 mRNA was expressed in AT at increased levels in lipodystrophy-positive compared with lipodystrophy-negative patients and healthy controls. Higher levels of IL-18 mRNA were found in femoral-gluteal AT compared with abdominal AT, and correlated with limb fat loss. These findings suggest that IL-18 is linked to HIV-associated lipodystrophy.     

Adipose tissue hormones

Adipose tissue had been traditionally considered a passive energy storage site without direct influence on energy homeostasis regulation. This view has been principally changed during early nineties by the discovery of hormonal production of adipose tissue. At present, the list of hormonally active substances of adipose tissue includes more than one hundred factors with paracrine or endocrine activity that play an important role in metabolic, food intake a inflammatory regulations and many other processes. Only minority of adipose tissue-derived hormones is produced exclusively in fat. Most of these factors is primarily put out by other tissues and organs. Adipose tissue-derived hormones are produced not only by adipocytes but also by preadipocytes, immunocompetent and endothelial cells and other cell types residing in fat. This paper summarizes current knowledge about endocrine function of adipose tissue with special respect to its changes in obesity. It also describes its possible role in the ethiopathogenesis of insulin resistance, atherosclerosis and other obesity-related pathologies.     

Adipose tissue hormones

It is now widely accepted that white adipose tissue (WAT) secretes a number of peptide hormones, including leptin, several cytokines, adipsin and acylation-stimulating protein (ASP), angiotensinogen, plasminogen activator inhibitor-1 (PAI-1), adiponectin, resistin etc., and also produces steroids hormones. This newly discovered secretory function has shifted our view of WAT, which is no longer considered only an energy storage tissue but a major endocrine organ, at the heart of a complex network influencing energy homeostasis, glucose and lipid metabolism, vascular homeostasis, immune response and even reproduction. Virtually all known adipose secreted proteins are dysregulated when the WAT mass is markedly altered, either increased in the obese state or decreased in lipoatrophy. This strongly implicates adipose-secreted products in the ethiopathology and/or complications of both obesity and cachexia. This review discusses the physiological relevance of adipose secretion by focusing on protein and steroid hormones. Regulation of WAT secretion by the major regulatory factors impinging on the adipocytes, i.e. insulin, glucocorticoids, catecholamines and thiazolidinediones (TZD) will be addressed. The rationale for therapeutic strategies aimed at compensating adverse effects resulting from overproduction or lack of a specific adipose secretory product will be discussed.     

Adipose tissue and cytokines

Adipose tissue is not simply a storage depot for excess energy intake, it is also able to produce and release several substances with local (autocrine) and systemic (endocrine) actions. An up-to-date review of our knowledge in this area is given here. Several of the compounds deriving from adipose tissue have been shown to play a role in obesity-related health complications. The production of cytokines, such as Tumor Necrosis Factor-alpha (TNF-alpha), IL-6, and leptin, is implicated in the development of several disorders. Insulin resistance is one of the most clinically significant.     

Fat depot-specific expression of adiponectin is impaired in Zucker fatty rats

Adiposity, particularly increased intra-abdominal fat, is a predisposing factor for the development of insulin resistance in obesity and type 2 diabetes. Visceral fat seems to differ from subcutaneous adipose tissue in adipocytokine production. This fat depot-related difference has been viewed as an important mechanism by which adipose tissue exerts its paracrine/autocrine effects on peripheral tissue in modulating insulin sensitivity. We have studied the relative expression of adiponectin in visceral versus subcutaneous fat in Zucker fatty versus lean rats. Visceral fat, as opposed to subcutaneous fat, exhibited relatively higher levels of adiponectin production in lean animals. However, in Zucker fatty rats, adiponectin expression in visceral fat was suppressed to basal levels, which correlated with significantly reduced plasma adiponectin concentrations and increased insulin resistance. These results suggest that an impaired depot-specific expression of adiponectin is a contributing factor for the development of insulin resistance in Zucker fatty rats.     

Adipose tissue metabolism and CD11b expression on monocytes in obese hypertensives

At a given degree of adiposity, metabolic and cardiovascular risk varies markedly between individuals. Animal studies suggest that differentially expressed systemic activation of monocytes contributes to the obesity-associated risk variability. We tested the hypothesis that systemic monocyte activation is associated with changes in adipose tissue and skeletal muscle metabolism. In 17 obese hypertensive patients, we assessed CD11b expression on circulating monocytes, gene expression in adipose tissue biopsies, and obtained blood samples and adipose tissue and skeletal muscle microdialysis samples in the fasted state and during a glucose load. Patients were stratified into groups with higher and lower CD11b expression on monocytes. Expression of the macrophage marker CD68 was increased markedly in adipose tissue of subjects with higher CD11b expression. Although no differences in systemic insulin sensitivity were found between both groups, patients with higher peripheral CD11b expression showed a markedly augmented increase in dialysate glucose in adipose tissue during oral glucose tolerance testing and increased adipose tissue lipolysis as well. Our data demonstrate that human monocyte activation is associated with tissue-specific changes in glucose and lipid metabolism. These findings may be explained in part by monocyte/macrophage infiltration of adipose tissue, which appears to interfere with insulin responsiveness.     

Adipose tissue 11beta-hydroxysteroid dehydrogenase type 1 expression in obesity and Cushing's syndrome

OBJECTIVE: To evaluate the expression of 11beta-hydrxysteroid dehydrogenase type 1 (11beta-HSD1) in omental adipose tissue of patients with Cushing's syndrome and simple obesity, compared with normal weight controls. DESIGN AND METHODS: We have performed a case-control study and studied omental adipose tissue from a total of 24 subjects (eight obese subjects, ten patients with Cushing's syndrome due to adrenal adenoma, and six normal weight controls). Body mass index, blood pressure, plasma glucose, plasma insulin, plasma cortisol, urinary free cortisol and post dexamethasone plasma cortisol were measured with standard methods. 11beta-HSD1 mRNA and protein expression were evaluated in real-time PCR and western blot analysis respectively. RESULTS: 11beta-HSD1 mRNA was 13-fold higher in obese subjects compared with controls (P=0.001). No differences were found between Cushing's patients and controls. Western blot analysis supported the mRNA expression results. CONCLUSIONS: Our data show the involvement of 11beta-HSD1 enzyme invisceral obesity, which is more evident in severely obese patients than in Cushing's syndrome patients. The lack of increase of 11beta-HSD1 expression in Cushing's syndrome could suggest downregulation of the enzyme as a result of long-term overstimulation.     

Adipose tissue inflammation in glucose metabolism

Obesity is now recognised as a low grade, chronic inflammatory disease that is linked to a myriad of disorders including cancer, cardiovascular disease and type 2 diabetes (T2D). With respect to T2D, work in the last decade has revealed that cells of the immune system are recruited to white adipose tissue beds (WAT), where they can secrete cytokines to modulate metabolism within WAT. As many of these cytokines are known to impair insulin action, blocking the recruitment of immune cells has been purported to have therapeutic utility for the treatment of obesity-induced T2D. As inflammation is critical for host defence, and energy consuming in nature, the blockade of inflammatory processes may, however, result in unwanted complications. In this review, we outline the immunological changes that occur within the WAT with respect to systemic glucose homeostasis. In particular, we focus on the role of major immune cell types in regulating nutrient homeostasis and potential initiating stimuli for WAT inflammation.