Adipose Tissue Growth Research Articles

Intrauterine Growth Restriction and the Sex Specific Programming of Leptin and Peroxisome Proliferator-Activated Receptor γ (PPARγ) mRNA Expression in Visceral Fat in the Lamb

Being born small is associated with an increased risk of visceral obesity and insulin resistance in adult life. We have investigated the effect of IUGR on adipogenic and lipogenic gene expression in visceral fat in the lamb at 3 wk of age. Perirenal fat mass, but not adipocyte size was greater in females than males, independent of birth weight. Plasma insulin concentrations during the first 24 h after birth predicted the size of the adipocytes and expression of adiponectin in visceral adipose tissue in both males and females. In females, plasma nonesterified fatty acids (NEFA) concentrations during the first 24 h after birth were directly related to peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA expression in the perirenal fat depot at 3 wk of age. In the males, in contrast to the females, PPARgamma and leptin expression in perirenal visceral fat were significantly lower in IUGR compared with control lambs. Thus, the early nutritional environment programs adipocyte growth and gene expression in visceral adipose tissue. The differential effect of sex and IUGR on PPARgamma and leptin expression in visceral fat may be important in the subsequent development of visceral obesity and the insulin resistant phenotype in later life.

Relatively lower body mass index is associated with an excess of severe truncal asymmetry in healthy adolescents: Do white adipose tissue, leptin, hypothalamus and sympathetic nervous system influence truncal growth asymmetry?

BackgroundIn healthy adolescents normal back shape asymmetry, here termed truncal asymmetry (TA), is evaluated by higher and lower subsets of BMI. The study was initiated after research on girls with adolescent idiopathic scoliosis (AIS) showed that higher and lower BMI subsets discriminated patterns of skeletal maturation and asymmetry unexplained by existing theories of pathogenesis leading to a new interpretation which has therapeutic implications (double neuro-osseous theory).Methods5953 adolescents age 11–17 years (boys 2939, girls 3014) were examined in a school screening program in two standard positions, standing forward bending (FB) and sitting FB. The sitting FB position is thought to reveal intrinsic TA free from back humps induced by any leg-length inequality. TA was measured in both positions using a Pruijs scoliometer as angle of trunk inclinations (ATIs) across the back at each of three spinal regions, thoracic, thoracolumbar and lumbar. Abnormality of ATIs was defined as being outside 2 standard deviations for each age group, gender, position and spinal region, and termed severe TA.ResultsIn the sitting FB position after correcting for age,relatively lower BMIs are statistically associated with a greater number of severe TAs than with relatively higher BMIs in both girls (thoracolumbar region) and boys (thoracolumbar and lumbar regions).The relative frequency of severe TAs is significantly higher in girls than boys for each of the right thoracic (56.76%) and thoracolumbar (58.82%) regions (p = 0.006, 0.006, respectively). After correcting for age, smaller BMIs are associated with more severe TAs in boys and girls.DiscussionBMI is a surrogate measure for body fat and circulating leptin levels. The finding that girls with relatively lower BMI have significantly later menarche, and a significant excess of TAs, suggests a relation to energy homeostasis through the hypothalamus. The hypothesis we suggest for the pathogenesis of severe TA in girls and boys has the same mechanism as that proposed recently for AIS girls, namely: severe TAs are initiated by a genetically-determined selectively increased hypothalamic sensitivity (up-regulation, i.e. increased sensitivity) to leptin with asymmetry as an adverse response to stress (hormesis), mediated bilaterally mainly to the growing trunk via the sympathetic nervous system (leptin-hypothalamic-sympathetic nervous system (LHS) concept). The putative autonomic dysfunction is thought to be increased by any lower circulating leptin levels associated with relatively lower BMIs. Sympathetic nervous system activation with asymmetry leads to asymmetries in ribs and/or vertebrae producing severe TA when beyond the capacity of postural mechanisms of the somatic nervous system to control the shape distortion of the trunk. A test of this hypothesis testing skin sympathetic responses, as in the Rett syndrome, is suggested.

Session on ‘Obesity’ Adipose tissue development, nutrition in early life and its impact on later obesity

It is now apparent that one key factor determining the current obesity epidemic within the developed world is the extent to which adipose tissue growth and function can be reset in early life. Adipose tissue can be either brown or white, with brown fat being characterised as possessing a unique uncoupling protein (uncoupling protein 1) that enables the rapid generation of heat by non-shivering thermogenesis. In large mammals this function is recruited at approximately the time of birth, after which brown fat is lost, not normally reappearing again throughout the life cycle. The origin and developmental regulation of brown fat in large mammals is therefore very different from that of small mammals in which brown fat is retained throughout the life cycle and may have the same origin as muscle cells. In contrast, white adipose tissue increases in mass after birth, paralleled by a rise in glucocorticoid action and macrophage accumulation. This process can be reset by changes in the maternal nutritional environment, with the magnitude of response being further determined by the timing at which such a challenge is imposed. Importantly, the long-term response within white adipocytes can occur in the absence of any change in total fat mass. The present review therefore emphasises the need to further understand the developmental regulation of the function of fat through the life cycle in order to optimise appropriate and sustainable intervention strategies necessary not only to prevent obesity in the first place but also to reverse excess fat mass in obese individuals.

Mammary adipose tissue and cancer cell growth: The role of adipose tissue in the tumor microenvironment

e22009 Background: Worldwide, the prevalence of obesity is rapidly increasing, correlating with a direct increase in cancer rates1. Adipose tissue is considered an important endocrine organ producing several important hormones and cytokines including leptin and adiponectin. Mechanisms for the role of obesity in cancer states includes the excess or unregulated secretion of adipocytokines from adipose tissue, and potentially the metabolic syndrome (a cluster of co-morbidities linked to metabolic dysregulation). Mammary adipose tissue is proposed to play a vital role in the microenvironment of normal and tumour states within the breast2. Breast adipose tissue is a good candidate to investigate effects of obesity and metabolic disturbances on cancer states. Methods: Peritumoural (PT) adipose tissue adjacent to the tumour and distal adipose tissue (D) within the breast was sampled in 10 patients. The tissue was processed and cultured for 72hrs in serum free minimal cytokine media. A-MB-231 and MCF-7 breast cancer cell lines were then cultured with this adipocyte conditioned media (ACM) and cell proliferation response was then measured using BrDU assays. The adipocytokine profile at the mRNA and protein level was measured in ACM and adipose tissue for comparative differences using RT-PCR, ELISA and Cytokine Profiler technology. Results: ACM from both sites promoted tumour cell survival. There was however, a differential cell proliferation response noted between the peritumoural (PT) ACM and that from the distant (D) ACM. Pro-inflammatory mediators (VEGF, TNF-α, EGF) were also demonstrated a trend to be differentially expressed between the 2 sites. Conclusions: Proliferation of breast cancer cell lines occurs in response to ACM, with differential effects seen between peritumoural ACM and distant ACM. This may be mediated through increased pro-inflammatory or pro- mitogenic adipocytokine production in adipose tissue surrounding tumour. Further analysis will determine what role obesity and the metabolic syndrome plays in the results noted. No significant financial relationships to disclose.

Curcumin Inhibits Adipogenesis in 3T3-L1 Adipocytes and Angiogenesis and Obesity in C57/BL Mice1–3

Angiogenesis is necessary for the growth of adipose tissue. Dietary polyphenols may suppress growth of adipose tissue through their antiangiogenic activity and by modulating adipocyte metabolism. We investigated the effect of curcumin, the major polyphenol in turmeric spice, on angiogenesis, adipogenesis, differentiation, apoptosis, and gene expression involved in lipid and energy metabolism in 3T3-L1 adipocyte in cell culture systems and on body weight gain and adiposity in mice fed a high-fat diet (22%) supplemented with 500 mg curcumin/kg diet for 12 wk. Curcumin (5–20 μmol/L) suppressed 3T3-L1 differentiation, caused apoptosis, and inhibited adipokine-induced angiogenesis of human umbilical vein endothelial cells. Supplementing the high-fat diet of mice with curcumin did not affect food intake but reduced body weight gain, adiposity, and microvessel density in adipose tissue, which coincided with reduced expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2. Curcumin increased 5′AMP-activated protein kinase phosphorylation, reduced glycerol-3-phosphate acyl transferase-1, and increased carnitine palmitoyltransferase-1 expression, which led to increased oxidation and decreased fatty acid esterification. The in vivo effect of curcumin on the expression of these enzymes was also confirmed by real-time RT-PCR in subcutaneous adipose tissue. In addition, curcumin significantly lowered serum cholesterol and expression of PPARγ and CCAAT/enhancer binding protein α, 2 key transcription factors in adipogenesis and lipogenesis. The curcumin suppression of angiogenesis in adipose tissue together with its effect on lipid metabolism in adipocytes may contribute to lower body fat and body weight gain. Our findings suggest that dietary curcumin may have a potential benefit in preventing obesity.

Downregulation of protein tyrosine phosphatase PTP-BL represses adipogenesis

The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway is a major regulator of adipose tissue growth and differentiation. We recently demonstrated that human protein tyrosine phosphatase (PTP) L1, a large cytoplasmic phosphatase also known as PTP-BAS/PTPN13/PTP-1E, is a negative regulator of IGF-1R/IRS-1/Akt pathway in breast cancer cells. This triggered us to investigate the potential role of PTPL1 in adipogenesis. To evaluate the implication of PTP-BL, the mouse orthologue of PTPL1, in adipose tissue biology, we analyzed PTP-BL mRNA expression in adipose tissue in vivo and during proliferation and differentiation of 3T3-L1 pre-adipocytes. To elucidate the role of PTP-BL and of its catalytic activity during adipogenesis we use siRNA techniques in 3T3-L1 pre-adipocytes, and mouse embryonic fibroblasts that lack wildtype PTP-BL and instead express a variant without the PTP domain (ΔP/ΔP MEFs). Here we show that PTP-BL is strongly expressed in white adipose tissue and that PTP-BL transcript and protein levels increase during proliferation and differentiation of 3T3-L1 pre-adipocytes. Strikingly, knockdown of PTP-BL expression in 3T3-L1 adipocytes caused a dramatic decrease in adipogenic gene expression levels (PPARγ, aP2) and lipid accumulation but did not interfere with the insulin/Akt pathway. ΔP/ΔP MEFs differentiate into the adipogenic lineage as efficiently as wildtype MEFs. However, when expression of either PTP-BL or PTP-BLΔP was inhibited a dramatic reduction in the number of MEF-derived adipocytes was observed. These findings demonstrate a key role for PTP-BL in 3T3-L1 and MEF-derived adipocyte differentiation that is independent of its enzymatic activity.

Hypertrophy and/or Hyperplasia: Dynamics of Adipose Tissue Growth

Adipose tissue grows by two mechanisms: hyperplasia (cell number increase) and hypertrophy (cell size increase). Genetics and diet affect the relative contributions of these two mechanisms to the growth of adipose tissue in obesity. In this study, the size distributions of epididymal adipose cells from two mouse strains, obesity-resistant FVB/N and obesity-prone C57BL/6, were measured after 2, 4, and 12 weeks under regular and high-fat feeding conditions. The total cell number in the epididymal fat pad was estimated from the fat pad mass and the normalized cell-size distribution. The cell number and volume-weighted mean cell size increase as a function of fat pad mass. To address adipose tissue growth precisely, we developed a mathematical model describing the evolution of the adipose cell-size distributions as a function of the increasing fat pad mass, instead of the increasing chronological time. Our model describes the recruitment of new adipose cells and their subsequent development in different strains, and with different diet regimens, with common mechanisms, but with diet- and genetics-dependent model parameters. Compared to the FVB/N strain, the C57BL/6 strain has greater recruitment of small adipose cells. Hyperplasia is enhanced by high-fat diet in a strain-dependent way, suggesting a synergistic interaction between genetics and diet. Moreover, high-fat feeding increases the rate of adipose cell size growth, independent of strain, reflecting the increase in calories requiring storage. Additionally, high-fat diet leads to a dramatic spreading of the size distribution of adipose cells in both strains; this implies an increase in size fluctuations of adipose cells through lipid turnover.

The anti-angiogenic herbal composition Ob-X inhibits adipose tissue growth in obese mice

Abstract Objective: The growth and development of adipose tissue are thought to be associated with angiogenesis and extracellular matrix remodeling. Since the composition of the herbal extract called Ob-X has been shown to have both anti-angiogenic and matrix metalloproteinase (MMP)-inhibiting activities, we hypothesized that growth of adipose tissue can be regulated by Ob-X. Materials and Methods: The effects of Ob-X on angiogenesis and extracellular matrix remodeling were measured using in vitro and ex vivo assays. The effects of Ob-X on adipose tissue growth were investigated with nutritionally obese mice. Results: Ob-X inhibited angiogenesis in a dose-dependent manner in the human umbilical vein endothelial cell (HUVEC) tube formation assay in vitro and the rat aortic ring assay ex vivo. Ob-X also suppressed MMP activity in vitro. Administration of Ob-X to high fat diet-induced obese mice produced significant reductions in body weight gain and adipose tissue mass, compared to controls. The mass of both subcutaneous (SC) and visceral (VSC) fat was reduced in Ob-X-treated mice. The size of adipocytes in SC and VSC adipose tissues was also significantly reduced in Ob-X-treated mice. Ob-X treatment decreased the blood vessel density and MMP activity in VSC adipose tissues of nutritionally obese mice. Ob-X reduced mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas it increased mRNA levels of angiogenesis inhibitors (TSP-1 and TIMP-2) in SC and VSC adipose tissues of nutritionally obese mice. Conclusion: Ob-X, which has anti-angiogenic and MMP-inhibitory activities, reduces adipose tissue mass in nutritionally induced obese mice, providing evidence that adipose tissue growth and development may be prevented by inhibiting angiogenesis. In addition, these data suggest that regulation of adipose tissue growth by inhibiting angiogenesis may alter the expression of genes involved in angiogenesis and the MMP system.

Effects of Growth Hormone on Glucose, Lipid, and Protein Metabolism in Human Subjects

In evolutionary terms, GH and intracellular STAT 5 signaling is a very old regulatory system. Whereas insulin dominates periprandially, GH may be viewed as the primary anabolic hormone during stress and fasting. GH exerts anabolic effects directly and through stimulation of IGF-I, insulin, and free fatty acids (FFA). When subjects are well nourished, the GH-induced stimulation of IGF-I and insulin is important for anabolic storage and growth of lean body mass (LBM), adipose tissue, and glycogen reserves. During fasting and other catabolic states, GH predominantly stimulates the release and oxidation of FFA, which leads to decreased glucose and protein oxidation and preservation of LBM and glycogen stores. The most prominent metabolic effect of GH is a marked increase in lipolysis and FFA levels. In the basal state, the effects of GH on protein metabolism are modest and include increased protein synthesis and decreased breakdown at the whole body level and in muscle together with decreased amino acid degradation/oxidation and decreased hepatic urea formation. During fasting and stress, the effects of GH on protein metabolism become more pronounced; lack of GH during fasting increases protein loss and urea production rates by approximately 50%, with a similar increase in muscle protein breakdown. GH is a counterregulatory hormone that antagonizes the hepatic and peripheral effects of insulin on glucose metabolism via mechanisms involving the concomitant increase in FFA flux and uptake. This ability of GH to induce insulin resistance is significant for the defense against hypoglycemia, for the development of "stress" diabetes during fasting and inflammatory illness, and perhaps for the "Dawn" phenomenon (the increase in insulin requirements in the early morning hours). Adult patients with GH deficiency are insulin resistant-probably related to increased adiposity, reduced LBM, and impaired physical performance-which temporarily worsens when GH treatment is initiated. Conversely, despite increased LBM and decreased fat mass, patients with acromegaly are consistently insulin resistant and become more sensitive after appropriate treatment.

The Role of the Neuropeptide Y2 Receptor in Liporemodeling: Neuropeptide Y–Mediated Adipogenesis and Adipose Graft Maintenance

Neuropeptide Y is a signaling molecule that was recently found to stimulate adipose tissue growth in vitro by means of a peripherally acting mechanism involving the neuropeptide Y2 receptor found on adipocytes and endothelial cells. This study aims to evaluate the translational applications of a neuropeptide Y2 receptor agonist for autologous fat grafting in plastic surgery. Murine and primate animal models were used to investigate the proliferative effects of neuropeptide Y on adipose tissue. The effect of applying neuropeptide Y to subcutaneous tissues in mice and monkeys was assessed by magnetic resonance imaging, histology, and immunohistochemistry. The effect of neuropeptide Y on human fat xenograft survival and vascularity in athymic mice was measured by ultrasonography and immunohistochemistry. Six animals per group were used in murine experiments, and two animals were used in the pilot primate study. Neuropeptide Y stimulated growth of adipose tissues when applied subcutaneously in mice and monkeys, and increased human fat xenograft survival and vascularity in athymic mice at 3 months. These data provide in vivo evidence for a critical role for neuropeptide Y/neuropeptide Y2 receptor interactions in adipogenesis, and suggest neuropeptide Y2 receptor as a potential target for agonist compounds that can be used to enhance fat graft survival or stimulate de novo adipogenesis.

Cellular and molecular effects ofn−3 polyunsaturated fatty acids on adipose tissue biology and metabolism

Adipose tissue and its secreted products, adipokines, have a major role in the development of obesity-associated metabolic derangements including Type 2 diabetes. Conversely, obesity and its metabolic sequelae may be counteracted by modulating metabolism and secretory functions of adipose tissue. LC-PUFAs (long-chain polyunsaturated fatty acids) of the n-3 series, namely DHA (docosahexaenoic acid; C(22:6n-3)) and EPA (eicosapentaenoic acid; C(20:5n-3)), exert numerous beneficial effects, such as improvements in lipid metabolism and prevention of obesity and diabetes, which partially result from the metabolic action of n-3 LC-PUFAs in adipose tissue. Recent studies highlight the importance of mitochondria in adipose tissue for the maintenance of systemic insulin sensitivity. For instance, both n-3 LC-PUFAs and the antidiabetic drugs TZDs (thiazolidinediones) induce mitochondrial biogenesis and beta-oxidation. The activation of this 'metabolic switch' in adipocytes leads to a decrease in adiposity. Both n-3 LC-PUFAs and TZDs ameliorate a low-grade inflammation of adipose tissue associated with obesity and induce changes in the pattern of secreted adipokines, resulting in improved systemic insulin sensitivity. In contrast with TZDs, which act as agonists of PPARgamma (peroxisome-proliferator-activated receptor-gamma) and promote differentiation of adipocytes and adipose tissue growth, n-3 LC-PUFAs affect fat cells by different mechanisms, including the transcription factors PPARalpha and PPARdelta. Some of the effects of n-3 LC-PUFAs on adipose tissue depend on their active metabolites, especially eicosanoids. Thus treatments affecting adipose tissue by multiple mechanisms, such as combining n-3 LC-PUFAs with either caloric restriction or antidiabetic/anti-obesity drugs, should be explored.

Effect of oxygen and heliox breathing on air bubbles in adipose tissue during 25-kPa altitude exposures

At altitude, bubbles are known to form and grow in blood and tissues causing altitude decompression sickness. Previous reports indicate that treatment of decompression sickness by means of oxygen breathing at altitude may cause unwanted bubble growth. In this report we visually followed the in vivo changes of micro air bubbles injected into adipose tissue of anesthetized rats at 101.3 kPa (sea level) after which they were decompressed from 101.3 kPa to and held at 25 kPa (10,350 m), during breathing of oxygen or a heliox(34:66) mixture (34% helium and 66% oxygen). Furthermore, bubbles were studied during oxygen breathing preceded by a 3-h period of preoxygenation to eliminate tissue nitrogen before decompression. During oxygen breathing, bubbles grew from 11 to 198 min (mean: 121 min, +/-SD 53.4) after which they remained stable or began to shrink slowly. During heliox breathing bubbles grew from 30 to 130 min (mean: 67 min, +/-SD 31.0) from which point they stabilized or shrank slowly. No bubbles disappeared during either oxygen or heliox breathing. Preoxygenation followed by continuous oxygen breathing at altitude caused most bubbles to grow from 19 to 179 min (mean: 51 min, +/-SD 47.7) after which they started shrinking or remained stable throughout the observation period. Bubble growth time was significantly longer during oxygen breathing compared with heliox breathing and preoxygenated animals. Significantly more bubbles disappeared in preoxygenated animals compared with oxygen and heliox breathing. Preoxygenation enhanced bubble disappearance compared with oxygen and heliox breathing but did not prevent bubble growth. The results indicate that oxygen breathing at 25 kPa promotes air bubble growth in adipose tissue regardless of the tissue nitrogen pressure.

Enhanced angiogenesis in obesity and in response to PPARγ activators through adipocyte VEGF and ANGPTL4 production

PPARgamma activators such as rosiglitazone (RSG) stimulate adipocyte differentiation and increase subcutaneous adipose tissue mass. However, in addition to preadipocyte differentiation, adipose tissue expansion requires neovascularization to support increased adipocyte numbers. Paradoxically, endothelial cell growth and differentiation is potently inhibited by RSG in vitro, raising the question of how this drug can induce an increase in adipose tissue mass while inhibiting angiogenesis. We find that adipose tissue from mice treated with RSG have increased capillary density. To determine whether adipose tissue angiogenesis was stimulated by RSG, we developed a novel assay to study angiogenic sprout formation ex vivo. Angiogenic sprout formation from equally sized adipose tissue fragments, but not from aorta rings, was greatly increased by obesity and by TZD treatment in vivo. To define the mechanism involved in RSG-stimulated angiogenesis in adipose tissue, the expression of proangiogenic factors by adipocytes was examined. Expression of VEGFA and VEGFB, as well as of the angiopoietin-like factor-4 (ANGPTL4), was stimulated by in vivo treatment with RSG. To define the potential role of these factors, we analyzed their effects on endothelial cell growth and differentiation in vitro. We found that ANGPTL4 stimulates endothelial cell growth and tubule formation, albeit more weakly than VEGF. However, ANGPTL4 mitigates the growth inhibitory actions of RSG on endothelial cells in the presence or absence of VEGF. Thus, the interplay between VEGF and ANGPTL4 could lead to a net expansion of the adipose tissue capillary network, required for adipose tissue growth, in response to PPARgamma activators.

Milk fermented byLactobacillus gasseriSBT2055 influences adipocyte size via inhibition of dietary fat absorption in Zucker rats

We have demonstrated previously that a diet containing skimmed milk (SM) fermented by Lactobacillus gasseri SBT2055 (LGSP) reduces adipocyte size in Sprague-Dawley rats. Two experiments were conducted to extend these observations in order to elucidate the mechanism involved. In experiment 1, lean and obese Zucker rats were fed a diet containing SM or LGSP for 4 weeks. The LGSP diet, compared with the SM diet, resulted in lowering of the mesenteric adipose tissue weight (23 %; P < 0.05), adipocyte sizes (28 %; P < 0.001) and serum leptin concentration (36 %; P < 0.05) in lean rats. Obese Zucker rats did not display such dietary effects. Only the number of smaller adipocytes was increased (P < 0.05) by the LGSP diet in the subcutaneous adipose tissue of obese rats. The LGSP diet significantly reduced the serum and hepatic cholesterol in rats. In addition, the LGSP diet led to an increased excretion of faecal fatty acids and total neutral faecal sterols in both rat strains. In experiment 2, Sprague-Dawley rats with permanent cannulation of the thoracic duct were fed either the SM or LGSP diets and their lymph was collected. The LGSP diet lowered the maximum transport rate of TAG and phospholipids. These results indicate that fermented milk regulates adipose tissue growth through inhibition at the stage of dietary fat absorption in lean Zucker rats.

Adipose Tissue Lymphocytes and Macrophages in Obesity and Insulin Resistance

Obesity, and more specifically accumulation of adipose tissue in the visceral and subcutaneous abdominal locations, is a major risk factor for the development of cardiovascular pathologies including hypertension and atherosclerosis, as well as metabolic disorders such as type 2 diabetes. During recent years, “metaflammation” or metabolically-triggered inflammation1 has emerged as a key process involved in the clustering of those conditions. Although several metabolically active organs such as the liver, muscle, and, recently, the intestine2 certainly play major roles, the white adipose tissue appears as a central and primary player as both a source and site of inflammation. Accumulation of adipose tissue macrophages (ATMs) has been well-described in obese conditions in mice and humans.3–5 Moreover, the ATM proinflammatory phenotype has been linked to the development of insulin resistance in mice,4 although the exact nature of the proinflammatory myeloid cells, ie, macrophages or dentritic cells, remains to be determined.6 Nevertheless, the causal link between inflammation and insulin resistance was further strengthened by the specific knock-out of the inflammation coordinator IkappaB kinase beta of myeloid cells, which gave protection against insulin resistance.7 The study of Kintscher and al in this issue8 extends those original observations to cells of adaptative immunity. The authors suggest that the accumulation of T-lymphocytes, assessed mainly through gene expression analyses and immunohistochemistry, occurs in the perigonadal adipose tissue of mice on …

Constant expression of hexose-6-phosphate dehydrogenase during differentiation of human adipose-derived mesenchymal stem cells

The reductase activity of 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) plays an important role in the growth and differentiation of adipose tissue via the prereceptorial activation of glucocorticoids. This enzyme colocalizes with hexose-6-phosphate dehydrogenase (H6PD) at the luminal surface of the endoplasmic reticulum membrane, and the latter enzyme provides NADPH to the former, which can thus act as an 11beta-reductase. It was suggested that, during adipogenesis, the increased expression of H6PD causes a dehydrogenase-to-reductase switch in the activity of HSD11B1. However, only the expression of the HSD11B1 has been extensively studied, and little is known about the expression of H6PD. Here, we investigated the expression and the activity of H6PD in the course of the differentiation of human adipose-derived mesenchymal stem cells (ADMSCs) and murine 3T3-L1 cells. It was found that H6PD is already present in adipose-derived stem cells and in 3T3-L1 fibroblasts even before the induction of adipogenesis. Moreover, mRNA and protein levels, as well as the microsomal H6PD activities remained unchanged during the differentiation. At the same time a great induction of HSD11B1 was observed in both cell types. The observed constant expression of H6PD suggests that HSD11B1 acts as a reductase throughout the adipogenesis process in human ADMSCs and murine 3T3-L1 cells.

Effects of milk fermented byLactobacillusgasseriSBT2055 on adipocyte size in rats

Despite adequate scientific evidence of the potential benefits of probiotics to human health or disease prevention, their contribution to the growth of adipose tissue remains to be established. Four-week-old male Sprague-Dawley rats were fed a diet containing skim milk (control diet) or skim milk fermented by Lactobacillus gasseri SBT2055 (LGSP diet) for 4 weeks. Their body weight gain, adipose tissue weight, adipocyte size distribution profile, blood and hepatic lipids, and serum leptin, glucose and adiponectin levels were determined. There was a significant reduction in average adipocyte size in mesenteric white adipose tissue (P = 0.004). Moreover, the rats fed the LGSP diet displayed greater numbers of small adipocytes from mesenteric and retroperitoneal adipose tissues than did those on the control diet. Whereas adiponectin concentrations did not differ between the groups, serum leptin concentrations were decreased to 32 % in the LGSP diet group compared with the control group. Concentrations of serum glucose and lipids, and liver lipids, except for the liver TAG level, were similar in the two groups. These results indicate a possible role for a fermented milk product in the regulation of adipose tissue growth.

Limitation of adipose tissue enlargement in rats chronically treated with semicarbazide-sensitive amine oxidase and monoamine oxidase inhibitors

Inhibition of semicarbazide-sensitive amine oxidases (SSAO) and monoamine oxidases (MAO) reduces fat deposition in obese rodents: chronic administration of the SSAO-inhibitor semicarbazide (S) in combination with pargyline (MAO-inhibitor) has been shown to reduce body weight gain in obese Zucker rats, while ( E)-2-(4-fluorophenethyl)-3-fluoroallylamine, an SSAO- and MAO-B inhibitor, has been reported to limit weight gain in obese and diabetic mice. Our aim was to state whether such weight gain limitation could occur in non-obese, non-diabetic rats and to extend these observations to other amine oxidase inhibitors. Prolonged treatment of non-obese rats with a high dose of S (900 μmol kg −1 day −1) reduced body weight gain and limited white adipose tissue enlargement. When chronically administered at a threefold lower dose, S also inhibited SSAO activity but not fat depot enlargement, suggesting that effects other than SSAO inhibition were involved in adipose tissue growth retardation. However, combined treatment of this lower dose of S with pargyline inhibited SSAO, MAO, energy intake, weight gain and fat deposition. Adipocytes from treated rats exhibited unchanged insulin responsiveness but impaired antilipolytic responses to amine oxidase substrates. Phenelzine clearly inhibited both MAO and SSAO when tested on adipocytes. Obese rats receiving phenelzine i.p. at 17 μmol kg −1 day −1 for 3 weeks, exhibited blunted MAO and SSAO activities in any tested tissue, diminished body weight gain and reduced intra-abdominal adipose tissue. Their adipocytes were less responsive to lipogenesis activation by tyramine or benzylamine. These observations suggest that SSAO inhibition is not sufficient to impair fat deposition. However, combined MAO and SSAO inhibition limits adiposity in non-obese as well as in obese rats.

Myogel, a Novel, Basement Membrane-Rich, Extracellular Matrix Derived from Skeletal Muscle, Is Highly Adipogenic in vivo and in vitro

Background/Aims: Biological and synthetic scaffolds play important roles in tissue engineering and are being developed towards human clinical applications. Based on previous work from our laboratory, we propose that extracellular matrices from skeletal muscle could be developed for adipose tissue engineering. Methods: Extracellular matrices (Myogels) extracted from skeletal muscle of various species were assessed using biochemical assays including ELISA and Western blotting. Biofunctionality was assessed using an in vitro differentiation assay and a tissue engineering construct model in the rat. Results: Myogels were successfully extracted from mice, rats, pigs and humans. Myogels contained significant levels of laminin α4- and α2-subunits and collagen I compared to Matrigel™, which contains laminin 1 (α1β1γ1) and collagen IV. Levels of growth factors such as fibroblast growth factor 2 were significantly higher than Matrigel, vascular endothelial growth factor-A levels were significantly lower and all other growth factors were comparable. Myogels reproducibly stimulated adipogenic differentiation of preadipocytes in vitro and the growth of adipose tissue in the rat. Conclusions: We found Myogel induces adipocyte differentiation in vitroand shows strong adipogenic potential in vivo, inducing the growth of well-vascularised adipose tissue. Myogel offers an alternative for current support scaffolds in adipose tissue engineering, allowing the scaling up of animal models towards clinical adipose tissue engineering applications.

Adipokine Protein Expression Pattern in Growth Hormone Deficiency Predisposes to the Increased Fat Cell Size and the Whole Body Metabolic Derangements

GH deficiency (GHD) in adults is associated with central adiposity, dyslipidemia, and insulin resistance. The objective of the study was to test the hypothesis that GHD might change the spectrum of adipokines and thus influence the adipose tissue and the whole-body metabolic and inflammatory status leading to development of insulin resistance. This was a single-center observational study with a cross-sectional design. Protein arrays were used to characterize adipokines expressed in the sc adipose tissue obtained from young GHD adults and compared with age-, gender-, and body mass index (BMI)-matched group of healthy individuals. All subjects underwent an oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and magnetic resonance imaging examination. Presence of abdominal obesity, enlarged adipocytes, increased circulating high-sensitivity C-reactive protein, impaired glucose tolerance, and decreased insulin action were found in GHD. Changes in adipokine protein expression due to GHD were highly dependent on the obesity phenotype. Lean GHD individuals (BMI approximately 23 kg/m(2)) had decreased protein levels for stem cell factor and epithelial growth factor, indicating a possible defect in adipocyte differentiation and proliferation. Decrease of vascular endothelial growth factor, stromal cell-derived factor, angiopoietin-2, and brain-derived neurotrophic factor advocated for attenuated angiogenesis and neurogenesis. Presence of obesity (BMI approximately 31 kg/m(2)) eliminated these inhibitory effects. However, adipose tissue expansion in GHD individuals was paralleled by an elevation of adipose tissue proinflammatory cytokines (IL-1beta, interferon-gamma) and chemoattractants (interferon-inducible T cell alpha-chemoattractant, monocyte chemotactic protein-2, monocyte chemotactic protein-3, eotaxin). Our data demonstrate that GHD modulates adipokine and cytokine protein expression pattern, which might influence the adipose tissue growth and differentiation and predispose to tissue hypoxia, inflammation, and a defect in the whole-body insulin action.