Enlarged adipocytes are associated with insulin resistance and are an independent predictor of type 2 diabetes. To understand the molecular link between these diseases and adipocyte hypertrophy, we ...developed a technique to separate human adipocytes from an adipose tissue sample into populations of small cells (mean 57.6±3.54 μm) and large cells (mean 100.1±3.94 μm). Microarray analysis of the cell populations separated from adipose tissue from three subjects identified 14 genes, of which five immune-related, with more than fourfold higher expression in large cells than small cells. Two of these genes were serum amyloid A (SAA) and transmembrane 4 L six family member 1 (TM4SF1). Real-time RT-PCR analysis of SAA and TM4SF1 expression in adipocytes from seven subjects revealed 19-fold and 22-fold higher expression in the large cells, respectively, and a correlation between adipocyte size and both SAA and TM4SF1 expression. The results were verified using immunohistochemistry. In comparison with 17 other human tissues and cell types by microarray, large adipocytes displayed by far the highest SAA and TM4SF1 expression. Thus, we have identified genes with markedly higher expression in large, compared with small, human adipocytes. These genes may link hypertrophic obesity to insulin resistance/type 2 diabetes.--Jernås, M., Palming, J., Sjöholm, K., Jennische, E., Svensson, P.-A., Gabrielsson, B. G., Levin, M., Sjögren, A., Rudemo, M., Lystig, T. C., Carlsson, B., Carlsson, L. M. S., Lönn, M. Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression.
Trial investigators often have a primary interest in the estimation of the survival curve in a population for which there exists acceptable historical information from which to borrow strength. ...However, borrowing strength from a historical trial that is non‐exchangeable with the current trial can result in biased conclusions. In this article we propose a fully Bayesian semiparametric method for the purpose of attenuating bias and increasing efficiency when jointly modeling time‐to‐event data from two possibly non‐exchangeable sources of information. We illustrate the mechanics of our methods by applying them to a pair of post‐market surveillance datasets regarding adverse events in persons on dialysis that had either a bare metal or drug‐eluting stent implanted during a cardiac revascularization surgery. We finish with a discussion of the advantages and limitations of this approach to evidence synthesis, as well as directions for future work in this area. The article's Supplementary Materials offer simulations to show our procedure's bias, mean squared error, and coverage probability properties in a variety of settings.
To identify genes predominantly expressed in omental adipocytes, microarray expression profiles from 33 human tissues or cell types were analyzed, using an algorithm developed for identification of ...transcripts predominantly expressed in a certain tissue. Both known adipocyte-specific and more unexpected genes were among the 28 genes identified. To validate the approach, adipocyte expression of three of these genes, acute-phase serum amyloid A (A-SAA), aquaporin 7, and transport secretion protein-2.2, was compared with 17 other human tissues by real-time PCR. The unexpectedly high expression of A-SAA in adipocytes was further verified by Northern blot and immunohistochemistry. The liver, reported to be the main production site for A-SAA, displayed the second highest expression using microarray and real-time PCR. In obese subjects, adipose tissue mRNA and serum A-SAA levels were down-regulated during an 18-wk diet regime (P < 0.05 and P < 0.0001, respectively). A-SAA serum levels were highly correlated to adipose tissue mRNA levels (P < 0.001) and to the total (P < 0.0001) and sc (P < 0.0001) adipose tissue areas, as analyzed by computed tomography.
We show that adipose tissue is a major expression site of A-SAA during the nonacute-phase reaction condition. This provides a direct link between adipose tissue mass and a marker for low-grade inflammation and cardiovascular risk.
Context: Cell death-inducing DNA fragmentation factor-α-like effector A (CIDEA) could be a potential target for the treatment of obesity via the modulation of metabolic rate, based on the findings ...that CIDEA inhibits the brown adipose tissue uncoupling process in rodents.
Objectives: Our objects were to investigate the putative link between CIDEA and basal metabolic rate in humans and to elucidate further the role of CIDEA in human obesity.
Design: We have explored CIDEA gene expression in adipose tissue in two different human studies: a cross-sectional and population-based study assessing body composition and metabolic rate (Mölndal Metabolic study, n = 92); and a longitudinal intervention study of obese subjects treated with a very low calorie diet (VLCD) (VLCD study, n = 24).
Results: The CIDEA gene was predominantly expressed in adipocytes as compared with other human tissues. CIDEA gene expression in adipose tissue was inversely associated with basal metabolic rate independently of body composition, age, and gender (P = 0.014). The VLCD induced an increase in adipose tissue CIDEA expression (P < 0.0001) with a subsequent decrease in response to refeeding (P < 0.0001). Reduced CIDEA gene expression was associated with a high body fat content (P < 0.0001) and high insulin levels (P < 0.01). No dysregulation of CIDEA expression was observed in individuals with the metabolic syndrome when compared with body mass index-matched controls. In a separate sample of VLCD-treated subjects (n = 10), uncoupling protein 1 expression was reduced during diet (P = 0.0026) and inversely associated with CIDEA expression (P = 0.0014).
Conclusion: The findings are consistent with the concept that CIDEA plays a role in adipose tissue energy expenditure.
Abstract Members of the cell death–inducing DFF45-like effector (CIDE) gene family have been shown to regulate lipid metabolism. In this article, we report that the third member of the human CIDE ...family, CIDEC, is down-regulated in response to a reduced caloric intake. The down-regulation was demonstrated by microarray and real-time polymerase chain reaction analysis of subcutaneous adipose tissue in 2 independent studies on obese patients undergoing treatment with a very low calorie diet. By analysis of CIDEC expression in 65 human tissues, we conclude that human CIDEC is predominantly expressed in subcutaneous adipocytes. Together, these observations led us to investigate the effect of decreased CIDEC expression in cultured 3T3-L1 adipocytes. Small interfering RNA–mediated knockdown of CIDEC resulted in an increased basal release of nonesterified fatty acids, decreased responsiveness to adrenergic stimulation of lipolysis, and increased oxidation of endogenous fatty acids. Thus, we suggest that CIDEC is a regulator of adipocyte lipid metabolism and may be important for the adipocyte to adapt to changes in energy availability.
Adipose tissue is an endocrine organ that produces and secretes adipokines. The aim of this study was to identify genes predominantly expressed in human subcutaneous adipocytes. For this purpose, an ...algorithm was developed and DNA microarray expression profiles from 33 human tissues and cell types were used to select genes. Inhibin beta B (INHBB; coding for the activin βB subunit) was identified and high expression in adipocytes was confirmed by real-time PCR and immunohistochemistry. INHBB expression in adipose tissue was down regulated by diet-induced weight loss (
p
<
0.001). Furthermore, INHBB expression was positively correlated to total (
p
<
0.001) and subcutaneous (
p
<
0.01) adipose tissue areas and serum levels of fasting insulin (
p
<
0.01) and cholesterol (
p
<
0.05). In conclusion, INHBB expression was high in human adipocytes, reduced by weight loss and adipose tissue INHBB mRNA levels correlated to metabolic risk factors. This suggests that activin B produced in adipocytes may play a role in the metabolic syndrome.
Abstract The study aimed to examine if dysmetabolic subjects (MetS+) have lower adiponectin gene expression and lower circulating adiponectin levels than non-dysmetabolic obese subjects (MetS−) at ...baseline, if adiponectin expression and adiponectin concentration rise more in the dysmetabolic group during weight loss, and if v-SNARE Vti1a (vesicle transport soluble NSF attachment protein receptor vps10p tail interacting 1a) expression increases during the weight loss, as a mechanism for increased adiponectin secretion. Twenty-one obese MetS+ and 19 obese MetS− subjects underwent a very low-energy diet for 16 weeks followed by 2 weeks of refeeding. Abdominal subcutaneous adipose tissue biopsies and blood samples were taken before, during, and after dieting for DNA microarray, reverse transcriptase–polymerase chain reaction, and biochemical analyses. Serum adiponectin was also assessed in a sex- and age-matched healthy, nonobese reference group. Weight decreased by 26.3 ± 9.8 kg in the MetS+ group and 28.2 ± 8.4 kg in the MetS− group with concomitant reductions in insulin, hemoglobin A1c , and triglycerides that were more pronounced in the MetS+ group. Initially, the MetS+ subjects had lower serum adiponectin, but the differences disappeared at week 8, with a continuous increase in serum adiponectin throughout the study in both groups to a level that was higher than in the reference group. The expression of adiponectin and v-SNARE Vti1a did not differ between the groups or over time. In conclusion, obese subjects with the metabolic syndrome had lower circulating adiponectin than subjects without the syndrome. Weight loss increased serum levels of adiponectin without a parallel increase in adiponectin gene expression. The mechanisms involved in the regulation of adiponectin levels merits further investigation.
Context: We have previously identified nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1), an enzyme involved in the protection against oxidative stress, as a gene ...predominantly expressed in human adipocytes. Studies in mice deficient in NQO1 activity suggest that NQO1 may also play an important role in metabolism.
Objective: The aim of this study was to explore the expression and regulation of NQO1 in human adipose tissue (AT) and isolated adipocytes.
Patients and Results: The high expression of NQO1 in adipocytes was verified in human adipocytes and AT by real-time PCR. DNA microarray analysis showed that NQO1 was expressed at higher levels in large compared with small adipocytes, isolated from the same fat biopsy. Furthermore, NQO1 mRNA levels were positively correlated with adipocyte size (n = 7; P < 0.002). During an 18-wk diet regime (n = 24; mean weight loss 27 kg), the NQO1 expression in human sc AT was down-regulated (P < 0.0001), and mRNA levels correlated with body mass index (P = 0.0005), sc, and total abdominal AT areas, as determined by computerized tomography (P < 0.0001, both) and metabolic parameters. NQO1 mRNA levels were also positively correlated with aspartate aminotransferase (P = 0.0028) and alanine aminotransferase (P = 0.0219), markers known to be associated with severity of hepatic steatosis.
Conclusions: NQO1 is highly expressed in human AT, particularly in large adipocytes. AT NQO1 expression is reduced during diet-induced weight loss, and the expression levels positively correlate with adiposity, glucose tolerance, and markers of liver dysfunction. Together, these findings indicate a role for NQO1 in the metabolic complications of human obesity.
1 Departments of Pathobiology and Nutritional Sciences,
2 Department of Biostatistics, and 3 Department of
Medicine, University of Washington, Seattle, Washington 98195
The aim of this study was ...to
determine whether phenotypes associated with type 2 diabetes are
altered in dyslipidemic obese mice. C57BL/6 wild-type, low-density
lipoprotein (LDL) receptor-deficient (LDLR / ), and
apolipoprotein E-deficient (apoE / ) mice were fed a high-fat,
high-carbohydrate diet (diabetogenic diet), and the development of
obesity, diabetes, and hypertriglyceridemia was examined. Wild-type
mice became obese and developed hyperglycemia, but not
hypertriglyceridemia, in response to this diet. LDLR / mice fed the
diabetogenic diet became more obese than wild-type mice and developed
severe hypertriglyceridemia and hyperleptinemia. Surprisingly, glucose
levels were only modestly higher and insulin levels and
insulin-to-glucose ratios were not strikingly different from those of
wild-type mice. In contrast, diabetogenic diet-fed apoE / mice were
resistant to changes in glucose and lipid homeostasis despite becoming
obese. These data suggest that modifications in lipoprotein profiles
associated with loss of the LDL receptor or apoE function have profound
and unique consequences on susceptibility to diet-induced obesity and
type 2 diabetic phenotypes.
obesity; type 2 diabetes; triglycerides; leptin; lipoproteins
The aims of this study were to determine whether mice induced to become obese also exhibited accelerated atherosclerosis, and to determine whether obesity itself or dyslipidemia associated with ...obesity enhanced atherosclerosis. Wild-type (C57BL/6) mice and mice deficient for the low density lipoprotein receptor (LDLR−/−) or apolipoprotein E (apoE−/−) were fed a low fat, rodent chow diet or a high fat, high sucrose (diabetogenic) diet to induce obesity. As compared with wild-type mice, diabetogenic diet-fed LDLR−/− mice became more obese and developed severe dyslipidemia. Consequently, atherosclerotic lesions were increased in the LDLR−/− mice 3.7-fold over chow fed values. ApoE−/− mice showed weight gain profiles similar to those observed for wild-type mice. However, no differences in plasma lipid levels, lipoprotein profiles or atherosclerotic lesion areas were observed between chow-fed and diabetogenic diet-fed apoE−/− mice. These data demonstrate that lipid storage and partitioning as mediated by the low density lipoproteins (LDL) receptor or apoE−/− have profound and opposing consequences for dyslipidemia and atherosclerosis susceptibility associated with obesity.
PDF
