Age-Related Modulation of the Effects of Obesity on Gene Expression Profiles of Mouse Bone Marrow and Epididymal Adipocytes (original) (raw)
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Age and depot-specific adipokine responses to obesity in mice
Health, 2012
Leptin and adiponectin are the most abundant adipokines that regulate energy homeostasis. Here, we report the changes of leptin and adiponectin in response to age and their depotspecific expression in lean and genetically obese mice. Fat deposition patterns, adipokine levels and their adipose-tissue depot-specific expression patterns were examined in both sexes of lean and obese mice on two different diets at four and 20 weeks. In obese mice, body fat mass was higher than in lean mice and was increased with age. Leptin levels correlated with body fat mass and therefore increased with age. Leptin levels were correlated higher with the weight of subcutaneous than with the weight of reproductive adipose tissue. Likewise, leptin mRNA levels in subcutaneous adipose tissue corresponded well with serum leptin levels. Adiponectin levels did not differ significantly between the ages and did not correlate with body fat mass or with either of the adipose-tissue depots, although obese mice had lower adiponectin levels than lean mice. Nevertheless, serum adiponectin levels showed a pattern of changes that was similar to that of the adiponectin transcript amounts in the reproductive adipose tissue. Our results confirm that serum leptin levels are regulated by the body fat mass, predominantly by the subcutaneous adipose tissue mass. Furthermore, our data provide evidence that serum adiponectin levels are influenced by other factors than body fat mass alone.
Adipogenesis and aging: does aging make fat go MAD?
Experimental Gerontology, 2002
In advanced old age, fat depot size declines while lipid is redistributed to muscle, bone marrow, and other tissues. Decreased fat depot size is related to reduced fat cell size and function and impaired differentiation of preadipocytes into fat cells. Reduced differentiation-dependent gene expression results from decreased abundance of the adipogenic transcription factors, CCAAT/ enhancer binding a (C/EBPa) and peroxisome proliferator activated receptor g (PPARg). Increased expression of anti-adipogenic C/EBP family members contributes, perhaps due to cellular stress response pathway activation with aging. Hence, dysfunctional adipocyte-like cells appear in adipose tissue that are smaller and less insulin responsive than fully differentiated fat cells. Adipogenesis can be restored by overexpressing adipogenic transcription factors in preadipocytes from old animals. Redistribution of lipid to extra-adipose sites with aging could result from loss of lipid storage capacity in fat depots, altered fatty acid handling resulting in lipid accumulation, dysdifferentiation of mesenchymal precursors, such as muscle satellite cells and osteoblast precursors, into a partial adipocyte phenotype, or a combination of these mechanisms. Thus, accumulation of mesenchymal adipocyte-like default (MAD) cells in fat depots, muscle, bone marrow, and elsewhere is a potentially reversible process that could contribute to maldistribution of fat in old age.
Age-associated adaptations in murine adipose tissues
Endocrine Journal, 2010
Adipose tissue development is a highly organized process, that involves either hypertrophy (enlargement of existing adipocytes) or hyperplasia (increase in the number of mature adipocytes) or a combination of both [1]. White adipose tissue (WAT) is a major endocrine and secretory organ, releasing fatty acids, different lipid moieties and a multiplicity of adipokines [2]. Ageing has been associated with an increase in visceral obesity in both men and women, putting the elderly population at a high risk to develop age-associated diseases such as hypertension, dyslipidemia, insulin resistance, type 2 diabetes, metabolic syndrome and cardiovascular disease [3]. Over the last decades, wildtype C57Bl/6 mice of different age range have been extensively used in studies on obesity and metabolic syndrome. However, little information is available on
Adipogenic signaling in rat white adipose tissue: Modulation by aging and calorie restriction
Experimental Gerontology, 2007
Alterations in adipogenesis could have significant impact on several aging processes. We previously reported that calorie restriction (CR) in rats significantly increases the level of circulating adiponectin, a distinctive marker of differentiated adipocytes, leading to a concerted modulation in the expression of key transcription target genes and, as a result, to increased fatty acid oxidation and reduced deleterious lipid accumulation in other tissues. These findings led us to investigate further the effects of aging on adipocytes and to determine how CR modulates adipogenic signaling in vivo. CR for 2 and 25 months, significantly increased the expression of PPARγ, C/EBPβ and Cdk-4, and partially attenuated age-related decline in C/EBPα expression relative to rats fed ad libitum (AL). As a result, adiponectin was upregulated at both mRNA and protein levels, resulting in activation of target genes involved in fatty acid oxidation and fatty acid synthesis, and greater responsiveness of adipose tissue to insulin. Moreover, CR significantly decreased the ratio of C/EBPβ isoforms LAP/LIP, suggesting the suppression of gene transcription associated with terminal differentiation while facilitating preadipocytes proliferation. Morphometric analysis revealed a greater number of small adipocytes in CR relative to AL feeding. Immunostaining confirmed that small adipocytes were more strongly positive for adiponectin than the large ones. Overall these results suggest that CR increased the expression of adipogenic factors, and maintained the differentiated state of adipocytes, which is critically important for adiponectin biosynthesis and insulin sensitivity.
The Journal of Clinical Endocrinology & Metabolism, 2001
This study was performed to compare the expression of key proteins [lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), complement 3 (C3), and peroxisome proliferator-stimulated receptor-␥ (PPAR␥)] involved in sc abdominal adipose tissue (AT) metabolism of young (n ϭ 13) vs. middle-aged (n ϭ 16) men. The sc abdominal AT-LPL activity as well as fat cell lipolysis were also measured in both groups of men. Young and middle-aged men displayed similar body weight and sc abdominal fat accumulation, measured by computed tomography. However, middle-aged men were characterized by a higher percent body fat (28 Ϯ 5% vs. 22 Ϯ 7%; P Ͻ 0.05) than young subjects. No difference between groups was observed in sc abdominal adipose tissue LPL activity. On the other hand, maximal lipolytic responses of sc abdominal adipocytes to isoproterenol (-adrenergic agonist) or to postadrenoceptor agents such as dibutyryl cAMP, forskolin, and theophylline were lower in middle-aged than in young men (P Ͻ 0.05). AT-LPL messenger ribonucleic acid (mRNA) levels were similar regardless of the subject's age. However, HSL, C3, and PPAR␥ mRNA levels were higher in middle-aged than in young individuals (P Ͻ 0.01-0.05). After correction for percent body fat, only HSL and C3 mRNA levels remained significantly different between groups (P Ͻ 0.05). Taken together, these results suggest that aging has an effect on the up-regulation of HSL and C3 mRNA levels, whereas PPAR␥ expression seems to be related mainly to increased adiposity. (J Clin Endocrinol Metab 86: 828 -833, 2001)
Proteomic analysis of mature adipo cytes from obese patients in relation to aging
Obesity and aging are interrelated conditions that both cause changes in adipocyte metabolism and affect the distribution of fat in both subcutaneous and visceral depots. In addition, both weight gain and aging can lead to similar clinical outcomes such as insulin resistance, cardiovascular disease, type 2 diabetes mellitus, atherosclerosis and stroke. Our objective was to examine the changes in protein expression within the subcutaneous adipose tissue of obese patients, matched for BMI, in relation to age. Mature adipocytes were isolated from liposuction samples of abdominal subcutaneous adipose tissue collected from both young (26.2 ± 4.3 (mean age ± SD); n = 7) and old (52.2 ± 4.7 (mean age ± SD); n = 7) obese individuals. Total protein extracts were then compared by two-dimensional difference in gel electrophoresis (2D DIGE). Thirty differentially expressed protein spots (ANOVA test, p ≤ 0.05; fold-change ≥1.8) were detected, of which, 15 were identified by MALDI-TOF mass spectrometry. These were comprised of a total of thirteen unique protein sequences. Nine proteins were more abundant in the adipocytes isolated from old vs. young individuals. These proteins included prohibitin 1, protein disulphide isomerase A3, beta actin, profilin, aldo-ketoreductase 1 C2, alpha crystallin B and the annexins A1, A5 and A6. Four other proteins were less abundant in the adipocytes from old, obese subjects and these included keratin type 2 cytoskeletal 1, keratin type 2 cytoskeletal 10 and hemoglobins A and B. The differentially abundant proteins were investigated by Ingenuity Pathway Analysis (IPA) to reveal their associations with known biological functions. This analysis identified signal transducer and activator of transcription 3 as the central molecule in the connectivity map and the apoptotic pathway as the pathway with the highest score. Differences in the abundances of several proteins were confirmed by immunoblotting: i.e., prohibitin 1, protein disulphide isomer-ase A3, beta actin, profilin and signal transducer and activator of transcription 3 proteins. In conclusion, proteo-mic analysis of subcutaneous adipose tissue reveals differences in the abundance of proteins in adipocytes isolated from young vs. old individuals. These differentially abundant proteins are involved in the regulation of apoptosis, cellular senescence and inflammatory response. All these are common pathologic events in both obesity and aging.
Molecular and Cellular Biochemistry, 2011
Adipose tissue development is a highly regulated phenomenon orchestrated by several check points (recruitment of mesenchymal stem cells and their lineage commitment) to form mature adipocytes. Once committed to obesity, expansion of adipose tissue occurs either by hypertrophy or hyperplasia or by both resulting in an altered physiological status. This precipitates as inflammatory responses, leading to endoplasmic reticulum and oxidative stress altering the gene expression of adipose tissue in a depot-specific manner. However, such studies reporting a phased gene expression profile in conditions of rodent obesity are not reported so far. WNIN/Ob mutant obese rat, developed at our institute is an excellent model to study the pathophysiological changes underlying obesity. Here, we report the gene expression profile of this mutant rat (obese and lean), compared with the parental control, with reference to markers of embryonic stem cells, adipogenesis, inflammation, and senescence in both subcutaneous (SCAT) and retroperitoneal (RPAT) adipose depots representing abdominal fat. We demonstrate an upregulation of genes such as Sox-2, Pref-1, PPARc2, LPL, IRS-1, GLUT-4, IL-6, TNFa, and telomerase in SCAT and RPAT depots of the obese rat compared to its lean counterpart indicating no difference in fat depots at different locations. This is suggestive of a similar phenotypic expression of mutant gene. Data form the phased gene expression changes of adipogenesis (embryonic/adipogenic/inflammatory) in the present obese rat model system advocate for inflammatory mediated response(s) associated with obesity-a condition often seen in humans.
Journal of Applied Genetics, 2007
Recently, quantitative trait loci (QTLs) for body weight and obesity have been mapped in an intercross population between the high body weight-selected mouse line DU6i and the inbred line DBA/2. Most QTLs were highly significant, but had small effects only. Under the hypothesis that small-effect QTLs might result from changes in gene activity, our strategy to identify candidate genes for the observed effects was directed towards the identification of differentially expressed genes. Therefore, here we compare the transcription profile of about 11 000 genes in epididymal fat tissues of males of two high body weight-selected (DU6 and DU6i) and two unselected mouse lines (DUKs and DBA/2). For the hybridisation of GeneChips, we used pooled samples of 20 individual mice. By pair-wise comparisons between selected and unselected mouse lines, a set of 77 genes was identified representing genes whose level of expression differed between obese and lean mouse strains. According to the functional classification of genes, 69 differentially expressed genes were involved in regulatory and metabolic pathways, cell division, cell stability, or immune response, and thus might have an effect on body weight and fat accumulation. 14 out of these genes, occur in QTL regions for body weight or abdominal fat weight. Further analyses are necessary to discriminate between genes directly causing QTL effects and indirectly regulated differentially expressed genes.
The Journals …, 1999
Aging has been shown to have an effect on the capacity to differentiate preadipocytes and on the expression ofsome genes expressed in adipose tissue. The mRNA levels ofadipocyte differentiation-related genes were examined in rhesus monkeys (Macaca Mulatta) ranging in age from 7 to 30 years. The effect ofaging on the expression ofperoxisome proliferator activated receptor 'Y(PPAR'Y),adipocyte determination-and differentiation-dependentfactor lIsterol regulatory element binding protein 1 (ADDIISREBPl), CCAATlenhancer binding protein a (CIEBPa), lipoprotein lipase (LPL), GLUT4 glucose transporter, and adipsin were examined by slot blot analysis. Significant inverse correlations were observed between age and the mRNA levels ofPPAR'Y, ADDlISREBPl, LPL, and GLUT4. The coordinate downregulation ofthese genes may be linked to the declining fat mass ofsenescent animals. There was no correlation between age and the mRNA levels of adipsin. The mRNA levels ofthese genes were not correlated to body weight or fasting plasma insulin. These findings indicate that aging may have an effect on the adipocyte differentiation program and this effect appears to be gene specific.