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03/10/2019 7:19 am
my fat ruminations:
J Mol Endocrinol. 2007 Feb;38(1):19-34.
Growth hormone stimulates adipogenesis of 3t3-L1 cells through activation of the Stat5A/5B-PPAR{gamma} pathway.
Kawai M, Namba N, Mushiake S, Etani Y, Nishimura R, Makishima M, Ozono K.
Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Growth hormone-deficient (GHD) patients show a decreased number of adipocytes, which is normalized by GH replaKalpaent, indicating an adipogenic effect of GH. However, the precise mechanisms underlying this effect remain to be clarified. In this study, we investigated the adipogenic effect of GH. GH stimulated MDI (3-isobutyl-1-methylxanthine, dexamethasone, and insulin)-induced adipogenesis of 3T3-L1 cells with early induction of peroxisome proliferator-activated receptors (PPAR)gamma2 expression. This adipogenic effect of GH was suppressed by overexpression of Stat5A mutant (Stat5A-Y694F), a transcriptional suppressor for the GH-Stat5A/5B signaling pathway, with the reduction of PPARgamma2 expression. Next, we investigated the relationship between Stat5A/5B and CCAAT/enhancer binding protein (C/EBP)beta/delta orPPARgamma in 3T3-L1 cells. Stat5A/5B stimulated C/EBPbeta- and C/EBPdelta-induced adipogenesis with enhanKalpaent of PPARgamma2 expression. In addition, Stat5A/5B enhanced the transcriptional activity of C/EBPbeta/delta in the PPARgamma gene promoter. Furthermore, Stat5A/5B stimulated PPARgamma-induced adipogenesis and enhanced the transcriptional activity of PPARgamma. These results suggest that the GH-Stat5A/5B signaling pathway stimulates adipogenesis in cooperation with C/EBPbeta/delta and PPARgamma. To completely understand the effect of GH, cDNA microarray analysis was performed to screen genes affected by GH during MDI-induced adipogenesis. Among 4277 genes, 18 and 19 genes were up- and down-regulated respectively. cDNA microarray analysis also indicated the up-regulation of PPARgamma and the modulation of expression of genes coding for growth factors or growth factor receptors, suggesting that GH stimulates adipogenesis in association with the modulation of cell growth. Thus, the GH-Stat5A/B signaling pathway stimulates adipogenesis through two distinct steps. In addition, cDNA microarray data provide us the further insights underlying the adipogenic effect of GH.
J Clin Endocrinol Metab. 1997 Mar;82(3):727-34.
Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure.
Johannsson G, Mårin P, Lönn L, Ottosson M, Stenlöf K, Björntorp P, Sjöström L, Bengtsson BA.
Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital, Göteborg, Sweden.
The most central findings in both GH deficiency in adults and the metabolic syndrome are abdominal/visceral obesity and insulin resistance. Abdominal obesity is associated with blunted GH secretion and low serum insulin-like growth factor-I concentrations. GH treatment in GH-deficient adults has demonstrated favorable effects on most of the features of GH deficiency in adults, but it is not known whether GH can improve some of the metabolic aberrations observed in abdominal/visceral obesity. Thirty men, 48-66 yr old, with abdominal/visceral obesity were treated with recombinant human GH (rhGH) in a 9-month randomized, double-blind, placebo-controlled trial. The daily dose of rhGH was 9.5 micrograms/kg. Body fat was assessed from total body potassium, and abdominal sc and visceral adipose tissue was measured using computed tomography. The glucose disposal rate (GDR) was measured during an euglyKalpaic, hyperinsulinemic glucose clamp. In response to the rhGH treatment, total body fat and abdominal sc and visceral adipose tissue decreased by 9.2 +/- 2.4%, 6.1 +/- 3.2%, and 18.1 +/- 7.6%, respectively. After an initial decrease in the GDR at 6 weeks, the GDR increased in the rhGH-treated group as compared with the placebo-treated one (P < 0.05). The mean serum concentrations of total cholesterol (P < 0.01) and triglyceride (P < 0.05) decreased, whereas blood glucose and serum insulin concentrations were unaffected by the rhGH treatment. Furthermore, diastolic blood pressure decreased and systolic blood pressure was unchanged in response to rhGH treatment. This trial has demonstrated that GH can favorably affect some of the multiple perturbations associated with abdominal/visceral obesity. This includes a reduction in abdominal/visceral obesity, an improved insulin sensitivity, and favorable effects on lipoprotein metabolism and diastolic blood pressure.
Horm Metab Res. 2007 Apr;39(4):282-7.
The influence of preadipocyte differentiation capacity on lipolysis in human mature adipocytes.
Dicker A, Aström G, Sjölin E, Hauner H, Arner P, van Harmelen V.
Department of Medicine, Karolinska Institutet, Hudinge, Stockholm, Sweden.
The ability of catecholamines to maximally stimulate adipocyte lipolysis (lipolytic capacity) is decreased in obesity. It is not known whether the lipolytic capacity is determined by the ability of adipocytes to differentiate. The aim of the study was to investigate if lipolytic capacity is related to preadipocyte differentiation and if the latter can predict lipolysis in mature adipocytes. IN VITRO experiments were performed on differentiating preadipocytes and isolated mature adipocytes from human subcutaneous adipose tissue. In preadipocytes, noradrenaline-induced lipolysis increased significantly until terminal differentiation (day 12). However, changes in the expression of genes involved in lipolysis (hormone sensitive lipase, adipocyte triglyceride lipase, the alpha2-and beta1-adrenoceptors, perilipin, and fatty acid binding protein) reached a plateau much earlier during differentiation (day 8). A significant positive correlation between lipolysis in differentiated preadipocytes and mature adipocytes was observed for noradrenaline (r=0.5, p<0.01). The late differentiation capacity of preadipocytes measured as glycerol-3-phosphate dehydrogenase activity was positively correlated with noradrenaline-induced lipolysis in preadipocytes (r=0.51, p<0.005) and mature fat cells (r=0.35, p<0.05). In conclusion, intrinsic properties related to terminal differentiation determine the ability of catecholamines to maximally stimulate lipolysis in fat cells. The inability to undergo full differentiation might in part explain the low lipolytic capacity of fat cells among the obese.
Surg Endosc. 2007 Feb 8.
Expression of ectonucleotide pyrophosphate phosphodiesterase and peroxisome proliferator activated receptor gamma in morbidly obese patients.
Brody F, Hill S, Celenski S, Kar R, Kluk B, Pinzone J, Fu S.
The Department of Surgery, The George Washington University Medical Center, 2150 Pennsylvania Avenue, NW, Suite 6B, Washington, D.C., 20037, USA.
BACKGROUND: Recently, two genes, peroxisome proliferator activated receptor gamma (PPARgamma) and ectonucleotide pyrophosphate phosphodiesterase (ENPP1), have been localized and associated with diabetes and obesity. This report hypothesizes that there is a correlation between the genetic expression of ENPP1 and PPARgamma from gastrointestinal tissue and body mass index (BMI). METHODS: Preoperative demographic data were collected from 16 severely morbidly obese patients. Extraneous gastrointestinal tissue was obtained during laparoscopic gastric bypass and gastric banding procedures. The tissue was snap frozen in liquid nitrogen. Initially, RNA extraction was performed on the tissue, followed by reverse transcription using appropriate primers and controls. Subsequently, the samples were subjected to quantitative polymerase chain reaction (PCR). Preoperative demographic data were analyzed for their influence on ENPP1 and PPARgamma expression using multivariate analysis and logistic regression models. RESULTS: Expression of PPARgamma and ENPP1 was found in all samples. There was a higher level of PPARgamma expression in omental tissue than in enteric tissue. There was no significant difference in the expression of ENPP1 among the different tissue types. The relative level of PPARgamma expression in small bowel and gastric tissue was found to be inversely proportional to body mass index (BMI) using linear regression analysis (p = 0.01; r (2) = 0.586). Similarly, PPARgamma expression from omental tissue showed an inverse relationship with BMI (p = 0.04; r (2 )= 0.576). The levels of ENPP1 expression did not show a correlation with BMI (p = 0.25). CONCLUSION: The results suggest that increasing obesity correlates with a decrease in PPARgamma expression. This decrease may induce dysfunctional adipocyte differentiation, maturation, and function, leading to diabetes and the metabolic syndrome. Similarly, the increased volume of adipose tissue may lead to a downregulation of PPARgamma. The lack of correlation between ENPP1 and BMI may suggest that glucose metabolism is more complex than lipid metabolism. Further evaluation is warranted to establish metabolic pathways for glucose and lipid biomarkers.
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PPAR Gamma Isoforms Proportions
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Diabetes. 2002 Mar;51(3):718-23.
Regional differences in the response of human pre-adipocytes to PPARgamma and RXRalpha agonists.
Sewter CP, Blows F, Vidal-Puig A, O'Rahilly S.
University of Cambridge, Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom.
We have previously reported that omental (OM) preadipocytes respond less well to the prodifferentiating effects of thiazolidinediones than do preadipocytes from subcutaneous (SC) depots. This finding is consistent with in vivo alterations in fat distribution that occur in humans treated with thiazolidinediones. To explore these site-related differences further, we used real-time RT-PCR to quantify the specific mRNAs encoding peroxisome proliferator-activated receptor (PPAR) gamma1 and gamma2 and found that both isoforms were more highly expressed in SC than in OM preadipocytes. After 10 days of thiazolidinedione treatment, preadipocytes from both depots showed a small and comparable increase in expression of PPARgamma1 mRNA (1.7 +/- 0.2-fold [P = 0.007]) and 1.3 +/- 0.1-fold [P = 0.008] increase for SC and OM, respectively). There was a much larger increase in PPARgamma2 expression, which was significantly greater in SC compared with OM preadipocytes (11.1 +/- 2.8-fold [P = 0.0003] and 5.5 +/- 1.7-fold [P = 0.0003], respectively; P = 0.014 for SC versus OM). To establish whether the refractoriness of OM preadipocytes to differentiation was unique to activators of the PPARgamma pathway, we examined the effects of the retinoid X receptor (RXR) ligand LG100268. As assessed by glycerol-3-phosphate dehydrogenase activity, LG100268 had a greater effect on the differentiation of SC compared with OM preadipocytes when examined alone (SC = 5.7 +/- 1.7-fold vs. OM = 1.9 +/- 0.6-fold; P < 0.05) or in combination with rosiglitazone (SC = 27.0 +/- 7.5 vs. OM = 10.6 +/- 3.6-fold; P < 0.05). Consistent with this, RXRalpha mRNA levels were also higher in SC than in OM preadipocytes. In summary, the previously reported insensitivity of OM preadipocytes to the differentiating effects of thiazolidinediones may relate to their lower basal levels of PPARgamma1 and gamma2 mRNA and their diminished capacity to upregulate PPARgamma2 expression in response to ligand.That omentally derived cells also show reduced responsiveness to the prodifferentiating actions of an RXR ligand and a lower expression of RXRalpha in the undifferentiated state suggests that they may have a more generalized resistance to differentiation.
Clin Endocrinol (Oxf). 2007 Jan;66(1):7-12.
Abnormal expression of PPAR gamma isoforms in the subcutaneous adipose tissue of patients with Cushing's disease.
Bogazzi F, Ultimieri F, Raggi F, Russo D, Manetti L, Cosci C, Sardella C, Costa A, Santini F, Locci T, Bartalena L, Martino E.
Department of Endocrinology, University of Pisa, Italy.
BACKGROUND: Obesity is a clinical feature of patients with Cushing's disease. Peroxisome proliferators-activated receptor (PPAR)gamma is the master regulator of adipogenesis; however, the expression of PPARgamma isoforms in the subcutaneous adipose tissue (SAT) of patients with Cushing's disease is unknown. AIM AND METHODS: The expression of PPARgamma1 and PPARgamma2 was evaluated by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence (PPARgamma2 only) in SAT samples of 7 patients with untreated active Cushing's disease (Cushing(UNTR)), 8 with Cushing's disease in remission (Cushing(REM)) after pituitary adenomectomy, 15 normal lean subjects (Control(LEAN)), and 15 obese patients (Control(OBE)). RESULTS: Control(LEAN) had a higher degree of PPARgamma1 than PPARgamma2 (PPARgamma2/PPARgamma1 ratio, 0.55 +/- 0.35). PPARgamma2/PPARgamma1 ratio decreased in Cushing(UNTR) (0.10 +/- 0.043, P < 0.03 vs. Control(LEAN) and Control(OBE)), because of either increased PPARgamma1 or reduced PPARgamma2 expression. PPARgamma2/PPARgamma1 ratio was 0.48 +/- 0.07 in Cushing(REM) patients (P < 0.04 vs. Cushing(UNTR), P < 0.03 vs. Control(OBE)). PPARgamma2/PPARgamma1 ratio was higher in Control(OBE) 0.90 +/- 0.38 than in Control(LEAN) (P < 0.005 vs. Control(LEAN), P < 0.03 vs. Cushing(REM), P < 0.009 vs. Cushing(UNTR)). PPARgamma2/PPARgamma1 ratio was related to serum cortisol levels only in patients with Cushing'disease (r = 0.688, P < 0.02). CONCLUSIONS: Cushing(UNTR) patients had an abnormal expression of PPARgamma isoforms in SAT related to serum cortisol levels. Although further studies are necessary, it is conceivable that variations in the expression of PPARgamma isoforms might have a role in the abnormal adipogenesis of patients with Cushing's disease.
dr frankenstein
03/10/2019 7:45 am
interesting stuff..........thanks OSW!
03/10/2019 8:06 am
Long-term exercise increases the DNA binding activity of peroxisome proliferator-activated receptor gamma in rat adipose tissue.Petridou A, Tsalouhidou S, Tsalis G, Schulz T, Michna H, Mougios V.
Department of Physical Education and Sport Science, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece.
The aim of the present study was to examine the effect of 8 weeks of voluntary wheel running on the gene expression, at the protein level, of 2 enzymes involved in lipogenesis (fatty acid synthase [FAS] and diacylglycerol acyl transferase 1), 2 proteins involved in lipolysis (hormone-sensitive lipase [HSL] and perilipin), and 3 transcription factors mediating the induction of genes involved in lipid metabolism (the alpha, gamma, and delta members of the peroxisome proliferator-activated receptor, or PPAR, family) in rat liver, gastrocnemius muscle, epididymal fat, and subcutaneous fat. Proteins were measured through Western blot analysis in the tissues of 11 trained and 14 untrained rats. The trained rats had lower FAS in the liver; higher FAS, HSL, and perilipin in epididymal fat; and higher HSL in subcutaneous fat. In addition, the trained rats had higher total protein concentrations in both fat depots. No significant differences in the liver, muscle, or adipose tissue PPAR contents were found between groups. However, the DNA binding activity of PPARgamma, measured through an enzyme immunoassay-based method, was higher in both fat depots of the trained rats. Our findings suggest that long-term wheel running had significant effects on the concentrations of proteins playing key roles in lipogenesis and lipolysis in rat liver and adipose tissue. These effects may be due to PPAR activation rather than induction, rendering the transcriptional regulation of target genes more economical and flexible. The activation of PPARgamma with exercise may mediate its beneficial effect on insulin sensitivity.
Topic starter
03/10/2019 8:33 am
interesting stuff..........thanks OSW!
at your service.
fat annihilation !
Long-term exercise increases the DNA binding activity of peroxisome proliferator-activated receptor gamma in rat adipose tissue.Petridou A, Tsalouhidou S, Tsalis G, Schulz T, Michna H, Mougios V.
Department of Physical Education and Sport Science, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece.
great find !
fat ruminations:Horm Metab Res. 2007 Apr;39(4):282-7.
The influence of preadipocyte differentiation capacity on lipolysis in human mature adipocytes.
Dicker A, Aström G, Sjölin E, Hauner H, Arner P, van Harmelen V.
Department of Medicine, Karolinska Institutet, Hudinge, Stockholm, Sweden.
The ability of catecholamines to maximally stimulate adipocyte lipolysis (lipolytic capacity) is decreased in obesity. It is not known whether the lipolytic capacity is determined by the ability of adipocytes to differentiate. The aim of the study was to investigate if lipolytic capacity is related to preadipocyte differentiation and if the latter can predict lipolysis in mature adipocytes. IN VITRO experiments were performed on differentiating preadipocytes and isolated mature adipocytes from human subcutaneous adipose tissue. In preadipocytes, noradrenaline-induced lipolysis increased significantly until terminal differentiation (day 12). However, changes in the expression of genes involved in lipolysis (hormone sensitive lipase, adipocyte triglyceride lipase, the alpha2-and beta1-adrenoceptors, perilipin, and fatty acid binding protein) reached a plateau much earlier during differentiation (day 8). A significant positive correlation between lipolysis in differentiated preadipocytes and mature adipocytes was observed for noradrenaline (r=0.5, p<0.01). The late differentiation capacity of preadipocytes measured as glycerol-3-phosphate dehydrogenase activity was positively correlated with noradrenaline-induced lipolysis in preadipocytes (r=0.51, p<0.005) and mature fat cells (r=0.35, p<0.05). In conclusion, intrinsic properties related to terminal differentiation determine the ability of catecholamines to maximally stimulate lipolysis in fat cells. The inability to undergo full differentiation might in part explain the low lipolytic capacity of fat cells among the obese.
J Pharmacol Exp Ther. 2006 Aug;318(2):863-71.
A selective peroxisome proliferator-activated receptor gamma modulator with distinct fat cell regulation properties.
Fujimura T, Kimura C, Oe T, Takata Y, Sakuma H, Aramori I, Mutoh S.
Molecular Medicine Research Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
Adipogenesis is an important process for the improvement of insulin resistance by peroxisome proliferator-activated receptor (PPAR) gamma agonists, such as rosiglitazone and pioglitazone. FK614 [3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3-Hbenzimidazole-5-carboxamide] is a structurally novel class of PPARgamma agonist that improves insulin sensitivity in animal models of type 2 diabetes. Herein, we characterize FK614, a selective PPARgamma modulator (SPPARM) with differential properties affecting the regulation of fat cell function. FK614 behaves as a partial agonist in inducing the interaction of PPARgamma with both transcriptional coactivators, cAMP response element-binding protein-binding protein and steroid receptor coactivator-1, but as a full agonist with both PPAR-binding protein and PPAR-interacting protein, which are required for PPARgamma-mediated adipogenesis. In the differentiating 3T3-L1 adipocytes, the levels of adipose fatty acid-binding protein (aP2) mRNA expression and triglyceride accumulation induced by FK614 were as efficacious as those of rosiglitazone and pioglitazone. In contrast, the effect of FK614 on aP2 gene expression in mature adipocytes was less than that of the other PPARgamma agonists. Furthermore, the long-term treatment of mature adipocytes with rosiglitazone and pioglitazone reduced the expression of phosphodiesterase 3B, the down-regulation of which has an important role in the development of insulin resistance; however,FK614 had no such effect in mature adipocytes. Thus, FK614 behaves as an SPPARM with differential effects on the activation of PPARgamma at each stage of adipocyte differentiation. The stage-dependent selectivity of FK614 may contribute to its enhanced insulin sensitization in differentiating adipocytes and to reduced insulin resistance at the stage of adipocyte hypertrophy.
J Clin Invest. 1997 May 15;99(10):2416-22.
Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids.
Vidal-Puig AJ, Considine RV, Jimenez-Liñan M, Werman A, Pories WJ, Caro JF, Flier JS.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
............(a) human PPAR gamma mRNA expression is most abundant in adipose tissue, but lower level expression of both splice variants is seen in skeletal muscle; to an extent that is unlikely to be due to adipose contamination. (b) RNA derived from adipose tissue of obese humans has increased expression of PPAR gamma 2 mRNA, as well as an increased ratio of PPAR gamma2/gamma1 splice variants that is proportional to the BMI; (c) a low calorie diet specifically down-regulates the expression of PPAR gamma2 mRNA in adipose tissue of obese humans; (d) insulin and corticosteroids synergistically induce PPAR gamma mRNA after in vitro exposure to isolated human adipocytes; and (e) the in vivo modulation of PPAR gamma2 mRNA levels is an additional level of regulation for the control of adipocyte development and function, and could provide a molecular mechanism for alterations in adipocyte number and function in obesity...............
. Last edited by oswaldosalcedo on 07-11-2007 at 04:26 PM
dr frankenstein
03/10/2019 8:51 am
Hypolipidemic effects of silymarin are not mediated by the peroxisome proliferator-activated receptor alpha.Orolin J, Vecera R, Jung D, Meyer UA, Skottová N, Anzenbacher P.
Institute of Pharmacology, Faculty of Medicine, Palacky University. Czech Republic.
Silymarin is widely used in supportive therapy of liver diseases. It has been shown lately that silymarin has beneficial effects on some risk factors of atherosclerosis owing to its hypolipidemic properties. PPARalpha plays a key role in lipid metabolism and homeostasis as its target genes are involved in catabolism of fatty acids by beta-oxidation (e.g. acyl-CoA oxidase) and by omega-oxidation (e.g. cytochrome P4504A). Here we studied the possibility that hypolipidemic effects of silymarin may be mediated by PPARalpha. Rats fed with a high-cholesterol diet with either silymarin or fenofibrate (as a positive control both for PPARalpha expression as well as for lipid determination) were used. The effects of silymarin on expression of PPARalpha both at the mRNA (including selected target genes) as well as the protein level were determined. In parallel, the levels of cholesterol and triacylglycerols were determined. Our results confirmed the hypolipidemic effects of silymarin and demonstrated that these effects are probably not mediated by PPARalpha because of unchanged mRNA levels of PPARalpha target genes. Furthermore, this work shows for the first time that cholesterol itself inhibits expression of CYP4A mRNA.