Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The orphan nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma, is implicated in mediating expression of fat-specific genes and in activating the program of adipocyte differentiation. The potential for regulation of PPAR gamma gene expression in vivo is unknown. We cloned a partial mouse PPAR gamma cDNA and developed an RNase protection assay that permits simultaneous quantitation of mRNAs for both gamma l and gamma 2 isoforms encoded by the PPAR gamma gene. Probes for detection of adipocyte P2, the obese gene product, leptin, and 18S mRNAs were also employed. Both gamma l and gamma 2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma 1 expression was also detected at lower levels in liver, spleen, and heart; whereas, gamma l and gamma 2 mRNA were expressed at low levels in skeletal muscle. Adipose tissue levels of gamma l and gamma 2 were not altered in two murine models of obesity (gold thioglucose and ob/ob), but were modestly increased in mice with toxigene-induced brown fat ablation uncoupling protein diphtheria toxin A mice. Fasting (12-48 h) was associated with an 80% fall in PPAR gamma 2 and a 50% fall in PPAR gamma mRNA levels in adipose tissue. Western blot analysis demonstrated a marked effect of fasting to reduce PPAR gamma protein levels in adipose tissue. Similar effects of fasting on PPAR gamma mRNAs were noted in all three models of obesity. Insulin-deficient (streptozotocin) diabetes suppressed adipose tissue gamma l and gamma 2 expression by 75% in normal mice with partial restoration during insulin treatment. Levels of adipose tissue PPAR gamma 2 mRNA were increased by 50% in normal mice exposed to a high fat diet. In obese uncoupling protein diphtheria toxin A mice, high fat feeding resulted in de novo induction of PPAR gamma 2 expression in liver. We conclude (a) PPAR gamma 2 mRNA expression is most abundant in adipocytes in normal mice, but lower level expression is seen in skeletal muscle; (b) expression of adipose tissue gamma1 or gamma2 mRNAs is increased in only one of the three models of obesity; (c) PPAR gamma 1 and gamma 2 expression is downregulated by fasting and insulin-deficient diabetes; and (d) exposure of mice to a high fat diet increases adipose tissue expression of PPAR gamma (in normal mice) and induces PPAR gamma 2 mRNA expression in liver (in obese mice). These findings demonstrate in vivo modulation of PPAR gamma mRNA levels over a fourfold range and provide an additional level of regulation for the control of adipocyte development and function.
 ...
PMID:Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. 864 48

Members of the peroxisome proliferator-activated receptor (PPAR) family might be involved in pathologies with altered lipid metabolism. They participate in the control of the expression of genes involved in lipid metabolism and adipocyte differentiation. In addition, thiazolidinediones improve insulin resistance in vivo by activating PPAR gamma. However, little is known regarding their tissue distribution and relative expression in humans. Using a quantitative and sensitive reverse transcription (RT)-competitive polymerase chain reaction (PCR) assay, we determined the distribution and relative mRNA expression of the four PPARs (alpha,beta, gamma1, and gamma2) and liver X receptor-alpha (LXR alpha) in the main tissues implicated in lipid metabolism. PPAR alpha and LXR alpha were mainly expressed in liver, while PPAR gamma1 predominated in adipose tissue and large intestine. We found that PPAR gamma2 mRNA was a minor isoform, even in adipose tissue, thus causing question of its role in humans. PPAR beta mRNA was present in all the tissues tested at low levels. In addition, PPAR gamma mRNA was barely detectable in skeletal muscle, suggesting that improvement of insulin resistance with thiazolidinediones may not result from a direct effect of these agents on PPAR gamma in muscle. Obesity and NIDDM were not associated with change in PPARs and LXR alpha expression in adipose tissue. The mRNA levels of PPAR gamma1, the predominant form in adipocytes, did not correlate with BMI, leptin mRNA levels, or fasting insulinemia in 29 subjects with various degrees of obesity. These results indicated that obesity is not associated with alteration in PPAR gene expression in abdominal subcutaneous adipose tissue in humans.
Diabetes 1997 Aug
PMID:Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. 923 57

Thiazolidinediones (TZDs) such as BRL 49653 are a class of antidiabetic agents that are agonists for the peroxisome proliferator-activated nuclear receptor (PPAR-gamma2). In vivo, TZDs reduce circulating levels of free fatty acids (FFAs) and ameliorate insulin resistance in individuals with obesity and NIDDM. Adipocyte production of TNF-alpha is proposed to play a role in the development of insulin resistance, and because BRL 49653 has been shown to antagonize some of the effects of TNF-alpha, we examined the effects of TNF-alpha and BRL 49653 on adipocyte lipolysis. After a 24-h incubation of TNF-alpha (10 ng/ml) with 3T3-L1 adipocytes, glycerol release increased by approximately 7-fold, and FFA release increased by approximately 44-fold. BRL 49653 (10 pmol/l) reduced TNF-alpha-induced glycerol release by approximately 50% (P < 0.001) and FFA release by approximately 90% (P < 0.001). BRL 49653 also reduced glycerol release by approximately 50% in adipocytes pretreated for 24 h with TNF-alpha. Prolonged treatment (5 days) with either BRL 49653 or another PPAR-gamma2 agonist, 15-d delta-12,14-prostaglandin J2 (15-d deltaPGJ2), blocked TNF-alpha-induced glycerol release by approximately 100%. Catecholamine (isoproterenol)-stimulated lipolysis was unaffected by BRL 49653 and 15-d deltaPGJ2. BRL 49653 partially blocked the TNF-alpha-mediated reduction in protein levels of hormone-sensitive lipase and perilipin A, two proteins involved in adipocyte lipolysis. These data suggest a novel pathway that may contribute to the ability of the TZDs to reduce serum FFA and increase insulin sensitivity.
Diabetes 1998 Apr
PMID:BRL 49653 blocks the lipolytic actions of tumor necrosis factor-alpha: a potential new insulin-sensitizing mechanism for thiazolidinediones. 956 6

Peroxisome proliferator-activated receptor (PPAR)-gamma is one of the key actors of adipocyte differentiation. This study demonstrates 1) that PPAR-gamma mRNA expression is not altered in subcutaneous adipose tissue (n = 44) or in skeletal muscle (n = 19) of subjects spanning a wide range of BMIs (20-53 kg/m2) and 2) that insulin acutely increases PPAR-gamma mRNA expression in human adipocytes both in vivo and in vitro. The effect of insulin was investigated in abdominal subcutaneous biopsies obtained before and at the end of a 3-h euglycemic-hyperinsulinemic clamp. Insulin significantly increased PPAR-gamma mRNA levels in lean subjects (88 +/- 17%, n = 6), in type 2 diabetic patients (100 +/- 19%, n = 6), and in nondiabetic obese patients (91 +/- 20%, n = 6). Both PPAR-gamma1 and PPAR-gamma2 mRNA variants were increased (P < 0.05) after insulin infusion. In isolated human adipocytes, insulin induced the two PPAR-gamma mRNAs in a dose-dependent manner, with half-maximal stimulation at a concentration of approximately 1-5 nmol/l. However, PPAR-gamma2 mRNA was rapidly (2 h) and transiently increased, whereas a slow and more progressive induction of PPAR-gamma1 was observed during the 6 h of incubation. In explants of human adipose tissue, PPAR-gamma protein levels were significantly increased (42 +/- 3%, P < 0.05) after 12 h of incubation with insulin. These data demonstrate that PPAR-gamma belongs to the list of the insulin-regulated genes and that obesity and type 2 diabetes are not associated with alteration in the expression of this nuclear receptor in adipose tissue.
Diabetes 1999 Apr
PMID:Insulin acutely regulates the expression of the peroxisome proliferator-activated receptor-gamma in human adipocytes. 1010 84

We have examined the effects of underfeeding and obesity on the density of hypothalamic melanocortin MC3 and MC4 receptors (MC3-R and MC4-R, respectively), which may mediate the hypophagic effects of alpha-melanocyte-stimulating hormone (MSH) in the rat. MC3-R and MC4-R were measured by quantitative autoradiography in brain sections using 125I-labeled Nle4-D-Phe7-alpha-MSH (125I-NDP-MSH) and discriminated by masking MC3-R with excess unlabelled gamma2-MSH. High densities of MC4-R occurred in the ventromedial (VMH) and arcuate (ARC) nuclei, median eminence (ME), and medial habenular nucleus (MHb), with lower densities in the dorsomedial hypothalamus (DMH) and forebrain regions. MC3-R were confined to the VMH, ARC, and MHb. After 10-days of food restriction (14% weight loss), density of MC4-R was significantly increased by 20-65% in the VMH, ARC, ME, and DMH, with no changes elsewhere. Similarly, obese (fa/fa) Zucker rats showed 43-98% increases in MC4-R in the same regions. By contrast, rats with diet-induced obesity (18% heavier than controls) showed significantly decreased binding to MC4-R, especially in the VMH, ARC, and ME. MC3-R showed no significant alterations in any model. We suggest that increased density of MC4-R with food restriction and in obese Zucker rats reflects receptor upregulation secondary to decreased release of alpha-MSH, consistent with increased hunger in these models. Conversely, downregulation of MC4-R in diet-induced obesity may indicate increased alpha-MSH secretion in an attempt to limit overeating. This alpha-MSH/MC4-R system may be inhibited by leptin and/or insulin. MC3-R are not apparently involved in regulating feeding.
Diabetes 1999 Feb
PMID:Altered energy balance causes selective changes in melanocortin-4(MC4-R), but not melanocortin-3 (MC3-R), receptors in specific hypothalamic regions: further evidence that activation of MC4-R is a physiological inhibitor of feeding. 1033

Peroxisome proliferator-activated receptor (PPAR)-gamma is a major regulator of adipogenesis and insulin sensitivity. The PPAR-gamma gene generates two isoforms through alternative splicing, PPAR-gamma1 and -gamma2, the latter having an additional stretch of 28 amino acids at its NH2-terminus in the ligand-independent activation domain. This extension renders PPAR-gamma2 more sensitive to insulin action. Since there is a Pro12Ala substitution in this domain, we tested whether it is related to type 2 diabetes or insulin resistance. Therefore, 131 type 2 diabetic patients and 312 normoglycemic control subjects were screened for the presence of the mutation and for major clinical and metabolic features. The frequency of the mutation did not differ significantly between diabetic patients and control subjects. BMI, insulin, and other metabolic and anthropometric variables were also not associated with the mutation. Although the study was carried out on a sufficiently large sample, the conclusions do not support a major role for the Pro12Ala substitution of the PPAR-gamma gene in the etiology of type 2 diabetes.
Diabetes 1999 Jul
PMID:Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes. 1038 55

Little is known about the mechanisms involved in the preferential channeling of different fuels to fat and how the target tissue participates in this process. Dietary fatty acids have been shown to act as signaling molecules that bind and activate a new class of nuclear receptors, the peroxisome proliferator-activated receptors (PPARs). PPAR-gamma is particularly interesting because it may have the potential to link particular fatty acids with a program of gene expression involved in lipid storage and metabolism. We investigated whether a nutrient-sensing pathway is activated by an increased availability of lipid fuels in nine normal weight male volunteers. Using reverse transcriptase-polymerase chain reaction analysis, the mRNA expression of fatty acid translocase (FAT)/CD36, PPAR-gamma2, leptin, uncoupling protein (UCP)-2 and UCP-3, and tumor necrosis factor (TNF)-alpha was investigated in gluteal subcutaneous fat biopsies before and after 5 h infusions of saline or Intralipid (Pharmacia and Upjohn, Milan, Italy) plus heparin, which does not modify insulinemia. Marked increases in FAT/CD36 (724+/-18%; P < 0.05), PPAR-gamma2 (200+/-8%; P < 0.05), leptin (110+/-13%; P < 0.05), UCP-2 (120+/-7%; P < 0.05), UCP-3 (80+/-5%; P < 0.05), and TNF-alpha mRNA (130+/-12%; P < 0.05) were observed in comparison with pretreatment levels, whereas there was no change after saline infusion. These data suggest that the in vivo gene expression of FAT/CD36, PPAR-gamma2, leptin, UCP-2, UCP-3, and TNF-alpha in subcutaneous adipose tissue is regulated by circulating lipids independent of insulin and that prolonged hyperlipidemia may therefore contribute to increased fat metabolism and storage as a result of the increased expression of these proteins.
Diabetes 2000 Mar
PMID:Induction of fatty acid translocase/CD36, peroxisome proliferator-activated receptor-gamma2, leptin, uncoupling proteins 2 and 3, and tumor necrosis factor-alpha gene expression in human subcutaneous fat by lipid infusion. 1086 51

The effect of the thiazolidinediones (TZDs) darglitazone and troglitazone on beta3-adrenergic receptor (AR) expression was studied in cultured cell lines representing several tissues. After 24 h of exposing HIB-1B brown adipocytes to 30 micromol/l darglitazone or 20 micromol/l troglitazone, beta3-AR mRNA levels were reduced by 75%. This effect was significant within 1 h of exposure to a maximal dose of these drugs, with the full effect obtained within 10 h. The darglitazone ID50 was approximately 10 nmol/l, similar to the Kd of TZDs binding to peroxisome proliferator-activated receptor-gamma (PPAR-gamma). These drugs also decreased beta3-AR mRNA in 3T3-F442A white adipocytes, but not in SK-N-MC cells, which lack PPAR-gamma2. A luciferase reporter gene containing 1.4 kb of 5' flanking sequence of the mouse beta3-AR was transiently transfected, with or without PPAR-gamma2, in SK-N-MC cells. The vigorous expression of luciferase driven by the beta3-AR gene sequence was inhibited by TZDs in a PPAR-gamma2-dependent manner. The half-lives of gamma3-AR precursor RNA and mRNA were short, approximately 40 and approximately 100 min, respectively, and remained unaffected by TZD treatment. Exposure of HIB-1B cells to 30 micromol/l darglitazone was associated with reduced beta3-AR mRNA levels, as well as decreased response of uncoupling protein 1 to norepinephrine + propranolol (a beta1 beta2-AR antagonist) or the specific beta3-AR agonist CL 316, 243. Both the beta3-AR mRNA level and response to these stimuli fully recovered by 24 h of removing the drug, indicating that the beta3-AR protein and its coupling to adenylyl cyclase rapidly followed the changes in mRNA. Thus, TZDs can rapidly reduce beta3-AR expression at the transcriptional level, acting through PPAR-gamma2. The rapid turnover and responses of beta3-AR to perturbations, along with numerous other factors reported to regulate its expression, suggest a tight control of beta3-AR and function. Lastly, leptin being the only other known gene suppressed by TZDs, the present studies support a concerted lipogenic effect of these drugs.
Diabetes 2000 Dec
PMID:Thiazolidinediones inhibit the expression of beta3-adrenergic receptors at a transcriptional level. 1111 14

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)-gamma2 is associated with reduced transcriptional activity in vitro and increased insulin sensitivity in humans in vivo. The mechanism by which this polymorphism influences insulin sensitivity in humans is unclear. PPAR-gamma2 is mainly expressed in adipocytes, and free fatty acids released from adipose tissue are key mediators of peripheral insulin resistance. Therefore, we examined insulin suppression of lipolysis in 51 subjects without (Pro/Pro) and 17 subjects with the polymorphism (X/Ala). Both groups were lean (BMI <27.0 kg/m2) and matched for age, BMI, waist-to-hip ratio, and sex. The isotopically (infusion of d5 glycerol) determined glycerol rate of appearance was used as an index of lipolysis. Insulin sensitivity of lipolysis was expressed as the insulin concentration resulting in half-maximal suppression (EC50). This was directly determined during a three-step hyperinsulinemic-euglycemic clamp (n = 21) or estimated indirectly during a standard hyperinsulinemic-euglycemic clamp (n = 47). The insulin sensitivity index (ISI) of glucose disposal was 0.095+/-0.006 micromol x kg(-1) x min(-1) x pmol(-1) x l(-1) in the control group and 0.129+/-0.008 micromol x kg(-1) x min(-1) x pmol(-1) x l(-1) in the X/Ala group (P = 0.003). The EC50 was 56+/-2 pmol/l in the control group and 44+/-3 pmol/l in the X/Ala group (P = 0.001). The EC50 of lipolysis and ISI was significantly correlated (r = 0.42, P = 0.002). In conclusion, in lean subjects, the Pro12Ala polymorphism is associated with increased insulin sensitivity of glucose disposal and suppression of lipolysis. This result suggests that an altered transcriptional activity of PPAR-gamma2 in X/Ala subjects either causes a more efficient suppression of lipolysis in adipose tissue, which in turn results in improved insulin-stimulated glucose disposal in muscle, or, alternatively, beneficially affects insulin signaling in both tissues independently of one another.
Diabetes 2001 Apr
PMID:Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 gene is associated with increased antilipolytic insulin sensitivity. 1128 55

Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a nuclear receptor that regulates adipocyte differentiation and possibly insulin sensitivity. The Pro12Ala variant has been associated in some studies with diabetes-related traits and/or protection against type 2 diabetes. We examined this variant in 935 Finnish subjects, including 522 subjects with type 2 diabetes, 193 nondiabetic spouses, and 220 elderly nondiabetic control subjects. The frequency of the Pro12Ala variant was significantly lower in diabetic subjects than in nondiabetic subjects (0.15 vs. 0.21; P = 0.001). We also compared diabetes-related traits between subjects with and without the Pro12Ala variant within subgroups. Among diabetic subjects, the variant was associated with greater weight gain after age 20 years (P = 0.023) and lower triglyceride levels (P = 0.033). Diastolic blood pressure was higher in grossly obese (BMI >40 kg/m2) diabetic subjects with the variant. In nondiabetic spouses, the variant was associated with higher fasting insulin (P = 0.033), systolic blood pressure (P = 0.021), and diastolic blood pressure (P = 0.045). These findings support a role for the PPAR-gamma2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome.
Diabetes 2001 Apr
PMID:The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with type 2 diabetes and trait differences. 1128 57


1 2 3 4 5 6 Next >>