Regional Differences in the Response of Human Pre-Adipocytes to PPARγ and RXRα Agonists

Abstract

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) ␥1 and ␥2 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 PPAR␥1 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 PPAR␥2 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 PPAR␥ 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, RXR␣ 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 PPAR␥1 and ␥2 mRNA and their diminished capacity to upregulate PPAR␥2 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 RXR␣ in the undifferentiated state suggests that they may have a more generalized resistance to differentiation. Diabetes 51:718 -723, 2002

Regional differences in cellular mechanisms of adipose tissue gain with overfeeding

“…After 15 d of exposure to serum-free differentiation medium, the expression of the key adipogenic transcription factors PPARγ2 and C/EBPα was greater in abdominal than femoral preadipocytes. The importance of PPARγ2 for adipogenesis is well established (29,30), and PPARγ is positively associated with fat-cell size in mice (31) and with obesity in humans (29). Inherent differences in fat-cell hyperplasia and, potentially, in the production of mediators that recruit new fat-cell development may, together with differences in circulation, nutrient supply, innervation, or local hormonal and paracrine factors, contribute to the distinct responses of different fat depots to high caloric intake.…”

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…11 -HSD1 -/-mice had higher adipose PPAR mRNA levels in their fat. Since PPAR ligands cause insulin sensitisation and fat M a n u s c r i p t 11 redistribution to the periphery (Kelly et al, 1999, Sewter et al, 2002, a mechanism for the beneficial fat redistribution was suggested, on the assumption that increased circulating free fatty acids during high fat feeding were acting as endogenous ligands for the PPAR receptors . In agreement with both increased PPAR and reduced glucocorticoid action, insulin sensitisation is evident in isolated primary 11 -HSD1 -/-adipocytes which showed increased basal and insulin-stimulated glucose uptake.…”

Tissue expression, association analysis between three novel SNPs of the RXRα gene and growth traits in Chinese indigenous cattle

“…Schoonjans et al [14] pointed out that RXR/PPAR was combined with a specific sequence DR in promoter region of LPL gene and could promote the expression of LPL. The RXR ligand LG100268 acted together with PPAR agonists rosiglitazone to promote subcutaneous adipose differentiation of human [15]. In metabolism, it was known that many nuclear receptor-mediated pathways in fatty acid oxidation and lipid metabolism were disordered for the lack of RXR [16].…”