The effects of rexinoids and rosiglitazone on body weight and uncoupling protein isoform expression in the Zucker fa/fa rat

Agonists for the retinoid X receptor (RXR), the rexinoids, and the peroxisome proliferator-activated receptor gamma (PPARgamma), the thiazolidinediones, are effective in the treatment of insulin resistance in rodent models by enhancing insulin action and improving glycemic control. In the present study, we compared the effects of rexinoids and a thiazolidinedione on body weight and mitochondrial uncoupling protein (UCP) isoform mRNA expression in the obese Zucker fa/fa rat. Long-term (2 weeks) oral treatment with the rexinoids LG100268 and LG100324 reduced food intake and body weight gain, whereas rosiglitazone (BRL49653) tended to increase both food intake and weight gain. LG100268 and LG100324 increased brown adipose tissue (BAT) UCP-1 mRNA content by 2.7-fold (P < .002) and 3.1-fold (P < .001), respectively, while BRL49653 had no effect on BAT UCP-1 mRNA content. Neither the rexinoids nor the thiazolidinedione had any effect on the level of mRNA encoding UCP-2 and the recently described PPARgamma coactivator-1 (PGC-1). LG100324 increased UCP-3 mRNA content by 3.6-fold (P < .0005) in muscle and 4.3-fold (P < .0002) in white adipose tissue (WAT). LG100268 increased UCP-3 mRNA content in WAT by 2-fold (P < .005) but was without any effect on muscle UCP-3. BRL49653 increased UCP-3 mRNA content by 2.1-fold (P < .005) in muscle and 2.7-fold (P < .003) in WAT. Thus, the rexinoids, but not the thiazolidinedione, have an antiobesity action by reducing food intake, and the increase in UCP-1 mRNA content in BAT may reflect a stimulation of BAT UCP-1 activity.     

Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation

OBJECTIVE: To develop and to characterize a human preadipocyte cell strain with high capacity for adipose differentiation serving as a model for studying human adipocyte development and metabolism in vitro. METHODS: Cells were derived from the stromal cells fraction of subcutaneous adipose tissue of an infant with Simpson-Golabi-Behmel syndrome (SGBS). Adipose differentiation was induced under serum-free culture conditions by exposure to 10 nM insulin, 200 pM triiodothyronine, 1 microM cortisol and 2 microM BRL 49653, a PPAR gamma agonist. RESULTS: During the differentiation process SGBS cells developed a gene expression pattern similar to that found in differentiating human preadipocytes with a characteristic increase in fat cell-specific mRNAs encoding lipoprotein lipase (LPL), glycero-3-phosphate dehydrogenase (GPDH), GLUT4, leptin and others. Differentiated SGBS cells exhibited an increase in glucose uptake upon insulin stimulation and in glycerol release upon catecholamine exposure. SGBS adipocytes were morphologically, biochemically and functionally identical to in vitro differentiated adipocytes from healthy subjects. However, while preadipocytes from healthy control infants rapidly lost their capacity to differentiate after a few cell divisions in culture, SGBS cells maintained their differentiation capacity over many generations: upon appropriate stimulation 95% of SGBS cells of generation 30 developed into adipocytes. A mutation in the glypican 3 gene was not detected in the patient. Thus, it remains unclear whether the molecular alteration in SGBS cells is also responsible for the high differentiation capacity and further investigations are required. CONCLUSION: The human cell strain described here provides an almost unlimited source of human preadipocytes with high capacity for adipose differentiation and may, therefore, represent a unique tool for studying human fat cell development and metabolism. International Journal of Obesity (2001) 25, 8-15     

The effects of rexinoids and rosiglitazone on body weight and uncoupling protein isoform expression in the Zucker fa/fa rat

Agonists for the retinoid X receptor (RXR), the rexinoids, and the peroxisome proliferator-activated receptor gamma (PPAR γ), the thiazolidinediones, are effective in the treatment of insulin resistance in rodent models by enhancing insulin action and improving glycemic control. In the present study, we compared the effects of rexinoids and a thiazolidinedione on body weight and mitochondrial uncoupling protein (UCP) isoform mRNA expression in the obese Zucker fa/fa rat. Long-term (2 weeks) oral treatment with the rexinoids LG100268 and LG100324 reduced food intake and body weight gain, whereas rosiglitazone (BRL49653) tended to increase both food intake and weight gain. LG100268 and LG100324 increased brown adipose tissue (BAT) UCP-1 mRNA content by 2.7-fold (P < .002) and 3.1-fold (P < .001), respectively, while BRL49653 had no effect on BAT UCP-1 mRNA content. Neither the rexinoids nor the thiazolidinedione had any effect on the level of mRNA encoding UCP-2 and the recently described PPAR γ coactivator-1 (PGC-1). LG100324 increased UCP-3 mRNA content by 3.6-fold (P < .0005) in muscle and 4.3-fold (P < .0002) in white adipose tissue (WAT). LG100268 increased UCP-3 mRNA content in WAT by 2-fold (P < .005) but was without any effect on muscle UCP-3. BRL49653 increased UCP-3 mRNA content by 2.1-fold (P < .005) in muscle and 2.7-fold (P < .003) in WAT. Thus, the rexinoids, but not the thiazolidinedione, have an antiobesity action by reducing food intake, and the increase in UCP-1 mRNA content in BAT may reflect a stimulation of BAT UCP-1 activity.     

Decreased expression of apM1 in omental and subcutaneous adipose tissue of humans with type 2 diabetes

We have screened a subtracted cDNA library in order to identify differentially expressed genes in omental adipose tissue of human patients with Type 2 diabetes. One clone (#1738) showed a marked reduction in omental adipose tissue from patients with Type 2 diabetes. Sequencing and BLAST analysis revealed clone #1738 was the adipocyte-specific secreted protein gene apM1 (synonyms ACRP30, AdipoQ, GBP28). Consistent with the murine orthologue, apM1 mRNA was expressed in cultured human adipocytes and not in preadipocytes. Using RT-PCR we confirmed that apM1 mRNA levels were significantly reduced in omental adipose tissue of obese patients with Type 2 diabetes compared with lean and obese normoglycemic subjects. Although less pronounced, apM1 mRNA levels were reduced in subcutaneous adipose tissue of Type 2 diabetic patients. Whereas the biological function of apM1 is presently unknown, the tissue specific expression, structural similarities to TNFalpha, and the dysregulated expression observed in obese Type 2 diabetic patients suggest that this factor may play a role in the pathogenesis of insulin resistance and Type 2 diabetes.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

RAS阻断剂对人前脂肪细胞脂联素表达的部位特异性影响

肾素-血管紧张素系统(RAS)阻断剂可提高体外原代培养的人网膜和皮下前脂肪细胞中脂联素mRNA的表达和蛋白分泌.与噻唑烷二酮类药物相比,RAS阻断剂对网膜来源的细胞具有更强的作用,提示其在以腹型肥胖为特征的代谢综合征干预方面可能具有较大潜力.     

Production and release of macrophage migration inhibitory factor from human adipocytes

BACKGROUND AND AIM OF THE STUDY: Macrophage migration inhibitory factor (MIF) has been identified as a critical mediator of inflammatory responses. Because of its potent migration inhibition activity, it regulates macrophage accumulation in tissues. We therefore analyzed whether human adipocytes produce MIF, in the search of candidate mediators of macrophage infiltration of obese adipose tissue. METHODS: Human adipose tissue samples were obtained from various depots. The precursor cells were allowed to differentiate under defined adipogenic culture conditions. MIF expression was analyzed by RT-PCR, ELISA, and immunocytochemistry. RESULTS: Human preadipocytes secreted MIF in a differentiation-dependent fashion with maximum concentrations at d 12, whereas MIF mRNA was detected in both undifferentiated and differentiated cells at relatively constant levels. Immunocytochemical analysis showed that MIF protein was present in preadipocytes and more pronounced in differentiated adipocytes. Freshly isolated mature adipocytes from sc, omental, and mammary depots released MIF at rates of up to 10,000 pg/ml.24 h. Most importantly, MIF production was positively correlated with donor body mass index. Secretion of MIF was not influenced by lipopolysaccharide, interferon-gamma, or IL-4. The rates of MIF release from sc and omental adipocytes were similar but approximately 10 times higher compared with mammary adipocytes. CONCLUSIONS: Human preadipocytes and mature adipocytes from different depots spontaneously release substantial amounts of MIF. Expression levels were positively associated with donor body mass index. Hence, MIF may be an obesity-dependent mediator of macrophage infiltration of adipose tissue.     

Regulation of differentiation of sheep subcutaneous and abdominal preadipocytes in culture.

Factors regulating the differentiation of sheep subcutaneous and abdominal (omental or perirenal) preadipocytes from foetal lambs, suckling lambs and fattening sheep have been investigated using a serum-free cell culture system. Differentiation was assessed by changes in the activity of the enzyme glycerol 3-phosphate dehydrogenase. Insulin or IGF-I was essential for differentiation. Dexamethasone, a lipid supplement (Excyte) and the thiazolidinedione, rosiglitazone (BRL 49653) (a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist) all enhanced preadipocyte differentiation, whereas fibroblast growth factor and GH were inhibitory. The most effective combination was insulin, triiodothyronine, dexamethasone and rosiglitazone. Under suboptimal conditions, preadipocytes from fattening sheep differentiated less well than cells from suckling and foetal lambs. Also, under suboptimal conditions, abdominal preadipocytes did not differentiate as well as subcutaneous preadipocytes. However, age and depot differences were minimised when cells were cultured with insulin, triiodothyronine, rosiglitazone and either dexamethasone or lipid. The results suggest that variation in the ability to produce the natural ligand for PPAR-gamma contributes to depot- and age-specific differences in the ability of preadipocytes to differentiate.