Discovery of INT131: A selective PPARγ modulator that enhances insulin sensitivity

PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure–activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.     

Selective PPARγ modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice

INT131 is a potent non-thiazolidinedione (TZD)-selective peroxisome proliferator-activated receptor-γ modulator being developed for the treatment of type 2 diabetes. In preclinical studies and a phase II clinical trial, INT131 has been shown to lower glucose levels and ameliorate insulin resistance without typical TZD side effects. To determine whether the insulin-sensitizing action of INT131 is mediated by effects on insulin-mediated glucose homeostasis and insulin signaling, high-fat diet-induced obese (DIO) insulin-resistant mice treated with INT131 were studied. INT131's effects on bone density were also investigated. Treatment with INT131 enhanced systemic insulin sensitivity, as revealed by lower insulin levels in the fasted state and an increase in the area above the curve during an insulin tolerance test. These effects were independent of changes in adiposity. Insulin-stimulated PI3K activity in skeletal muscle and adipose tissue of DIO mice was significantly reduced ～50-65%, but this was restored completely by INT131 therapy. The INT131 effects on PI3K activity are most likely due to increased IRS-1 tyrosine phosphorylation. Concurrently, insulin-mediated Akt phosphorylation also increased after INT131 treatment in DIO mice. Importantly, INT131 therapy caused a significant increase in bone mineral density without alteration in circulating osteocalcin in these mice. These data suggest that a newly developed insulin-sensitizing agent, INT131, normalizes obesity-related defects in insulin action on PI3K signaling in insulin target tissues by a mechanism involved in glycemic control. If these data are confirmed in humans, INT131 could be used for treating type 2 diabetes without loss in bone mass.     

Promotion of adiponectin multimerization by emodin: A novel AMPK activator with PPARγ-agonist activity

Adiponectin is an important insulin‐sensitizing adipokine with multiple beneficial effects on obesity‐associated medical complications. It is secreted from adipocytes into circulation as high, medium, and low molecular weight forms (HMW, MMW, and LMW). Each oligomeric form of adiponectin exerts non‐overlapping biological functions, with the HMW oligomer possessing the most potent insulin‐sensitizing activity. In this study, we reported that emodin, a natural product and active ingredient of various Chinese herbs, activates AMPK in both 3T3‐L1 adipocytes and 293T cells. Activation of AMPK by emodin promotes the assembly of HMW adiponectin and increases the ratio of HMW adiponectin to total adiponectin in 3T1‐L1 adipocytes. Emodin might activate AMPK by an indirect mechanism similar to berberine. We also found that emodin activates PPARγ and promotes differentiation and adiponectin expression during differentiation of 3T3‐L1 preadipocytes. Therefore, emodin is a novel AMPK activator with PPARγ‐agonist activity. Our results demonstrate that the effects of emodin on adiponectin expression and multimerization are the ultimate effects resulting from both AMPK activation and PPARγ activation. The dual‐activity makes emodin or the derivatives potential drug candidates for the treatment of type 2 diabetes and other obesity‐related metabolic diseases. J. Cell. Biochem. 113: 3547–3558, 2012. © 2012 Wiley Periodicals, Inc.     

Differential activity of rosiglitazone enantiomers at PPARγ

Analysis of the enantiomers of rosiglitazone in a PPARγ binding assay suggests that the (S)-(−)-isomer is responsible for the antidiabetic activity.     

Identification of a PPARδ agonist with partial agonistic activity on PPARγ

The discovery and optimization of a series of potent PPARδ full agonists with partial agonistic activity against PPARγ is described.     

FGF21 and the second coming of PPARγ

Peptide hormone fibroblast growth factor-21 (FGF21) has insulin-mimetic properties. Dutchak et?al. now suggest that FGF21 also acts in an autocrine fashion in adipocytes and is required to mediate effects of the PPARγ agonist class of antidiabetic drugs. Does this new property improve FGF21's fledgling clinical prospects or endorse a clinical resuscitation of PPARγ agonists?     

PPARγ与代谢性疾病

过氧化物酶体增殖物激活受体γ(PPARγ)是一种可由多种脂肪酸及其衍生物激活的核转录因子,在机体糖脂代谢中起重要调节作用,一些可作为其配体的合成化合物现已应用于Ⅱ型糖尿病的临床治疗。该简单介绍PPARγ作用的分子机制以及PPARγ与一些代谢性疾病的关系。     

PPARα、PPARγ及其双激动剂与动脉粥样硬化

过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptors,PPARs）是核受体超家族中的一类配体依赖的核转录因子,其中两种重要的亚型PPARα和PPARγ在脂肪细胞分化、能量代谢和炎症过程中都发挥重要作用。研究显示,PPARα和PPARγ的配体激动剂不仅可以改善包括糖尿病、高血压和肥胖等在内的胰岛素抵抗综合征,而且还可以通过作用于血管壁从而减缓动脉粥样硬化的进程。本文将就PPARα和PPARγ及其双激动剂与动脉粥样硬化发病机制和治疗的相关研究进展进行概括介绍。     

A Novel Class of Fungicides: α-Benzylidene-γ-valerolactones

Enzyme activities involved in the initial step of glycerol metabolism were determined in cells of methylotrophic yeasts grown on glycerol, methanol or glucose. In Candida boidinii (Kloeckera sp.) No. 2201, the activities of glycerol kinase and dihydroxyacetone kinase were detected in cells grown on glycerol and methanol, respectively. The activity of NAD⁺-linked glycerol dehydrogenase of Hansenula polymorpha dl-1 was induced by glycerol and methanol, while that of Hansenula ofunaensis was induced by glycerol. The enzymes of both strains were subject to catabolite repression by glucose.

The yeasts tested were divided into three groups as to the glycerol dissimilation patterns. Strains of the genera Candida, Saccharomyces, Pichia and Torulopsis had the phosphorylative pathway, in which glycerol is first phosphorylated. H. ofunaensis had the oxidative pathway, in which glycerol is first oxidized. H. polymorpha dl-1 had both the phosphorylative and oxidative pathways.     

γ-Butyrobetaine hydroxylase: A unique protective effect of catalase

Catalase stimulates the activity of homogeneous γ-butyrobetaine hydroxylase by approximately 300-fold. The stimulation of the hydroxylation reaction elicited by catalase is saturable, and although a number of proteins may be substituted for catalase, none is as effective. γ-Butyrobetaine hydroxylase is also irreversibly inactivated in the presence of one of its substrates, oxygen, and its cofactor, ascorbate. This inactivation of the hydroxylase activity may be prevented by (i) the presence of high concentrations (2 mg/ml) of various proteins, (ii) the presence of catalytic concentrations (20 μg/ml) of catalase, or (iii) the presence of 10 mm histidine or dithiothreitol. Oxidized species of ascorbate do not appear to be responsible for the inactivation process. Time-dependent inactivation is also observed when γ-butyrobetaine hydroxylase is preincubated with hydrogen peroxide generated by the glucose oxidase-catalyzed oxidation of glucose. At low concentrations, superoxide dismutase was not as effective as an equivalent protein concentration of catalase in protecting against inactivation, and hydroxyl radical scavengers were completely ineffective. In measurements of γ-butyrobetaine hydroxylase activity, the presence of catalase both stimulates the catalytic activity of the hydroxylase and protects the enzyme from inactivation by a product of the interaction of components in the assay mixture, presumably hydrogen peroxide.     

激活PPARα缓解PPARγ诱导的小鼠脂肪肝

目的研究PPARα激活后对PPARγ诱导小鼠脂肪肝的影响。方法以4~5周龄C57BL/6J小鼠为模型,实验分为4组:正常饮食组;0.125%Wy-14,643处理组;PPARγ腺病毒(Ad/PPARγ)注射组;先给予0.125%Wy-14,643饮食再注射Ad/PPARγ组。实验结束时,收集肝脏组织称重、照相,HE、油红O染色观察PPARα激活后对PPARγ诱导肝脏脂肪变性的影响。结果野生型小鼠给予PPARα激动剂Wy-14,643处理8 d,与对照组相比,处理组小鼠肝脏明显增大,呈现过氧化物酶体增殖反应;野生型小鼠给予Ad/PPARγ5 d,小鼠肝脏显著增大,出现脂肪肝;给予PPARα激动剂Wy-14,643 3 d,再给予Ad/PPARγ5 d,小鼠肝脏增大更加显著,HE染色、油红O染色结果显示小鼠肝脏脂肪变性明显减轻。结论激活PPARα能够缓解PPARγ诱导的小鼠肝脏脂肪变,为脂肪肝的预防和治疗提供了新的研究思路和靶点。     

PPARγ天然激动剂的研究进展

过氧化物酶体增殖剂活化受体γ(PPARγ)是一个由配体激活的核转录因子,属于核激素受体(nuclear hormone receptor)超家族.它与脂肪形成、免疫应答以及脂质和糖类代谢等生理过程极其相关.尽管PPARγ的合成激动剂已广泛应用于胰岛素致敏剂,但是PPARγ的天然激动剂的鉴定一直不是很清楚,目前,PPARγ的天然激动剂主要有氧化的脂肪酸和硝基脂肪酸,包括9-羟十八碳二烯醇(9-HODE),13-羟十八碳二烯醇(13-HODE),5-脱氧前列腺素J2,油酸和亚油酸的硝基衍生物(分别为OA-NO2和LNO2)等.本文综述了近年的PPARγ的天然激动剂的研究进展.     

PPARγ的翻译后修饰

过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor gamma,PPARγ)是一种配体依赖性核转录因子,它具有调控细胞分化、脂肪代谢、糖代谢及炎症等多种生物学功能.机体对PPARγ转录活性的调控方式是多种多样的,包括蛋白表达水平、配体以及转录辅助因子等不同层次上的调控.近年来众多证据揭示,蛋白翻译后修饰(posttranslational modifications,PTMs)是机体调节PPARγ转录活性的另一重要方式.目前,已报道的PPARγ翻译后修饰包括磷酸化、泛素化、SUMO化和亚硝基化等,它们能够改变蛋白构象、调控蛋白相互作用、改变受体与配体间的亲和力,从而调控PPARγ下游基因的转录.重要的是,PPARγ的翻译后修饰与一些疾病如糖尿病、动脉粥样硬化、肿瘤等密切相关.本文将主要围绕PPARγ的各种翻译后修饰及其在疾病的发生、发展和治疗中的意义作一综述.