Adrenomedullin 2 (AM2) or intermedin is a member of the calcitonin gene-related peptide (CGRP)/calcitonin family of peptides and was discovered in 2004. Unlike other members of this family, no unique receptor has yet been identified for it. It is extensively distributed throughout the body. It causes hypotension when given peripherally, but when given into the CNS, it increases blood pressure and causes sympathetic activation. It also increases prolactin release, is anti-diuretic and natriuretic and reduces food intake. Whilst its effects resemble those of AM, it is frequently more potent. Some characterization of AM2 has been done on molecularly defined receptors; the existing data suggest that it preferentially activates the AM2 receptor formed from calcitonin receptor-like receptor and receptor activity modifying protein 3. On this complex, its potency is generally equivalent to that of AM. There is no known receptor-activity where it is more potent than AM. In tissues and in animals it is frequently antagonised by CGRP and AM antagonists; however, situations exist in which an AM2 response is maintained even in the presence of supramaximal concentrations of these antagonists. Thus, there is a partial mismatch between the pharmacology seen in tissues and that on cloned receptors. The only AM2 antagonists are peptide fragments, and these have limited selectivity. It remains unclear as to whether novel AM2 receptors exist or whether the mismatch in pharmacology can be explained by factors such as metabolism. -piperidinecarboxamide, N-[2-[[5-amino-1-[[4-(4- LINKED ARTICLES IntroductionThe peptide known either as adrenomedullin 2 (AM2) or intermedin (IMD) was independently discovered by two groups in Takei et al., 2004a). It is most closely related to AM. In fish it is one of a family of five AM-related peptides, but in mammals, there is currently only evidence for widespread expression of AM and AM2; in some mammals (such as ungulates and lower primates but not rodents or humans), the equivalent of fish AM5 is also found (Takei et al., 2008). AM2/IMD sits within the wider calcitonin (CT) generelated peptide (CGRP)/CT family of peptides, which also includes amylin. It is expressed in both peripheral tissues and in the CNS; its effects generally resemble those of AM, but it is sometimes more potent and appears to have some unique actions ( ). This review considers the pharmacology of AM2/ IMD, both on molecularly defined receptors and in native cells and tissues. It considers its specificity for known receptors belonging to the CGRP/CT peptide family and also evaluates the evidence that it may act on other receptors. Distribution of AM2/IMDThe distribution of AM2/IMD in cells and tissues overlaps with AM. Compared with AM, AM2/IMD is less widely distributed in mammals . Table 1 summarizes the distribution of AM2/IMD in organs and tissues of different species. Generally, this peptide is found in the brain, pituitary, heart, kidney, gastrointestinal tract, plasma Takei et al., 2004a;Takahashi et al., 2006), pancre...

The antidiabetic thiazolidinediones, which include troglitazone and rosiglitazone, are ligands for the nuclear receptor peroxisome proliferator-a c t i v a t e d receptor (PPA R )-and exert their antihyperglycemic e ffects by regulation of PPA R--responsive genes. We report here that PPA R-activation by troglitazone depends on the experimental setting. Troglitazone acts as a partial agonist for PPA R-in transfected muscle (C2C12) and kidney (HEK 293T) cells, producing a submaximal transcriptional response (1.8-to 2.5-fold activation) compared with rosiglitazone (7.4-to 13-fold activation). Additionally, troglitazone antagonizes rosiglitazone-stimulated PPA R-transcriptional activity. Limited protease digestion of PPA R-suggests conformational differences in the receptor bound to troglitazone versus rosiglitazone. Consistent with this fin d i n g , an in vitro coactivator association assay demonstrated that troglitazone-bound PPA R-recruited the transcriptional coactivators p300 and steroid receptor coactivator 1 less efficiently than rosiglitazone-bound receptor. In contrast to these observations, troglitazone behaves as a full agonist of PPA R-in 3T3L1 adipocytes. Tw odimensional protein gel electrophoresis demonstrated that troglitazone and rosiglitazone regulated distinct but overlapping sets of genes in several cell types. Thus, troglitazone may behave as a partial agonist under certain physiological circumstances and as a full agonist in others. These differences could be caused by variations in the amount of specific cofactors, differences in PPA R response elements, or the presence of different isoforms of PPA R-. D i a b e t e s 4 9 :5 3 9-547, 2000 T ype 2 diabetes is characterized by decreased insulin sensitivity of peripheral tissues. Glucose homeostasis is maintained under these circumstances by increased insulin secretion from pancreatic -cells. In some cases, the -cell is unable to maintain increased output. The antidiabetic thiazolidinediones (TZDs), such as troglitazone, improve peripheral insulin sensitivity, leading to reduced blood glucose and insulin levels and the preservation of pancreatic function (1-4). Improvement of insulin sensitivity by TZDs is most likely due to the activation of the peroxisome proliferator-activated receptor (PPA R )-(5). The TZDs are high-affinity ligands for PPA R-in vitro, and the rank order of receptor affinity correlates with their in vivo hypoglycemic activity (6), with one reported exception (7). Although many of the molecular details are not clearly understood, a model has emerged in which activated PPA R-m o dulates the transcriptional activity of a set of genes encoding proteins that are important in glucose and lipid metabolism. H o w e v e r, the identity of these genes and the precise pathways leading to the normalization of insulin sensitivity remain largely unknown.R e c e n t l y, the X-ray crystal structure of the ligand-binding domain of PPA R-has been elucidated (3,8), revealing that ligand binding causes a conformational change within P PA R-such...

RUNX2, a key transcription factor for osteoblast differentiation, is regulated by ERK1/2 and p38 MAP kinase-mediated phosphorylation. However, the specific contribution of each kinase to RUNX2-dependent transcription is not known. Here we investigate ERK and p38 regulation of RUNX2 using a unique P-RUNX2-specific antibody. Both MAP kinases stimulated RUNX2 Ser319 phosphorylation and transcriptional activity. However, a clear preference for ERK1 versus p38α/β was seen when the ability of these MAPKs to phosphorylate and activate RUNX2 was compared. Similarly, ERK1 preferentially bound to a consensus MAPK binding site on RUNX2 that was essential for the activity of either kinase. To assess the relative contribution of ERK1/2 and p38 to osteoblast gene expression, MC3T3-E1 preosteoblast cells were grown in control or ascorbic acid (AA)-containing medium ± BMP2/7. AA-induced gene expression, which requires collagen matrix synthesis, was associated with parallel increases in P-ERK and RUNX2-S319-P in the absence of any changes in P-p38. This response was blocked by ERK, but not p38, inhibition. Significantly, in the presence of AA, BMP2/7 synergistically stimulated RUNX2 S319 phosphorylation and transcriptional activity without affecting total RUNX2 and this response was totally dependent on ERK/MAPK activity. In contrast, although p38 inhibition partially blocked BMP-dependent transcription, it did not affect RUNX2 S319 phosphorylation, suggesting the involvement of other phosphorylation sites and/or transcription factors in this response. Based on this work, we conclude that extracellular matrix and BMP regulation of RUNX2 phosphorylation and transcriptional activity in osteoblasts is predominantly mediated by ERK rather than p38 MAPKs.

Clinical studies have shown that metabolic syndrome (MetS) is associated with increased risk of developing periodontitis. However, the underlying mechanisms remain largely unknown. Since it is known that lipopolysaccharide (LPS)-activated toll-like receptor 4 signaling pathways play a crucial role in periodontitis, we hypothesized that MetS enhances LPS-induced periodontal inflammation and alveolar bone loss. In this study, we induced MetS in C57BL/6 mice by feeding them high-fat diet (HFD), and we induced periodontitis by periodontal injection of Aggregatibacter actinomycetemcomitans LPS. We found that mice fed a HFD had significantly increased body weight, plasma lipids, insulin, and insulin resistance when compared with mice fed regular chow, indicating that the mice developed MetS. We also found that a HFD markedly increased LPSinduced alveolar bone loss, osteoclastogenesis, and inflammatory infiltration. Analysis of gene expression in periodontal tissue revealed that HFD and LPS injection cooperatively stimulated expression of cytokines that are known to be involved in periodontal tissue inflammation and osteoclastogenesis-such as interleukin 6, monocyte-chemotactic protein 1, receptor activator of nuclear factor kappa-B ligand, and macrophage colony-stimulating factor. To further understand the potential mechanisms involved in MetS-boosted tissue inflammation, our in vitro studies showed that palmitic acid-the most abundant saturated fatty acid (SFA) and the major SFA in the HFD used in our animal study-potently enhanced LPS-induced proinflammatory gene expression in macrophages. In sum, this study demonstrated that MetS was associated with increased periodontal inflammation and alveolar bone loss in an LPS-induced periodontitis animal model. This study also suggests that SFA palmitic acid may play an important role in MetS-associated periodontitis by enhancing LPS-induced expression of inflammatory cytokines in macrophages.

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Background We have previously shown that systemic infusion of insulin-like growth factor-1 (IGF-1) exerts anti-inflammatory and anti-oxidant effects and reduces atherosclerotic burden in apolipoprotein E (Apoe) deficient mice. Monocytes/macrophages express high levels of IGF-1 receptor (IGF1R) and play a pivotal role in atherogenesis but the potential effects of IGF-1 on their function are unknown. Methods and Results To determine mechanisms whereby IGF-1 reduces atherosclerosis and to explore the potential involvement of monocytes/macrophages, we created monocyte/ macrophage specific IGF1R knockout (MΦ-IGF1R-KO) mice on Apoe−/− background. We assessed atherosclerotic burden, plaque features of stability, and monocyte recruitment to atherosclerotic lesions. Phenotypic changes of IGF1R-deficient macrophages were investigated in culture. MΦ-IGF1R-KO significantly increased atherosclerotic lesion formation, as assessed by Oil-red-O staining of en face aortae and aortic root cross-sections, and changed plaque composition to a less stable phenotype, characterized by increased macrophage and decreased α-smooth muscle actin-positive cell population, fibrous cap thinning, and decreased collagen content. Brachiocephalic artery lesions of MΦ-IGF1R-KO mice had histological features implying plaque vulnerability. Macrophages isolated from MΦ-IGF1R-KO mice showed enhanced proinflammatory responses upon stimulation by IFNγ and oxidized LDL and elevated antioxidant gene expression levels. Moreover, IGF1R deficient macrophages had decreased expression of ABCA1 and ABCG1 and reduced lipid efflux. Conclusions Our data indicate that macrophage IGF1R signaling suppresses macrophage and foam cell accumulation in lesions and reduces plaque vulnerability, providing a novel mechanism whereby IGF-1 exerts anti-atherogenic effects.

Objectives: To evaluate the psychometric properties of the Chinese Eating Disorders Inventory (EDI‐1) in a nonclinical population in Hong Kong. Method: 1,172 (females 606, males 566) Chinese undergraduates completed the Chinese EDI‐1; 105 of them also completed the 12‐item General Health Questionnaire (GHQ‐12). Results: In female subjects, the Chinese EDI‐1 and its subscales met conventional standards of internal consistency, item‐total, item‐subscale, and subscale correlations, and exhibited an excellent degree of factorial integrity. The subscales discriminated among male, female, high Drive for Thinness, high Body Dissatisfaction, constitutionally slim, and Canadian female subjects. Female GHQ‐12 cases and noncases were only distinguished by the Interpersonal Distrust, Interoceptive Awareness, and Ineffectiveness subscales. 3.3% of female subjects could be characterized as being pathologically weight preoccupied. Discussion: This study provides preliminary evidence that the Chinese EDI‐1 is an economical, reliable, and potentially useful self‐report instrument for investigating the psychological and behavioral dimensions of eating disorders in Hong Kong. But further work is needed to evaluate its transcultural validity in clinical and less modernized Chinese populations. © 1997 by John Wiley & Sons, Inc. Int J Eat Disord 21: 187–194, 1997.