Background-Macrophage activation plays a crucial role in regulating adipose tissue inflammation and is a major contributor to the pathogenesis of obesity-associated cardiovascular diseases. On various types of stimuli, macrophages respond with either classic (M1) or alternative (M2) activation. M1-and M2-mediated signaling pathways and corresponding cytokine production profiles are not completely understood. The discovery of microRNAs provides a new opportunity to understand this complicated but crucial network for macrophage activation and adipose tissue function. Methods and Results-We have examined the activity of microRNA-223 (miR-223) and its role in controlling macrophage functions in adipose tissue inflammation and systemic insulin resistance. miR-223 Ϫ/Ϫ mice on a high-fat diet exhibited an increased severity of systemic insulin resistance compared with wild-type mice that was accompanied by a marked increase in adipose tissue inflammation. The specific regulatory effects of miR-223 in myeloid cell-mediated regulation of adipose tissue inflammation and insulin resistance were then confirmed by transplantation analysis. Moreover, using bone marrow-derived macrophages, we demonstrated that miR-223 is a novel regulator of macrophage polarization, which suppresses classic proinflammatory pathways and enhances the alternative antiinflammatory responses. In addition, we identified Pknox1 as a genuine miR-223 target gene and an essential regulator for macrophage polarization. Conclusion-For the first time, this study demonstrates that miR-223 acts to inhibit Pknox1, suppressing proinflammatory activation of macrophages; thus, it is a crucial regulator of macrophage polarization and protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance. (Circulation. 2012;125:2892-2903.)Key Words: adipose tissue Ⅲ insulin resistance Ⅲ macrophages Ⅲ microRNAs A dipose tissue inflammation is a hallmark of obesity and a causal factor of metabolic disorders such as insulin resistance 1-5 and a wide variety of metabolic diseases, including atherosclerosis and type 2 diabetes mellitus. 4 -6 Mice fed a high-fat diet (HFD) frequently develop chronic low-grade inflammation within adipose tissues, characterized by increased infiltration of immune cells and the production of proinflammatory cytokines. 1,2 Consequently, adipocytes produce a number of inflammatory mediators that contribute to atherosclerotic cardiovascular disease. 7,8 Importantly, elevated adipose tissue inflammation is a significant factor contributing to systemic insulin resistance, 9 -14 which is an additional risk factor for cardiovascular disease through both inflammation-dependent and -independent mechanisms. Given the importance of adipose tissue inflammation in metabolic diseases, there is a critical need to better understand the mechanisms underlying these inflammatory processes. Editorial see p 2815 Clinical Perspective on p 2903Several reports demonstrate that macrophages are key regulators of adipose tissue inflammat...

Polarized activation of adipose tissue macrophages (ATMs) is crucial for maintaining adipose tissue function and mediating obesity-associated cardiovascular risk and metabolic abnormalities; however, the regulatory network of this key process is not well defined. Here, we identified a PPARγ/microRNA-223 (miR-223) regulatory axis that controls macrophage polarization by targeting distinct downstream genes to shift the cellular response to various stimuli. In BM-derived macrophages, PPARγ directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARγ binding 3 PPARγ regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPARγ-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified Rasa1 and Nfat5 as genuine miR-223 targets that are critical for PPARγ-dependent macrophage alternative activation, whereas the proinflammatory regulator Pknox1, which we reported previously, mediated miR-223-regulated macrophage classical activation. In summary, this study provides evidence to support the crucial role of a PPARγ/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes.

The lysosomal cysteine peptidase cathepsin L (CTSL) is an important lysosomal proteinase involved in a variety of cellular functions including intracellular protein turnover, epidermal homeostasis, and hair development. Deficiency of CTSL in mice results in a progressive dilated cardiomyopathy. In the present study, we tested the hypothesis that cardiac overexpression of human CTSL in the murine heart would protect against cardiac hypertrophy in vivo. The effects of constitutive human CTSL expression on cardiac hypertrophy were investigated using in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding (AB) in CTSL transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by two-dimensional and M-mode echocardiography as well as by molecular and pathological analyses of heart samples. Constitutive overexpression of human CTSL in the murine heart attenuated the hypertrophic response, markedly reduced apoptosis, and fibrosis. Cardiac function was also preserved in hearts with increased CTSL levels in response to hypertrophic stimuli. These beneficial effects were associated with attenuation of the Akt/GSK3beta signaling cascade. Our in vitro studies further confirmed that CTSL expression in cardiomyocytes blunts cardiac hypertrophy through blocking of Akt/GSK3beta signaling. The study indicates that CTSL improves cardiac function and inhibits cardiac hypertrophy, inflammation, and fibrosis through blocking Akt/GSK3beta signaling.

Normal function of the dopaminergic system is necessary for speech fluency. There was evidence that the activities of dopamine transporter (DAT) and dopamine D2 receptor (DRD2) could be altered in people with speech disfluency. This study aims to ascertain the possible correlation between two dopaminergic genes (SLC6A3 and DRD2) and disorder of speech fluency, and to determine the allelic frequencies of the five single-nucleotide polymorphisms (SNPs) (rs2617604, rs28364997, rs28364998 in SLC6A3 and rs6275, rs6277 in DRD2) among Han Chinese patients with this disorder. A sample of 112 patients with speech disfluency and 112 gender-matched controls were included in this case-control study. The results show that the presence of C allele at rs6277 in DRD2 gene is associated with increased susceptibility to the disorder, whereas T allele is protective. Haplotype 939T/957T is also a protective factor. Keywords: case-control study; dopamine D2 receptor; dopamine transporter; disorder of fluent speech; Han Chinese; SNPs INTRODUCTIONLanguage is a particular type of human cognitive function that can be divided into 'language' and 'speech.' 1 Speech production is a process that transforms conceptual ideas within the brain into specific language form and expresses it vocally. 2 Fluent speech depends on the balance of the three steps: conceptualization, formulation and articulation, 3 but the detailed mechanism has not been fully understood yet. Stuttering has been used as a model of speech disfluency to understand the mechanism of speech production. 4 It is characterized by involuntary syllable repetitions, syllable prolongations or interruptions (blocks) in a smooth flow of speech. Developmental stuttering begins during the period of rapid speech and language development in childhood and is characterized by a disturbance in the normal fluency and time patterning of speech. 5 Dopamine has a major role in fine motor movements, and speech requires the coordination of many small muscles. 6 The dopamine excess theory of stuttering suggests that stuttering may be related to excess levels of the neurotransmitter in the brain. [7][8][9] Further evidence for the theory came from attempts at treating stuttering with antipsychotic medications that block dopamine in the brain. 10-13 A study to evaluate the efficacy of risperidone in the treatment of developmental stuttering showed that a significant decrease of stuttering severity occurred in the risperidone treatment group than in that of the placebo group. 14 The risperidone research supports dopamine having a regulatory role in stuttering.