Highlights d Beige fat progenitors are marked by cell surface proteins, PDGFRa, Sca1, and CD81 d Beige APC proliferation is regulated by temperature, genetic background, and aging d CD81 mediates integrin-FAK signaling in response to irisin d CD81 loss causes obesity, insulin resistance, and adipose tissue inflammation

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Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy.KEYWORDS cardiac hypertrophy, collagen, Hsp90, myocyte-fibroblast cross talk, STAT-3 M yocardial fibrosis is a hallmark of cardiac hypertrophy and a proposed substrate for heart failure (1, 2). The extracellular space is frequently the site for such abnormal accumulation of fibrillar collagen, accounting for myocardial stiffness and ventricular dysfunction during cardiac hypertrophy (3). The cardiac fibroblast is the principal cell type in the myocardium and synthesizes and secretes collagen in response to pressure-overload hypertrophy (4). A close relationship between angiotensin II (AngII) and profibrotic cytokines has been suggested, and several molecular signaling networks have been implicated in the progression of cardiac fibrosis (5, 6). A few reports have also shown that the role of myocytes in myocardial collagen production is mediated by myocyte-derived paracrine factors (7,8). However, the precise mechanisms involving the role of different signaling intermediates in the regulation of collagen gene expression during cardiac hypertrophy have remained unsolved.In an earlier report, we described the mechanism of interleukin-6 (IL-6)-mediated activation of the signal transducer and activator of transcription 3 (STAT-3) and consequent collagen synthesis in the hypertrophied rat heart (9). STAT-3 activation has also

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The role of integrins, in particular αv integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the αvβ5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis. We show that acute blockade of the MFGE8/β5 pathway enhances while acute augmentation dampens insulin-stimulated glucose uptake. Moreover, we find that insulin itself induces cell-surface enrichment of MFGE8 in skeletal muscle, which then promotes interaction between the αvβ5 integrin and the insulin receptor leading to dampening of skeletal-muscle insulin receptor signaling. Blockade of the MFGE8/β5 pathway also enhances hepatic insulin sensitivity. Our work identifies an autoregulatory mechanism by which insulin-stimulated signaling through its cognate receptor is terminated through up-regulation of MFGE8 and its consequent interaction with the αvβ5 integrin, thereby establishing a pathway that can potentially be targeted to improve insulin sensitivity.