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cAMP-inducible coactivator CRTC3 attenuates brown adipose tissue thermogenesis
Yoon, Young-Sil,Tsai, Wen-Wei,Van de Velde, Sam,Chen, Zhijiang,Lee, Kuo-Fen,Morgan, Donald A.,Rahmouni, Kamal,Matsumura, Shigenobu,Wiater, Ezra,Song, Youngsup,Montminy, Marc National Academy of Sciences 2018 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.115 No.23
<P>In response to cold exposure, placental mammals maintain body temperature by increasing sympathetic nerve activity in brown adipose tissue (BAT). Triggering of beta-adrenergic receptors on brown adipocytes stimulates thermogenesis via induction of the cAMP/PKA pathway. Although cAMP response element-binding protein (CREB) and its coactivators-the cAMP-regulated transcriptional coactivators (CRTCs)-mediate transcriptional effects of cAMP in most tissues, other transcription factors such as ATF2 appear critical for induction of thermogenic genes by cAMP in BAT. Brown adipocytes arise from Myf5-positive mesenchymal cells under the control of PRDM16, a coactivator that concurrently represses differentiation along the skeletal muscle lineage. Here, we show that the CREB coactivator CRTC3 is part of an inhibitory feedback pathway that antagonizes PRDM16-dependent differentiation. Mice with a knockout of CRTC3 in BAT (BKO) have increased cold tolerance and reduced adiposity, whereas mice overexpressing constitutively active CRTC3 in adipose tissue are more cold sensitive and have greater fat mass. CRTC3 reduced sympathetic nerve activity in BAT by up-regulating the expression of miR-206, a microRNA that promotes differentiation along the myogenic lineage and that we show here decreases the expression of VEGFA and neurotrophins critical for BAT innervation and vascularization. Sympathetic nerve activity to BAT was enhanced in BKO mice, leading to increases in catecholamine signaling that stimulated energy expenditure. As reexpression of miR-206 in BAT from BKO mice reversed the salutary effects of CRTC3 depletion on cold tolerance, our studies suggest that small-molecule inhibitors against this coactivator may provide therapeutic benefit to overweight individuals.</P>
Offner, Fritz,Samoilova, Olga,Osmanov, Evgenii,Eom, Hyeon-Seok,Topp, Max S.,Raposo, Joã,o,Pavlov, Viacheslav,Ricci, Deborah,Chaturvedi, Shalini,Zhu, Eugene,van de Velde, Helgi,Enny, Christopher American Society of Hematology 2015 Blood Vol.126 No.16
<P>This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL), centrally confirmed by immunohistochemistry (Hans method). In total, 164 patients were randomized 1:1 to receive six 21-day cycles of rituximab 375 mg/m<SUP>2</SUP>, cyclophosphamide 750 mg/m<SUP>2</SUP>, and doxorubicin 50 mg/m<SUP>2</SUP>, all IV day 1, prednisone 100 mg/m<SUP>2</SUP> orally days 1-5, plus either bortezomib 1.3 mg/m<SUP>2</SUP> IV days 1, 4, 8, 11 (rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib [VR-CAP]; n = 84) or vincristine 1.4 mg/m<SUP>2</SUP> (maximum 2 mg) IV day 1 (R-CHOP; n = 80). There were no significant differences between VR-CAP and R-CHOP in complete response rate (64.5%, 66.2%; odds ratio [OR], 0.91; <I>P</I> = .80), overall response rate (93.4%, 98.6%; OR, 0.21; <I>P</I> = .11), progression-free survival (hazard ratio [HR], 1.12; <I>P</I> = .76), or overall survival (HR, 0.89; <I>P</I> = .75). Rates of grade ≥3 adverse events (AEs; 88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%) were similar with VR-CAP and R-CHOP. Grade ≥3 peripheral neuropathy rates were 6% and 3%, respectively. VR-CAP did not improve efficacy vs R-CHOP in non-GCB DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT01040871.</P>