The mechanism by which leptin reverses diabetic ketoacidosis (DKA) is unknown. We examined the acute insulin-independent effects of leptin replacement therapy in a streptozotocin-induced rat model of DKA. Leptin infusion reduced rates of lipolysis, hepatic glucose production (HGP), and hepatic ketogenesis by 50% within 6 hours and were independent of any changes in plasma glucagon concentrations; these effects were abrogated by coinfusion of corticosterone. Treating leptin- and corticosterone-infused rats with an adipose triglyceride lipase inhibitor blocked corticosterone-induced increases in plasma glucose concentrations and rates of HGP and ketogenesis. Similarly, adrenalectomized type 1 diabetic (T1D) rats exhibited decreased rates of lipolysis, HGP, and ketogenesis; these effects were reversed by corticosterone infusion. Leptin-induced decreases in lipolysis, HGP, and ketogenesis in DKA were also nullified by relatively small increases (15 to 70 pM) in plasma insulin concentrations. In contrast, the chronic glucose-lowering effect of leptin in a STZ-induced mouse model of poorly controlled T1D was associated with decreased food intake, reduced plasma glucagon and corticosterone concentrations, and decreased ectopic lipid (triacylglycerol/diacylglycerol) content in liver and muscle. Collectively, these studies demonstrate marked differences in the acute insulin-independent effects by which leptin reverses fasting hyperglycemia and ketoacidosis in a rodent model of DKA versus the chronic pleotropic effects by which leptin reverses hyperglycemia in a non-DKA rodent model of T1D.
Rachel J. Perry, Liang Peng, Abudukadier Abulizi, Lynn Kennedy, Gary W. Cline, Gerald I. Shulman
Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1–infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1–induced immune hyperactivation and rescued anti–HIV-1 immune responses in T cells from HIV-1–infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1–infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1–associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART.
Liang Cheng, Jianping Ma, Jingyun Li, Dan Li, Guangming Li, Feng Li, Qing Zhang, Haisheng Yu, Fumihiko Yasui, Chaobaihui Ye, Li-Chung Tsao, Zhiyuan Hu, Lishan Su, Liguo Zhang
Huntington’s disease (HD) is a polyglutamine disorder caused by a CAG expansion in the Huntingtin (
Laura Rué, Mónica Bañez-Coronel, Jordi Creus-Muncunill, Albert Giralt, Rafael Alcalá-Vida, Gartze Mentxaka, Birgit Kagerbauer, M. Teresa Zomeño-Abellán, Zeus Aranda, Veronica Venturi, Esther Pérez-Navarro, Xavier Estivill, Eulàlia Martí
Enhancing energy expenditure (EE) is an attractive strategy to combat obesity and diabetes. Global deletion of
Qingzhang Zhu, Sarbani Ghoshal, Ana Rodrigues, Su Gao, Alice Asterian, Theodore M. Kamenecka, James C. Barrow, Anutosh Chakraborty
Adil I. Daud, Kimberly Loo, Mariela L. Pauli, Robert Sanchez-Rodriguez, Priscila Munoz Sandoval, Keyon Taravati, Katy Tsai, Adi Nosrati, Lorenzo Nardo, Michael D. Alvarado, Alain P. Algazi, Miguel H. Pampaloni, Iryna V. Lobach, Jimmy Hwang, Robert H. Pierce, Iris K. Gratz, Matthew F. Krummel, Michael D. Rosenblum
Autonomous thyroid adenomas (ATAs) are a frequent cause of hyperthyroidism. Mutations in the genes encoding the TSH receptor (
Davide Calebiro, Elisa S. Grassi, Markus Eszlinger, Cristina L. Ronchi, Amod Godbole, Kerstin Bathon, Fabiana Guizzardi, Tiziana de Filippis, Knut Krohn, Holger Jaeschke, Thomas Schwarzmayr, Rifat Bircan, Hulya Iliksu Gozu, Seda Sancak, Marek Niedziela, Tim M. Strom, Martin Fassnacht, Luca Persani, Ralf Paschke
The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the
Saskia N. van der Crabben, Marije P. Hennus, Grant A. McGregor, Deborah I. Ritter, Sandesh C.S. Nagamani, Owen S. Wells, Magdalena Harakalova, Ivan K. Chinn, Aaron Alt, Lucie Vondrova, Ron Hochstenbach, Joris M. van Montfrans, Suzanne W. Terheggen-Lagro, Stef van Lieshout, Markus J. van Roosmalen, Ivo Renkens, Karen Duran, Isaac J. Nijman, Wigard P. Kloosterman, Eric Hennekam, Jordan S. Orange, Peter M. van Hasselt, David A. Wheeler, Jan J. Palecek, Alan R. Lehmann, Antony W. Oliver, Laurence H. Pearl, Sharon E. Plon, Johanne M. Murray, Gijs van Haaften
Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Little is known about the molecular pathways that precipitate IMT formation. Here, we report the identification of somatic mutations in
JingWei Lu, Terra-Dawn Plank, Fang Su, XiuJuan Shi, Chen Liu, Yuan Ji, ShuaiJun Li, Andrew Huynh, Chao Shi, Bo Zhu, Guang Yang, YanMing Wu, Miles F. Wilkinson, YanJun Lu
Transplantation is the only cure for end-stage organ failure, but without immunosuppression, T cells rapidly reject allografts. While genetic disparities between donor and recipient are major determinants of the kinetics of transplant rejection, little is known about the contribution of environmental factors. Because colonized organs have worse transplant outcome than sterile organs, we tested the influence of host and donor microbiota on skin transplant rejection. Compared with untreated conventional mice, pretreatment of donors and recipients with broad-spectrum antibiotics (Abx) or use of germ-free (GF) donors and recipients resulted in prolonged survival of minor antigen–mismatched skin grafts. Increased graft survival correlated with reduced type I IFN signaling in antigen-presenting cells (APCs) and decreased priming of alloreactive T cells. Colonization of GF mice with fecal material from untreated conventional mice, but not from Abx-pretreated mice, enhanced the ability of APCs to prime alloreactive T cells and accelerated graft rejection, suggesting that alloimmunity is modulated by the composition of microbiota rather than the quantity of bacteria. Abx pretreatment of conventional mice also delayed rejection of major antigen–mismatched skin and MHC class II–mismatched cardiac allografts. This study demonstrates that Abx pretreatment prolongs graft survival, suggesting that targeting microbial constituents is a potential therapeutic strategy for enhancing graft acceptance.
Yuk Man Lei, Luqiu Chen, Ying Wang, Andrew T. Stefka, Luciana L. Molinero, Betty Theriault, Keston Aquino-Michaels, Ayelet S. Sivan, Cathryn R. Nagler, Thomas F. Gajewski, Anita S. Chong, Caroline Bartman, Maria-Luisa Alegre
Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages. Here, we found that CD47 is highly expressed on the surface of human SCLC cells; therefore, we investigated CD47-blocking immunotherapies as a potential approach for SCLC treatment. Disruption of the interaction of CD47 with SIRPα using anti-CD47 antibodies induced macrophage-mediated phagocytosis of human SCLC patient cells in culture. In a murine model, administration of CD47-blocking antibodies or targeted inactivation of the
Kipp Weiskopf, Nadine S. Jahchan, Peter J. Schnorr, Sandra Cristea, Aaron M. Ring, Roy L. Maute, Anne K. Volkmer, Jens-Peter Volkmer, Jie Liu, Jing Shan Lim, Dian Yang, Garrett Seitz, Thuyen Nguyen, Di Wu, Kevin Jude, Heather Guerston, Amira Barkal, Francesca Trapani, Julie George, John T. Poirier, Eric E. Gardner, Linde A. Miles, Elisa de Stanchina, Shane M. Lofgren, Hannes Vogel, Monte M. Winslow, Caroline Dive, Roman K. Thomas, Charles M. Rudin, Matt van de Rijn, Ravindra Majeti, K. Christopher Garcia, Irving L. Weissman, Julien Sage
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