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Gökhan S Hotamisligil, Roger J Davis
Stress-signaling pathways are evolutionarily conserved and play an important role in the maintenance of homeostasis. These pathways are also critical for adaptation to new cellular environments. The endoplasmic reticulum (ER) unfolded protein response (UPR) is activated by biosynthetic stress and leads to a compensatory increase in ER function. The JNK and p38 MAPK signaling pathways control adaptive responses to intracellular and extracellular stresses, including environmental changes such as UV light, heat, and hyperosmotic conditions, and exposure to inflammatory cytokines...
October 3, 2016: Cold Spring Harbor Perspectives in Biology
Ismail Çimen, Begüm Kocatürk, Seda Koyuncu, Özlem Tufanlı, Umut I Onat, Asli D Yıldırım, Onur Apaydın, Şeyma Demirsoy, Zaliha G Aykut, Uyen T Nguyen, Steven M Watkins, Gökhan S Hotamışlıgil, Ebru Erbay
De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. However, organ-specific DNL can also generate distinct lipids with beneficial metabolic bioactivity, prompting a great interest in their use for the treatment of metabolic diseases. Palmitoleate (PAO), one such bioactive lipid, regulates lipid metabolism in liver and improves glucose utilization in skeletal muscle when it is generated de novo from the obese adipose tissue...
September 28, 2016: Science Translational Medicine
Meric Erikci Ertunc, Gökhan S Hotamisligil
Lipids encompass a wide variety of molecules such as fatty acids, sterols, phospholipids and triglycerides. These molecules represent a highly efficient energy resource and can act as structural elements of membranes, or as signaling molecules that regulate metabolic homeostasis through many mechanisms. Cells possess an integrated set of response systems to adapt to stresses such as those imposed by nutrient fluctuations during feeding-fasting cycles. While lipids are pivotal for these homeostatic processes, they can also contribute to detrimental metabolic outcomes...
June 21, 2016: Journal of Lipid Research
Vladimir R Babaev, Michele Yeung, Ebru Erbay, Lei Ding, Youmin Zhang, James M May, Sergio Fazio, Gökhan S Hotamisligil, MacRae F Linton
OBJECTIVE: The c-Jun NH2-terminal kinases (JNK) are regulated by a wide variety of cellular stresses and have been implicated in apoptotic signaling. Macrophages express 2 JNK isoforms, JNK1 and JNK2, which may have different effects on cell survival and atherosclerosis. APPROACH AND RESULTS: To dissect the effect of macrophage JNK1 and JNK2 on early atherosclerosis, Ldlr(-/-) mice were reconstituted with wild-type, Jnk1(-/-), and Jnk2(-/-) hematopoietic cells and fed a high cholesterol diet...
June 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Ling Yang, Danilo Licastro, Edda Cava, Nicola Veronese, Francesco Spelta, Wanda Rizza, Beatrice Bertozzi, Dennis T Villareal, Gökhan S Hotamisligil, John O Holloszy, Luigi Fontana
Calorie restriction (CR) retards aging, acts as a hormetic intervention, and increases serum corticosterone and HSP70 expression in rodents. However, less is known regarding the effects of CR on these factors in humans. Serum cortisol and molecular chaperones and autophagic proteins were measured in the skeletal muscle of subjects on CR diets for 3-15 years and in control volunteers. Serum cortisol was higher in the CR group than in age-matched sedentary and endurance athlete groups (15.6 ± 4.6 ng/dl versus 12...
January 26, 2016: Cell Reports
M Furkan Burak, Karen E Inouye, Ariel White, Alexandra Lee, Gurol Tuncman, Ediz S Calay, Motohiro Sekiya, Amir Tirosh, Kosei Eguchi, Gabriel Birrane, Daniel Lightwood, Louise Howells, Geofrey Odede, Hanna Hailu, Shauna West, Rachel Garlish, Helen Neale, Carl Doyle, Adrian Moore, Gökhan S Hotamisligil
The lipid chaperone aP2/FABP4 has been implicated in the pathology of many immunometabolic diseases, including diabetes in humans, but aP2 has not yet been targeted for therapeutic applications. aP2 is not only an intracellular protein but also an active adipokine that contributes to hyperglycemia by promoting hepatic gluconeogenesis and interfering with peripheral insulin action. Serum aP2 levels are markedly elevated in mouse and human obesity and strongly correlate with metabolic complications. These observations raise the possibility of a new strategy to treat metabolic disease by targeting serum aP2 with a monoclonal antibody (mAb) to aP2...
December 23, 2015: Science Translational Medicine
Chen-Wei Yu, Xiaoliang Liang, Samantha Lipsky, Cagatay Karaaslan, Harry Kozakewich, Gokhan S Hotamisligil, Joyce Bischoff, Sule Cataltepe
Fatty acid-binding proteins (FABP) are small molecular mass intracellular lipid chaperones that are expressed in a tissue-specific manner with some overlaps. FABP4 and FABP5 share ~55 % amino acid sequence homology and demonstrate synergistic effects in regulation of metabolic and inflammatory responses in adipocytes and macrophages. Recent studies have shown that FABP4 and FABP5 are also co-expressed in a subset of endothelial cells (EC). FABP4, which has a primarily microvascular distribution, enhances angiogenic responses of ECs, including proliferation, migration, and survival...
January 2016: Angiogenesis
Yi Zhou, Xueqing Yu, Huimei Chen, Sara Sjöberg, Joséphine Roux, Lijun Zhang, Al-Habib Ivoulsou, Farid Bensaid, Cong-Lin Liu, Jian Liu, Joan Tordjman, Karine Clement, Chih-Hao Lee, Gokhan S Hotamisligil, Peter Libby, Guo-Ping Shi
Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue (WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro- and anti-inflammatory cytokines, but do not affect T cell differentiation...
December 1, 2015: Cell Metabolism
Gökhan S Hotamisligil, David A Bernlohr
Intracellular and extracellular interactions with proteins enables the functional and mechanistic diversity of lipids. Fatty acid-binding proteins (FABPs) were originally described as intracellular proteins that can affect lipid fluxes, metabolism and signalling within cells. As the functions of this protein family have been further elucidated, it has become evident that they are critical mediators of metabolism and inflammatory processes, both locally and systemically, and therefore are potential therapeutic targets for immunometabolic diseases...
October 2015: Nature Reviews. Endocrinology
Ling Yang, Ediz S Calay, Jason Fan, Alessandro Arduini, Ryan C Kunz, Steven P Gygi, Abdullah Yalcin, Suneng Fu, Gökhan S Hotamisligil
The association between inflammation and endoplasmic reticulum (ER) stress has been observed in many diseases. However, if and how chronic inflammation regulates the unfolded protein response (UPR) and alters ER homeostasis in general, or in the context of chronic disease, remains unknown. Here, we show that, in the setting of obesity, inflammatory input through increased inducible nitric oxide synthase (iNOS) activity causes S-nitrosylation of a key UPR regulator, IRE1α, which leads to a progressive decline in hepatic IRE1α-mediated XBP1 splicing activity in both genetic (ob/ob) and dietary (high-fat diet-induced) models of obesity...
July 31, 2015: Science
Ana Paula Arruda, Gökhan S Hotamisligil
A number of chronic metabolic pathologies, including obesity, diabetes, cardiovascular disease, asthma, and cancer, cluster together to present the greatest threat to human health. As research in this field has advanced, it has become clear that unresolved metabolic inflammation, organelle dysfunction, and other cellular and metabolic stresses underlie the development of these chronic metabolic diseases. However, the relationship between these systems and pathological mechanisms is poorly understood. Here we discuss the role of cellular Ca(2+) homeostasis as a critical mechanism integrating the myriad of cellular and subcellular dysfunctional networks found in metabolic tissues such as liver and adipose tissue in the context of metabolic disease, particularly in obesity and diabetes...
September 1, 2015: Cell Metabolism
Flora Brozzi, Tarlliza R Nardelli, Miguel Lopes, Isabelle Millard, Jenny Barthson, Mariana Igoillo-Esteve, Fabio A Grieco, Olatz Villate, Joana M Oliveira, Marina Casimir, Marco Bugliani, Feyza Engin, Gökhan S Hotamisligil, Piero Marchetti, Decio L Eizirik
AIMS/HYPOTHESIS: Proinflammatory cytokines contribute to beta cell damage in type 1 diabetes in part through activation of endoplasmic reticulum (ER) stress. In rat beta cells, cytokine-induced ER stress involves NO production and consequent inhibition of the ER Ca(2+) transporting ATPase sarco/endoplasmic reticulum Ca(2+) pump 2 (SERCA2B). However, the mechanisms by which cytokines induce ER stress and apoptosis in mouse and human pancreatic beta cells remain unclear. The purpose of this study is to elucidate the role of ER stress on cytokine-induced beta cell apoptosis in these three species and thus solve ongoing controversies in the field...
October 2015: Diabetologia
Suneng Fu, Abdullah Yalcin, Grace Y Lee, Ping Li, Jason Fan, Ana Paula Arruda, Benedicte M Pers, Mustafa Yilmaz, Kosei Eguchi, Gökhan S Hotamisligil
The endoplasmic reticulum (ER) plays a critical role in protein, lipid, and glucose metabolism as well as cellular calcium signaling and homeostasis. Perturbation of ER function and chronic ER stress are associated with many pathologies ranging from diabetes and neurodegenerative diseases to cancer and inflammation. Although ER targeting shows therapeutic promise in preclinical models of obesity and other pathologies, the available chemical entities generally lack the specificity and other pharmacological properties required for effective clinical translation...
June 17, 2015: Science Translational Medicine
Xia Sheng, Yke Jildouw Arnoldussen, Margrethe Storm, Martina Tesikova, Hatice Zeynep Nenseth, Sen Zhao, Ladan Fazli, Paul Rennie, Bjørn Risberg, Håkon Wæhre, Håvard Danielsen, Ian G Mills, Yang Jin, Gökhan Hotamisligil, Fahri Saatcioglu
The unfolded protein response (UPR) is a homeostatic mechanism to maintain endoplasmic reticulum (ER) function. The UPR is activated by various physiological conditions as well as in disease states, such as cancer. As androgens regulate secretion and development of the normal prostate and drive prostate cancer (PCa) growth, they may affect UPR pathways. Here, we show that the canonical UPR pathways are directly and divergently regulated by androgens in PCa cells, through the androgen receptor (AR), which is critical for PCa survival...
June 2015: EMBO Molecular Medicine
Osama A Youssef, Sarah A Safran, Takahisa Nakamura, David A Nix, Gökhan S Hotamisligil, Brenda L Bass
Protein kinase RNA-activated (PKR) has long been known to be activated by viral double-stranded RNA (dsRNA) as part of the mammalian immune response. However, in mice PKR is also activated by metabolic stress in the absence of viral infection, and this requires a functional kinase domain, as well as a functional dsRNA-binding domain. The endogenous cellular RNA that potentially leads to PKR activation during metabolic stress is unknown. We investigated this question using mouse embryonic fibroblast cells expressing wild-type PKR (PKRWT) or PKR with a point mutation in each dsRNA-binding motif (PKRRM)...
April 21, 2015: Proceedings of the National Academy of Sciences of the United States of America
Takahisa Nakamura, Ryan C Kunz, Cai Zhang, Taishi Kimura, Celvie L Yuan, Brenna Baccaro, Yuka Namiki, Steven P Gygi, Gökhan S Hotamisligil
Aberrant stress and inflammatory responses are key factors in the pathogenesis of obesity and metabolic dysfunction, and the double-stranded RNA-dependent kinase (PKR) has been proposed to play an important role in integrating these pathways. Here, we report the formation of a complex between PKR and TAR RNA-binding protein (TRBP) during metabolic and obesity-induced stress, which is critical for the regulation of eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation and c-Jun N-terminal kinase (JNK) activation...
April 14, 2015: Cell Reports
Meric Erikci Ertunc, Jørgen Sikkeland, Federico Fenaroli, Gareth Griffiths, Mathew P Daniels, Haiming Cao, Fahri Saatcioglu, Gökhan S Hotamisligil
Adipocyte fatty acid binding protein 4, aP2, contributes to the pathogenesis of several common diseases including type 2 diabetes, atherosclerosis, fatty liver disease, asthma, and cancer. Although the biological functions of aP2 have classically been attributed to its intracellular action, recent studies demonstrated that aP2 acts as an adipokine to regulate systemic metabolism. However, the mechanism and regulation of aP2 secretion remain unknown. Here, we demonstrate a specific role for lipase activity in aP2 secretion from adipocytes in vitro and ex vivo...
February 2015: Journal of Lipid Research
Ana Paula Arruda, Benedicte M Pers, Güneş Parlakgül, Ekin Güney, Karen Inouye, Gökhan S Hotamisligil
Proper function of the endoplasmic reticulum (ER) and mitochondria is crucial for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states, including metabolic diseases. Although the ER and mitochondria play distinct cellular roles, these organelles also form physical interactions with each other at sites defined as mitochondria-associated ER membranes (MAMs), which are essential for calcium, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a marked reorganization of MAMs resulting in mitochondrial calcium overload, compromised mitochondrial oxidative capacity and augmented oxidative stress...
December 2014: Nature Medicine
Yinan Zhang, Justin Nicholatos, John R Dreier, Stéphane J H Ricoult, Scott B Widenmaier, Gökhan S Hotamisligil, David J Kwiatkowski, Brendan D Manning
Eukaryotic cells coordinately control anabolic and catabolic processes to maintain cell and tissue homeostasis. Mechanistic target of rapamycin complex 1 (mTORC1) promotes nutrient-consuming anabolic processes, such as protein synthesis. Here we show that as well as increasing protein synthesis, mTORC1 activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits...
September 18, 2014: Nature
Magali Saint-Geniez, Elisa Ghelfi, Xiaoliang Liang, Chenwei Yu, Carrie Spencer, Stephanie Abend, Gokhan Hotamisligil, Sule Cataltepe
Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide due to increasing survival rates of premature infants. Initial suppression, followed by increased production of the retinal vascular endothelial growth factor-A (VEGF) expression are key events that trigger the pathological neovascularization in ROP. Fatty acid binding protein 4 (FABP4) is an intracellular lipid chaperone that is induced by VEGF in a subset of endothelial cells. FABP4 exhibits a pro-angiogenic function in cultured endothelial cells and in airway microvasculature, but whether it plays a role in modulation of retinal angiogenesis is not known...
2014: PloS One
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