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Alexander Bartelt, Scott B Widenmaier, Christian Schlein, Kornelia Johann, Renata L S Goncalves, Kosei Eguchi, Alexander W Fischer, Günes Parlakgül, Nicole A Snyder, Truc B Nguyen, Oliver T Bruns, Daniel Franke, Moungi G Bawendi, Matthew D Lynes, Luiz O Leiria, Yu-Hua Tseng, Karen E Inouye, Ana Paula Arruda, Gökhan S Hotamisligil
Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process...
February 5, 2018: Nature Medicine
Ana Paula Arruda, Benedicte Mengel Pers, Günes Parlakgul, Ekin Güney, Ted Goh, Erika Cagampan, Grace Yankun Lee, Renata L Goncalves, Gökhan S Hotamisligil
Defective Ca2+ handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca2+ level is in part monitored by the store-operated Ca2+ entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca2+ concentrations through the STIM proteins and facilitates import of the ion from the extracellular space. Here, we show that hepatocytes from obese mice displayed significantly diminished SOCE as a result of impaired STIM1 translocation, which was associated with aberrant STIM1 O-GlycNAcylation...
December 15, 2017: ELife
Scott B Widenmaier, Nicole A Snyder, Truc B Nguyen, Alessandro Arduini, Grace Y Lee, Ana Paula Arruda, Jani Saksi, Alexander Bartelt, Gökhan S Hotamisligil
Cholesterol is a critical nutrient requiring tight constraint in the endoplasmic reticulum (ER) due to its uniquely challenging biophysical properties. While the mechanisms by which the ER defends against cholesterol insufficiency are well described, it remains unclear how the ER senses and effectively defends against cholesterol excess. Here, we identify the ER-bound transcription factor nuclear factor erythroid 2 related factor-1, Nrf1/Nfe2L1, as a critical mediator of this process. We show that Nrf1 directly binds to and specifically senses cholesterol in the ER through a defined domain and that cholesterol regulates Nrf1 turnover, processing, localization, and activity...
November 16, 2017: Cell
Matthew D Lynes, Luiz O Leiria, Morten Lundh, Alexander Bartelt, Farnaz Shamsi, Tian Lian Huang, Hirokazu Takahashi, Michael F Hirshman, Christian Schlein, Alexandra Lee, Lisa A Baer, Francis J May, Fei Gao, Niven R Narain, Emily Y Chen, Michael A Kiebish, Aaron M Cypess, Matthias Blüher, Laurie J Goodyear, Gökhan S Hotamisligil, Kristin I Stanford, Yu-Hua Tseng
This corrects the article DOI: 10.1038/nm.4297.
November 7, 2017: Nature Medicine
Khanichi N Charles, Min-Dian Li, Feyza Engin, Ana Paula Arruda, Karen Inouye, Gökhan S Hotamisligil
Deterioration of metabolic health is a hallmark of aging and generally assumed to be detrimental to longevity. Exposure to a high-calorie diet impairs metabolism and accelerates aging; conversely, calorie restriction (CR) prevents age-related metabolic diseases and extends lifespan. However, it is unclear whether preservation of metabolic health is sufficient to extend lifespan. We utilized a genetic mouse model lacking Fabp4/5 that confers protection against metabolic diseases and shares molecular and lipidomic features with CR to address this question...
October 10, 2017: Cell Reports
Gökhan S Hotamisligil
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective...
September 19, 2017: Immunity
Benjamin P Garfinkel, Gökhan S Hotamisligil
A new mechanism linking ER dysfunction to metabolic inflammation is discovered in a recent study by Shan et al. (2017), which demonstrated ER stress-induced rewiring of adipose tissue macrophage polarization by IRE1α activation, leading to impaired systemic glucose homeostasis.
June 15, 2017: Molecular Cell
Güneş Parlakgul, Gökhan S Hotamisligil
The specific immunological components linking metabolic stresses to liver inflammation and systemic metabolic pathologies in obesity are not entirely known. A recent study (Ghazarian et al., 2017) reveals that obesity-induced type I interferon signaling drives the accumulation and activation of intrahepatic CD8(+) T cells, leading to systemic metabolic deterioration.
June 6, 2017: Cell Metabolism
Matthew D Lynes, Luiz O Leiria, Morten Lundh, Alexander Bartelt, Farnaz Shamsi, Tian Lian Huang, Hirokazu Takahashi, Michael F Hirshman, Christian Schlein, Alexandra Lee, Lisa A Baer, Francis J May, Fei Gao, Niven R Narain, Emily Y Chen, Michael A Kiebish, Aaron M Cypess, Matthias Blüher, Laurie J Goodyear, Gökhan S Hotamisligil, Kristin I Stanford, Yu-Hua Tseng
Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines'...
May 2017: Nature Medicine
Youdong Pan, Tian Tian, Chang Ook Park, Serena Y Lofftus, Shenglin Mei, Xing Liu, Chi Luo, John T O'Malley, Ahmed Gehad, Jessica E Teague, Sherrie J Divito, Robert Fuhlbrigge, Pere Puigserver, James G Krueger, Gökhan S Hotamisligil, Rachael A Clark, Thomas S Kupper
Tissue-resident memory T (TRM) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of TRM cells are obscure. Here we show that mouse CD8+ TRM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8+ TRM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (TCM) cells in lymph nodes...
March 9, 2017: Nature
Gökhan S Hotamisligil
Proper regulation and management of energy, substrate diversity and quantity, as well as macromolecular synthesis and breakdown processes, are fundamental to cellular and organismal survival and are paramount to health. Cellular and multicellular organization are defended by the immune response, a robust and critical system through which self is distinguished from non-self, pathogenic signals are recognized and eliminated, and tissue homeostasis is safeguarded. Many layers of evolutionarily conserved interactions occur between immune response and metabolism...
February 8, 2017: Nature
Scott B Widenmaier, Gökhan S Hotamışlıgil
Chronic metabolic challenges have severe consequences on physiological systems. In this issue of Immunity, Ito et al. (2016) show that defects in cholesterol metabolism in CD11c(+) immune cells result in impaired antigen presentation and ultimately in autoimmune disease.
December 20, 2016: Immunity
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...
December 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
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