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Inouye, Karen

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Inouye

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Karen

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Inouye, Karen

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2014 - 201962020 - 20211

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Author's Publications: search.filters.isAuthorOfPublication.cabf7abf-e46a-4538-b35b-1a8261ab8490

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Now showing 1 - 7 of 7
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    A hormone complex of FABP4 and nucleoside kinases regulates islet function
    (Springer Science and Business Media LLC, 2021-12-08) Prentice, Kacey J.; Saksi, Jani Pertti Kristian; Robertson, Lauren T.; Lee, Grace Y.; Inouye, Karen; Eguchi, Kosei; Lee, Alexandra; Cakici, Ozgur; Otterbeck, Emily; Cedillo, Paulina; Achenbach, Peter; Ziegler, Anette-Gabriele; Calay, Ediz; Engin, Feyza; Hotamisligil, Gökhan S.; Hotamisligil, Gokhan
    Liberation of energy stores from adipocytes is critical to support survival in times of energy deficit, however, uncontrolled or chronic lipolysis associated with insulin resistance and/or insulin insufficiency, disrupts metabolic homeostasis. Coupled to lipolysis is the release of a recently identified hormone, fatty acid-binding protein 4 (FABP4). While circulating FABP4 levels have been strongly associated with cardiometabolic diseases in both preclinical models and humans, no mechanism of action has yet been described. Here, we show that hormonal FABP4 forms a novel functional hormone complex with Adenosine Kinase (ADK) and Nucleoside Diphosphate Kinase (NDPK) to regulate extracellular ATP and ADP levels. We identify a substantial impact of this hormone on beta-cells and given the central role of beta-cell function in both the control of lipolysis and development of diabetes, postulate that hormonal FABP4 is a key regulator of an adipose-beta-cell endocrine axis. Antibody-mediated targeting of this hormone complex improves metabolic outcomes, enhances beta-cell function, and preserves beta-cell integrity to prevent both type 1 and type 2 diabetes. Thus, the FABP4-ADK-NDPK complex, Fabtin, represents a previously unknown hormone and mechanism of action integrating energy status with the function of metabolic organs, representing a promising target against metabolic disease.
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    Uncoupling of Metabolic Health from Longevity through Genetic Alteration of Adipose Tissue Lipid-Binding Proteins
    (Elsevier BV, 2017) Charles, Khanichi N.; Li, Min-Dian; Engin, Feyza; Arruda, Ana; Inouye, Karen; Hotamisligil, Gokhan
    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. Fabp-deficient mice exhibit extended metabolic healthspan, with protection against insulin resistance and glucose intolerance, inflammation, deterioration of adipose tissue integrity, and fatty liver disease. Surprisingly, however, Fabp-deficient mice did not exhibit any extension of lifespan. These data indicate that extension of metabolic healthspan in the absence of CR can be uncoupled from lifespan, indicating the potential for independent drivers of these pathways, at least in laboratory mice.
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    Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity
    (Springer Nature, 2018) Bartelt, Alexander; Widenmaier, Scott; Schlein, Christian; Johann, Kornelia; Goncalves, Renata; Eguchi, Kosei; Fischer, Alexander W; Parlakgul, Gunes; Snyder, Nicole; Nguyen, Truc B; Bruns, Oliver T; Franke, Daniel; Bawendi, Moungi G; Lynes, Matthew; Leiria, Luiz O; Tseng, Yu-Hua; Inouye, Karen; Arruda, Ana; Hotamisligil, Gokhan
    Objective Brown adipose tissue (BAT) generates heat in response to cold, and low BAT activity has been linked to obesity. However, recent studies were inconclusive as to whether BAT is involved in diet‐induced thermogenesis and mitigates weight gain from prolonged overeating. Therefore, this study investigated whether BAT activity is related to metabolic adaptation arising from 8 weeks of overfeeding in humans. Methods Fourteen men (aged 24 ± 3 years, BMI 24.5 ± 1.6 kg/m2) were overfed by 40% for 8 weeks. Before and after, energy expenditure and metabolic adaptation were measured by whole‐room respiratory calorimetry. A marker of BAT activity was measured using infrared imaging of the supraclavicular BAT depot. Results At the end of 8 weeks of overfeeding, metabolic adaptation—defined as the percent increase in sleeping energy expenditure beyond that expected from weight gain—rose from −0.9 ± 3.9% to 4.7 ± 5.6% (P = 0.001). However, BAT thermal activity was unchanged (P = 0.81). Moreover, BAT thermal activity did not correlate with the degree of metabolic adaptation (P = 0.32) or with the change in body weight (P = 0.51). Conclusions BAT thermal activity does not change in response to overfeeding, nor does it correlate with adaptive thermogenesis. Our data suggest that BAT does not mediate metabolic adaptation to overeating in humans.
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    A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid utilization
    (2014) Liu, Sihao; Brown, Jonathan D.; Stanya, Kristopher J.; Homan, Edwin; Leidl, Mathias; Inouye, Karen; Bhargava, Prerna; Gangl, Matthew; Dai, Lingling; Hatano, Ben; Hotamisligil, Gokhan; Saghatelian, Alan; Plutzky, Jorge; Lee, Chih-Hao
    Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or utilization. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding1,2 and is repressed by Rev-erbα/β and an HDAC3-containing complex3–5 during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes6–8, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat utilization by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, while hepatocyte-Ppard deletion reduces, muscle fatty acid (FA) uptake. Unbiased metabolite profiling identifies PC(18:0/18:1), or 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC), as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases FA utilization through muscle PPARα. High fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy utilization in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signaling in metabolic disorders including obesity.
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    Novel role of PKR in inflammasome activation and HMGB1 release
    (2014) Lu, Ben; Nakamura, Takahisa; Inouye, Karen; Li, Jianhua; Tang, Yiting; Lundbäck, Peter; Valdes-Ferrer, Sergio I; Olofsson, Peder S.; Kalb, Thomas; Roth, Jesse; Zou, Yongrui; Erlandsson-Harris, Helena; Yang, Huan; Ting, Jenny P-Y; Wang, Haichao; Andersson, Ulf; Antoine, Daniel J.; Chavan, Sangeeta S.; Hotamisligil, Gokhan; Tracey, Kevin J.
    The inflammasome regulates release of caspase activation-dependent cytokines, including IL-1β, IL-18, and high-mobility group box 1 (HMGB1)1-5. During the course of studying HMGB1 release mechanisms, we discovered an important role of double-stranded RNA dependent protein kinase (PKR) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminum, rotenone, live E. coli, anthrax lethal toxin, DNA transfection, and S. Typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1beta, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with multiple inflammasome components, including NLR family pyrin domain-containing 3 (NLRP3), NLR family pyrin domain-containing 1 (NLRP1), NLR family CARD domain-containing protein 4 (NLRC4), Absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell free system with recombinant NLRP3, ASC and pro-casapse-1 reconstitutes inflammasome activity. These results reveal a critical role of PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.
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    Chronic enrichment of hepatic ER-mitochondria contact sites leads to calcium dependent mitochondrial dysfunction in obesity
    (2015) Arruda, Ana; Pers, Benedicte Mengel; Parlakgul, Gunes; Guney, Ekin; Inouye, Karen; Hotamisligil, Gokhan
    Proper function of the endoplasmic reticulum (ER) and mitochondria is critical for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states including metabolic diseases. Although ER and mitochondria play distinct cellular roles, these organelles also form physical interactions at sites defined as mitochondria associated ER-membranes (MAMs), which are essential for Ca2+, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a significant reorganization of MAMs resulting in mitochondrial Ca2+ overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, while down-regulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering and calcium transport respectively, improves mitochondrial oxidative capacity and insulin sensitivity in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity, which may contribute to the development of metabolic pathologies such as insulin resistance.
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    Deficiency of FcεR1 increases body weight gain but improves glucose tolerance in diet-induced obese mice
    (Endocrine Society, 2015) Lee, Yun-Jung; Liu, Conglin; Liao, Mengyang; Sukhova, Galina; Shirakawa, Jun; Abdennour, Meriem; Iamarene, Karine; Andre, Sebastien; Inouye, Karen; Clement, Karine; Kulkarni, Rohit; Banks, Alexander; Libby, Peter; Shi, Guo-Ping
    Prior studies demonstrated increased plasma immunoglobulin E (IgE) in diabetic patients, but the direct participation of IgE in diabetes or obesity remains unknown. This study found that plasma IgE levels correlated inversely with body weight, body mass index, and body fat mass among a population of randomly selected obese women. IgE receptor FcεR1-deficient (Fcer1a–/–) mice and diet-induced obesity (DIO) mice demonstrated that FcεR1 deficiency in DIO mice increased food intake, reduced energy expenditure, and increased body weight gain, but improved glucose tolerance and glucose-induced insulin secretion. White adipose tissue (WAT) from Fcer1a–/– mice showed increased expression of phospho-AKT, C/EBPα, PPARγ, Glut4, and Bcl-2, but reduced UCP1 and phospho-JNK expression, tissue macrophage accumulation, and apoptosis, suggesting that IgE reduces adipogenesis and glucose uptake, but induces energy expenditure, adipocyte apoptosis, and WAT inflammation. In 3T3-L1 cells, IgE inhibited the expression of C/EBPα and PPARγ, and preadipocyte adipogenesis, and induced adipocyte apoptosis. IgE reduced 3T3-L1 cell expression of Glut4, phospho-AKT, and glucose uptake, which concurred with improved glucose tolerance in Fcer1a–/– mice. This study established two novel pathways of IgE in reducing body weight gain in DIO mice by suppressing adipogenesis and inducing adipocyte apoptosis, while worsening glucose tolerance by reducing Glut4 expression, glucose uptake, and insulin secretion.