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The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis Via Leptin Receptor Signaling Pathway

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The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis Via Leptin Receptor Signaling Pathway 1630 Diabetes Volume 65, June 2016 Yang Sun,1 Yili Yang,2 Zhen Qin,1 Jinya Cai,3 Xiuming Guo,1 Yun Tang,3 Jingjing Wan,1 Ding-Feng Su,1 and Xia Liu1 The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis via Leptin Receptor Signaling Pathway Diabetes 2016;65:1630–1641 | DOI: 10.2337/db15-1193 The acute-phase protein orosomucoid (ORM) exhibits a intake and energy expenditure. Energy homeostasis in the variety of activities in vitro and in vivo, notably modulation body is maintained by the integrated actions of multiple of immunity and transportation of drugs. We found in this factors (1,2), including adipose hormones (such as leptin study that mice lacking ORM1 displayed aberrant energy and adiponectin), gastrointestinal hormones (such as in- homeostasis characterized by increased body weight and sulin, ghrelin, and cholecystokinin), and nutrient-related fat mass. Further investigation found that ORM, predom- signals (such as free fatty acids). In addition to acting on fi inantly ORM1, is signi cantly elevated in sera, liver, and peripheral tissues, these actions can also influence central – adipose tissues from the mice with high-fat diet (HFD) circuits in the hypothalamus, brainstem, and limbic system db/db induced obesity and mice that develop obesity to modulate food intake and energy expenditure (1,3). spontaneously due to mutation in the leptin receptor Notably, the adipose tissue–produced leptin is a major (LepR). Intravenous or intraperitoneal administration of regulator of fat, and the level of leptin in circulation is exogenous ORM decreased food intake in C57BL/6, HFD, proportional to body fat (4) and is a reflection of long- and leptin-deficient ob/ob mice, which was absent in db/db OBESITY STUDIES fi term nutrition status as well as acute energy balance. mice and was signi cantly reduced in mice with arcu- fi ate nucleus (ARC) LepR knockdown, whereas enforced Furthermore, leptin de ciency or leptin receptor (LepR) expression of ORM1 in ARC significantly decreased food mutation leads to hyperphagia, obesity, and insulin resis- intake, body weight, and serum insulin level. Furthermore, tance (5), whereas administration of leptin causes weight we found that ORM is able to bind directly to LepR and loss and improved insulin resistance and hyperglycemia in activate the receptor-mediated JAK2–STAT3 signaling in type 2 diabetes mice (6,7). Patients with leptin deficiency hypothalamus tissue and GT1-7 cells, which was derived or LepR mutation also develop severe obesity (8,9). It is from hypothalamic tumor. These data indicated that ORM evident that hypothalamic LepR (10,11) is critical for leptin- could function through LepR to regulate food intake and mediated regulation of energy metabolism, as impairment energy homeostasis in response to nutrition status. Mod- of LepR signaling in the hypothalamus selectively results in ulating the expression of ORM is a novel strategy for the hyperphagia and adiposity (1,12,13). management of obesity and related metabolic disorders. Orosomucoid (ORM), also known as a1-acid glyco- protein (AGP), is one of the acute-phase proteins. There are two isoforms of ORM in human (ORM1 and ORM2), Obesity is a condition marked by excess accumulation of one isoform in rat (ORM), and three isoforms in mouse body fat that results from an imbalance between calorie (ORM1, ORM2, and ORM3) (14). These genes have an 1Department of Pharmacology, School of Pharmacy, Second Military Medical Received 26 August 2015 and accepted 11 March 2016. University, Shanghai, China This article contains Supplementary Data online at http://diabetes 2 Laboratory of Translational Medicine, Suzhou Institute of Systems Medicine, .diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1193/-/DC1. Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, Y.S., Y.Y., and Z.Q. contributed equally to this study. China 3Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East © 2016 by the American Diabetes Association. Readers may use this article as China University of Science and Technology, Shanghai, China long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Corresponding author: Xia Liu, lxfl[email protected], or Ding-Feng Su, dfsu@ smmu.edu.cn. diabetes.diabetesjournals.org Sun and Associates 1631 identical structure with six exons and five introns. Both LepR small interfering RNA and its control small interfering in humans and mice, constitutive level of ORM1 is much RNA were from Santa Cruz Biotechnology (Dallas, TX). higher (fivefold) than ORM2, and only ORM1 can be in- Lentivirus carrying full-length ORM1 or LepR short hairpin duced by acute-phase stimuli (15). Although it is mainly (sh)RNA was constructed by Shanghai GenePharma Co., synthesized by the liver, many extrahepatic tissues, includ- Ltd. (Shanghai, China). The sequence used for LepR shRNA ing adipocytes, heart, and brain, are capable of producing is 59-GCTGAAATTGTCTCAGCTACA-39. The 60% high-fat ORM under myriad physiological and pathological condi- diet (HFD) and standard chow were purchased from Shanghai tions (16–19). A variety of activities have been attributed SLAC Laboratory Animal Co., Ltd. (Shanghai, China). to ORM, which include modulating immunity, carrying Cell Culture and Transfection drugs, maintaining the capillary barrier, and mediating Mouse hypothalamic GT1-7 cells were generously pro- – sphingolipid metabolism (14,20 23). It has been reported vided by Professor Xiao-Ying Li from the Shanghai Clinical that the effects of ORM on macrophages, neutrophils, and Center for Endocrine and Metabolic Diseases at Shanghai liver parenchymal cells are mediated by membrane receptor Jiaotong University School of Medicine (Shanghai, China). b CCR5,Siglect-5,andhemoglobin -chain, respectively C2C12 cells (mouse muscle myoblasts) were obtained from – (24 26). Interestingly, increase of serum ORM level has Shanghai Institutes for Biological Sciences, Chinese Acad- been observed in obese humans, mice, and Ossabaw pigs emy of Sciences. These cells were cultured in DMEM (Gibco) – (17,27 29). The increased level is correlated with BMI, supplemented with 10% FBS (Gibco). All cells were in- body fat mass, serum leptin, and fasting plasma glucose cubated at 37°C in a 5% CO2 incubator. For knockdown level in human (27,30). In addition, adipose ORM level is studies, these cells were transfected with Lipofectamine correlated with adiponectin that regulates glucose level 2000 (Invitrogen, Carlsbad, CA) according to the manufac- and fatty acid breakdown and is regulated by insulin, turer’sinstructions. high glucose, and free fatty acid in differentiated adipo- cytes (17,27). These results suggested that ORM might Animals db/db ob/ob participate in the regulation of energy balance. Eight-week-old male and mice were purchased In this study, we found alterations of energy homeo- from Shanghai SLAC Laboratory Animal Co., Ltd. Male – – stasis in mice deficient of ORM1, which accounts for the C57BL/6 mice (18 22 g) and Sprague-Dawley rats (180 majority of serum ORM as well as most of the changes 200 g) were purchased from Sino-British SIPPR/BK Lab- induced by acute-phase stimuli (15,31). The aberrant en- oratory Animals (Shanghai, China). ORM1 knockout mice ergy homeostasis is characterized by significant elevation were generated as previously described (32) and were in body weight and fat mass, increased serum total cho- backcrossed 10 times with C57BL/6 mice before they lesterol (TC), fatty liver, and insulin and leptin resistance. were characterized. All animal experiments were under- We also found that ORM derived from adipose and liver taken in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals tissues is regulated by short- or long-term nutrition sig- and with fi nals and administration of ORM affects feeding behavior. the approval of the Scienti c Investigation Board of the Furthermore, we demonstrate that ORM binds to LepR Second Military Medical University. and activates the Janus kinase (JAK)2–signal transducer RNA Quantification and activator of transcription (STAT)3 pathway in hypo- Total RNA was extracted with TRIzol reagent (Invitrogen) thalamus. Thus, ORM could function as an agonist for following manufacturer’s instructions. Real-time quanti- LepR and is an important regulator in food intake and tative RT-PCR analysis was performed using the SYBR RT- energy homeostasis. PCR kits (Takara, Otsu, Japan). Primer sequences were showninSupplementaryTable1. RESEARCH DESIGN AND METHODS Blood Parameters Reagents Serum levels of ORM, leptin, and insulin were detected by ORM was purchased from Sigma-Aldrich (St. Louis, MO). ELISA kit according to the manufacturer’s instruction. A BSA was obtained from Boguang Biological Technology rat ORM ELISA kit was obtained from Abcam. A leptin (Shanghai, China). IgG was from Beyotime Institute of Bio- ELISA kit was bought from R&D Systems (Minneapolis, technology (Shanghai, China). Fluorescein isothiocyanate MN). An insulin ELISA kit was bought from Millipore (FITC)-labeled ORM and BSA were made by Youke Biological (Billerica, MA). Total plasma cholesterol and triglyceride Technology (Shanghai, China). Antibodies against ORM (rat) and LepR were purchased from Abcam (Cambridge, U.K.). (TG) were measured by the Clinical Biochemical Labora- tory in Changhai Hospital (Shanghai, China). Antibodies against JAK, phosphorylated (p)-JAK, STAT3, and p-STAT3 were from Cell Signaling Technology (Dan- Food Intake vers, MA). Antibody against ORM (mouse) was obtained The effect of ORM on eating behavior was evaluated by from Genway (San Diego, CA). Antibodies against GAPDH the amount of food intake. For fasting-induced food and tubulin were from Beyotime Institute of Biotechnology. intake, mice were starved overnight (no drinking limited), Secondary antibodies conjugated with IRDye 800CW were and the weight of consumed food at 2 h, 8 h, and 24 h was from Rockland Immunochemicals, Inc. (Limerick, PA). The recorded 30 min after tail vein injection of vehicle or 1632 ORM Regulates Energy Homeostasis Diabetes Volume 65, June 2016 ORM (100 mg/kg).
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