Epiregulin induces leptin secretion and energy expenditure in high-fat diet-fed mice

in Journal of Endocrinology
Authors:
Rumana Yasmeen Department of Human Sciences, The Ohio State University, Columbus, Ohio, USA

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Qiwen Shen Department of Human Sciences, The Ohio State University, Columbus, Ohio, USA

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Aejin Lee Department of Human Sciences, The Ohio State University, Columbus, Ohio, USA

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Jacob H Leung Department of Human Sciences, The Ohio State University, Columbus, Ohio, USA

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Devan Kowdley Department of Human Sciences, The Ohio State University, Columbus, Ohio, USA

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David J DiSilvestro Department of Human Sciences, The Ohio State University, Columbus, Ohio, USA

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Lu Xu Department of Human Sciences, The Ohio State University, Columbus, Ohio, USA
Department of Minimally Invasive Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China

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Kefeng Yang Department of Human Sciences, The Ohio State University, Columbus, Ohio, USA
Department of Nutrition, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Andrei Maiseyeu Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

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Naresh C Bal Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA
KIIT School of Biotechnology, KIIT University, Bhubaneswar, India

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Muthu Periasamy Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA

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Paolo Fadda Nucleic Acid Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA

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Ouliana Ziouzenkova Department of Human Sciences, The Ohio State University, Columbus, Ohio, USA

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Correspondence should be addressed to O Ziouzenkova: ziouzenkova.1@osu.edu
DOI:
https://doi.org/10.1530/JOE-18-0289
Volume/Issue:
Volume 239: Issue 3
Article Type:
Research Article
Page Range:
377–388
Online Publication Date:
Dec 2018
Copyright:
© 2018 Society for Endocrinology 2018
Restricted access
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Adipokine leptin regulates neuroendocrine circuits that control energy expenditure, thermogenesis and weight loss. However, canonic regulators of leptin secretion, such as insulin and malonyl CoA, do not support these processes. We hypothesize that epiregulin (EREG), a growth factor that is secreted from fibroblasts under thermogenic and cachexia conditions, induces leptin secretion associated with energy dissipation. The effects of EREG on leptin secretion were studied ex vivo, in the intra-abdominal white adipose tissue (iAb WAT) explants, as well as in vivo, in WT mice with diet-induced obesity (DIO) and in ob/ob mice. These mice were pair fed a high-fat diet and treated with intraperitoneal injections of EREG. EREG increased leptin production and secretion in a dose-dependent manner in iAb fat explants via the EGFR/MAPK pathway. After 2 weeks, the plasma leptin concentration was increased by 215% in the EREG-treated group compared to the control DIO group. EREG-treated DIO mice had an increased metabolic rate and core temperature during the active dark cycle and displayed cold-induced thermogenesis. EREG treatment reduced iAb fat mass, the major site of leptin protein production and secretion, but did not reduce the mass of the other fat depots. In the iAb fat, expression of genes supporting mitochondrial oxidation and thermogenesis was increased in EREG-treated mice vs control DIO mice. All metabolic and gene regulation effects of EREG treatment were abolished in leptin-deficient ob/ob mice. Our data revealed a new role of EREG in induction of leptin secretion leading to the energy expenditure state. EREG could be a potential target protein to regulate hypo- and hyperleptinemia, underlying metabolic and immune diseases.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2018 Society for Endocrinology 2018
Page(s):
12
Article Type:
Research Article
Received Date:
21 Aug 2018
Accepted Date:
19 Sep 2018
Print Publication Date:
01 Dec 2018
Online Publication Date:
Dec 2018
Keywords:
EPR; visceral fat; obesity; thermogenesis; energy balance; EGF

  • Bartness TJ, Liu Y, Shrestha YB & Ryu V 2014 Neural innervation of white adipose tissue and the control of lipolysis. Frontiers in Neuroendocrinology 35 473–493. (https://doi.org/10.1016/j.yfrne.2014.04.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, et al.2003 STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421 856–859. (https://doi.org/10.1038/nature01388)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Buettner C, Muse ED, Cheng A, Chen L, Scherer T, Pocai A, Su K, Cheng B, Li X, Harvey-White J, et al.2008 Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nature Medicine 14 667–675. (https://doi.org/10.1038/nm1775)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cote I, Sakarya Y, Green SM, Morgan D, Carter CS, Tumer N & Scarpace PJ 2018 iBAT sympathetic innervation is not required for body weight loss induced by central leptin delivery. American Journal of Physiology: Endocrinology and Metabolism 314 E224–E231. (https://doi.org/10.1152/ajpendo.00219.2017)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, et al.2002 Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. Journal of Clinical Investigation 110 1093–1103. (https://doi.org/10.1172/Jbib215693)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Freed DM, Bessman NJ, Kiyatkin A, Salazar-Cavazos E, Byrne PO, Moore JO, Valley CC, Ferguson KM, Leahy DJ, Lidke DS, et al.2017 EGFR ligands differentially stabilize receptor dimers to specify signaling kinetics. Cell 171 683.e618–695.e618. (https://doi.org/10.1016/j.cell.2017.09.017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Friedman J 2016 The long road to leptin. Journal of Clinical Investigation 126 4727–4734. (https://doi.org/10.1172/JCI91578)

  • Han D, Yamamoto Y, Munesue S, Motoyoshi S, Saito H, Win MT, Watanabe T, Tsuneyama K & Yamamoto H 2013 Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic beta-cell failure in type 2 diabetes. Genes to Cells 18 302–314. (https://doi.org/10.1111/gtc.12036)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hu ZJ, Han W, Cao CQ, Mao-Ying QL, Mi WL & Wang YQ 2018 Peripheral leptin signaling mediates formalin-induced nociception. Neuroscience Bulletin 34 321–329. (https://doi.org/10.1007/s12264-017-0194-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kaiyala KJ, Ogimoto K, Nelson JT, Muta K & Morton GJ 2016 Physiological role for leptin in the control of thermal conductance. Molecular Metabolism 5 892–902. (https://doi.org/10.1016/j.molmet.2016.07.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim K, Lee H, Threadgill DW & Lee D 2011 Epiregulin-dependent amphiregulin expression and ERBB2 signaling are involved in luteinizing hormone-induced paracrine signaling pathways in mouse ovary. Biochemical and Biophysical Research Communications 405 319–324. (https://doi.org/10.1016/j.bbrc.2011.01.039)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kir S, White JP, Kleiner S, Kazak L, Cohen P, Baracos VE & Spiegelman BM 2014 Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513 100–104. (https://doi.org/10.1038/nature13528)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kuntz E, Broca C, Komurasaki T, Kaltenbacher MC, Gross R, Pinget M & Damge C 2005 Effect of epiregulin on pancreatic beta cell growth and insulin secretion. Growth Factors 23 285–293. (https://doi.org/10.1080/08977190500233367)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mattioli B, Straface E, Matarrese P, Quaranta MG, Giordani L, Malorni W & Viora M 2008 Leptin as an immunological adjuvant: enhanced migratory and CD8+ T cell stimulatory capacity of human dendritic cells exposed to leptin. FASEB Journal 22 2012–2022. (https://doi.org/10.1096/fj.07-098095)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Niijima A 1998 Afferent signals from leptin sensors in the white adipose tissue of the epididymis, and their reflex effect in the rat. Journal of the Autonomic Nervous System 73 19–25. (https://doi.org/10.1016/S0165-1838(98)00109-X)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Park JY, Su YQ, Ariga M, Law E, Jin SL & Conti M 2004 EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 303 682–684. (https://doi.org/10.1126/science.1092463)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Peelman F, Zabeau L, Moharana K, Savvides SN & Tavernier J 2014 20 years of leptin: insights into signaling assemblies of the leptin receptor. Journal of Endocrinology 223 T9–T23. (https://doi.org/10.1530/JOE-14-0264)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Perez-Matute P, Marti A, Martinez JA, Fernandez-Otero MP, Stanhope KL, Havel PJ & Moreno-Aliaga MJ 2005 Eicosapentaenoic fatty acid increases leptin secretion from primary cultured rat adipocytes: role of glucose metabolism. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 288 R1682–R1688. (https://doi.org/10.1152/ajpregu.00727.2004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Perez-Matute P, Perez-Echarri N, Martinez JA, Marti A & Moreno-Aliaga MJ 2007 Eicosapentaenoic acid actions on adiposity and insulin resistance in control and high-fat-fed rats: role of apoptosis, adiponectin and tumour necrosis factor-alpha. British Journal of Nutrition 97 389–398. (https://doi.org/10.1017/S0007114507207627)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Riese DJ 2nd & Cullum RL 2014 Epiregulin: roles in normal physiology and cancer. Seminars in Cell and Developmental Biology 28 49–56. (https://doi.org/10.1016/j.semcdb.2014.03.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Roskoski R Jr 2014 The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacological Research 79 34–74. (https://doi.org/10.1016/j.phrs.2013.11.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shen Q, Yasmeen R, Marbourg J, Xu L, Yu L, Fadda P, Flechtner A, Lee LJ, Popovich PG & Ziouzenkova O 2018 Induction of innervation by encapsulated adipocytes with engineered vitamin A metabolism. Translational Research 192 1–14. (https://doi.org/10.1016/j.trsl.2017.10.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shiraishi K & Matsuyama H 2012 Local expression of epidermal growth factor-like growth factors in human testis and its role in spermatogenesis. Journal of Andrology 33 66–73. (https://doi.org/10.2164/jandrol.110.011981)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sugiyama S, Nakabayashi K, Baba I, Sasazuki T & Shirasawa S 2005 Role of epiregulin in peptidoglycan-induced proinflammatory cytokine production by antigen presenting cells. Biochemical and Biophysical Research Communications 337 271–274. (https://doi.org/10.1016/j.bbrc.2005.09.050)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Szkudelski T 2007 Intracellular mediators in regulation of leptin secretion from adipocytes. Physiological Research 56 503–512.

  • Tessitore L, Vizio B, Jenkins O, De Stefano I, Ritossa C, Argiles JM, Benedetto C & Mussa A 2000 Leptin expression in colorectal and breast cancer patients. International Journal of Molecular Medicine 5 421–426.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Toyoda H, Komurasaki T, Ikeda Y, Yoshimoto M & Morimoto S 1995 Molecular cloning of mouse epiregulin, a novel epidermal growth factor-related protein, expressed in the early stage of development. FEBS Letters 377 403–407. (https://doi.org/10.1016/0014-5793(95)01403-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Toyoda H, Komurasaki T, Uchida D & Morimoto S 1997 Distribution of mRNA for human epiregulin, a differentially expressed member of the epidermal growth factor family. Biochemical Journal 326 69–75. (https://doi.org/10.1042/bj3260069)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ukropec J, Anunciado RV, Ravussin Y & Kozak LP 2006 Leptin is required for uncoupling protein-1-independent thermogenesis during cold stress. Endocrinology 147 2468–2480. (https://doi.org/10.1210/en.2005-1216)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wauman J, Zabeau L & Tavernier J 2017 The leptin receptor complex: heavier than expected? Frontiers in Endocrinology 8 30. (https://doi.org/10.3389/fendo.2017.00030)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yamanaka Y, Hayashi K, Komurasaki T, Morimoto S, Ogihara T & Sobue K 2001 EGF family ligand-dependent phenotypic modulation of smooth muscle cells through EGF receptor. Biochemical and Biophysical Research Communications 281 373–377. (https://doi.org/10.1006/bbrc.2001.4385)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang X, Sui W, Zhang M, Dong M, Lim S, Seki T, Guo Z, Fischer C, Lu H, Zhang C, et al.2017 Switching harmful visceral fat to beneficial energy combustion improves metabolic dysfunctions. JCI Insight 2 e89044. (https://doi.org/10.1172/jci.insight.98094)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yasmeen R, Reichert B, Deiuliis J, Yang F, Lynch A, Meyers J, Sharlach M, Shin S, Volz KS, Green KB, et al.2012 Autocrine function of aldehyde dehydrogenase 1 as a determinant of diet- and sex-specific differences in visceral adiposity. Diabetes 62 124–136. (https://doi.org/10.2337/db11-1779)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang J, Matheny MK, Tumer N, Mitchell MK & Scarpace PJ 2007 Leptin antagonist reveals that the normalization of caloric intake and the thermic effect of food after high-fat feeding are leptin dependent. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 292 R868–R874. (https://doi.org/10.1152/ajpregu.00213.2006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang C, Rexrode KM, van Dam RM, Li TY & Hu FB 2008 Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality: sixteen years of follow-up in US women. Circulation 117 1658–1667. (https://doi.org/10.1161/CIRCULATIONAHA.107.739714)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhou YT, Wang ZW, Higa M, Newgard CB & Unger RH 1999 Reversing adipocyte differentiation: implications for treatment of obesity. PNAS 96 2391–2395. (https://doi.org/10.1073/pnas.96.5.2391)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation