Our Vision
Obesity has become a worldwide epidemic in western countries, leading to insulin resistance, heart disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). In this respect, the enteroendocrine cells lining the gastrointestinal tract secrete dozens of hormones, upon sensing ingested nutrients, which act in an autocrine, paracrine and endocrine manner to regulate glucose homeostasis and energy balance. Intriguingly, these molecules also possess immunoregulatory properties, which create wide-ranging crosstalk between the secreted peptides, the immune system and different fat tissue depots. Our group aim to decipher the specific role of gut-derived peptides and immune cells-derived molecules, which all play at the interface between the immune system and metabolism. We strive to delineate how the gut-derived peptides affect inflammation and insulin resistance at specific sites, especially fat depots and liver and how they regulate whole body energy homeostasis. We believe that mechanistic insights derived from our research would enable the design of more effective therapies to combat obesity and the metabolic syndrome.
Our Team
- Prof. Sigal Fishman - Lab PI
- Dr. Isabel Zvibel - Lab Manager
Senior Researcher
- Dr. Isabel Zvibel
Research associate
- Anat Neumann
PhD student
- Dr. Irina Efimova
Lubna Kahir
MSc student
- Roni Tron
- Shani Ben Shlomo, PhD student
- Dana Fernanda Mantelmacher, PhD student
- Inbar Steinberg, MSc student
Research
Insulinotropic Polypeptide (GIP) at the interface between immunity and metabolism
Our group has being studying the immunoregulatory properties of an incretin hormone produced in the gut in response to food intake – the glucose-dependent insulinotropic polypeptide (GIP). We have found that GIP is directly involved in bone marrow hematopoiesis and tunes immune cell abundance in the circulation and in adipose tissue during obesity. Moreover, we demonstrated for the first time that GIP regulates energy homeostasis during obesity by increasing adaptive thermogenesis capacity. This improvement is mediated by restraining the production of the alarmin S100A8/A9 in myeloid cells and by maintaining type 2 immunity in adipose tissue, both leading to enhanced transformation of white adipose tissue into “brown like” adipose tissue (“beiging”)(Mantelmacher, Nature Metabolism, 2019; Efimova, Front Immunology, 2021).
We currently use GIPR-reporter mice and conditional knockout mice to identify the repertoire of immune cells expressing the GIPR and its effect on their immunometabolic activity.
and their heterodimer in adaptive thermogenesis
Adaptive thermogenesis is induced by cold or stress, which are sensed by the central nervous system and result in a sympathetic response that releases NE which acts on thermogenic fat depots to dissipate energy as heat . Therefore, this process has become an attractive target as a therapeutic mean to treat obesity. We have found that alarmins S100A9, S100A8 , which are mostly derived from immune cells but also from adipocytes , are crucial for β adrenergic receptor agonism- induced thermogenesis. We currently use lean and obese mice and conditional knockout mice to identify the source of these alarmins, affecting thermogenesis ( adipocytes vs. immune cell) an t to decipher the mechanism and signaling pathways which are involved in the process.
From The Press
Hormone that helps the body "waste" excess energy and reduce fat accumulation
Highlight Publications
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Glucagon-Like Peptide-1 reduces hepatic lipogenesis via activation of AMP-activated Protein Kinase Ben Shlomo S , Zvibel I, Oren R, Fishman S J. Hepatol 2011; 54:1214-23 |
Hubel E, Fishman S, Holopainen M, Käkelä R, Shaffer O, Houri I, Zvibel I, Shibolet O.Am J Physiol Gastrointest Liver Physiol. 2021 Sep
Efimova I, Steinberg I, Zvibel I, Neumann A, Mantelmacher DF, Drucker DJ, Fishman S, Varol C.Front Immunol. 2021 Feb 25;12:643144. doi: 10.3389/fimmu.2021.643144. eCollection 2021
Shapira S, Kazanov D, Dankner R, Fishman S, Stern N, Arber N.J Pers Med. 2021 Jan 15;11(1):50
Shapira S, Kazanov D, Dankner R, Fishman S, Stern N, Arber N.J Pers Med. 2021 Jan 15;11(1):50
Distinct extracellular-matrix remodeling events precede symptoms of inflammation.
Shimshoni E, Adir I, Afik R, Solomonov I, Shenoy A, Adler M, Puricelli L, Sabino F, Savickas S, Mouhadeb O, Gluck N, Fishman S, Werner L, Salame TM, Shouval DS, Varol C, Auf dem Keller U, Podestà A, Geiger T, Milani P, Alon U, Sagi I.Matrix Biol. 2021 Feb;96:47-68
GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9.
Mantelmacher FD, Zvibel I, Cohen K, Epshtein A, Pasmanik-Chor M, Vogl T, Kuperman Y, Weiss S, Drucker DJ, Varol C, Fishman S.Nat Metab. 2019 Jan;1(1):58-69
Deutsch L, Ben Haim L, Sofer Y, Gluck N, Santo E, Fishman S.
Erez N, Hubel E, Avraham R, Cohen R, Fishman S, Bantel H, Manns M, Tirosh B, Zvibel I, Shibolet O.Toxicol Sci. 2017 Oct 1;159(2):402-412
Mantelmacher FD, Fishman S, Cohen K, Pasmanik Chor M, Yamada Y, Zvibel I, Varol C.J Immunol. 2017 Apr 15;198(8):3089-3098
Predictors for advanced fibrosis in morbidly obese non-alcoholic fatty liver patients.
Zelber-Sagi S, Shoham D, Zvibel I, Abu-Abeid S, Shibolet O, Fishman S.World J Hepatol. 2017 Jan 18;9(2):91-98.
Hubel E, Saroha A, Park WJ, Pewzner-Jung Y, Lavoie EG, Futerman AH, Bruck R, Fishman S, Dranoff JA, Shibolet O, Zvibel I.Am J Pathol. 2017 Jan;187(1):122-133.
Catalogna M, Fishman S, Halpern Z, Ben-Shlomo S, Nevo U, Ben-Jacob E.Metabolism. 2016 Jun;65(6):863-73
Varol C, Zvibel I, Spektor L, Mantelmacher FD, Vugman M, Thurm T, Khatib M, Elmaliah E, Halpern Z, Fishman S.J Immunol. 2014 Oct 15;193(8):4002-9
Rabinowich L, Fishman S, Hubel E, Thurm T, Park WJ, Pewzner-Jung Y, Saroha A, Erez N, Halpern Z, Futerman AH, Zvibel I.J Hepatol. 2015 Jan;62(1):175-8
Khatib M, Zvibel I, Zelber-Sagi S, Varol C, Lahat G, Abu-Abeid S, Klausner JM, Halpern Z, Fishman S.J Clin Transl Endocrinol. 2014 Jul 16;1(3):115-119
Ben-Shlomo S, Zvibel I, Varol C, Spektor L, Shlomai A, Santo EM, Halpern Z, Oren R, Fishman S.Obesity (Silver Spring). 2013 Nov;21(11):2331-41
Artificial neural networks based controller for glucose monitoring during clamp test.
Catalogna M, Cohen E, Fishman S, Halpern Z, Nevo U, Ben-Jacob E.PLoS One. 2012;7(8):e44587.
Ben-Shlomo S, Zvibel I, Rabinowich L, Goldiner I, Shlomai A, Santo EM, Halpern Z, Oren R, Fishman S.Dig Dis Sci. 2013 Jan;58(1):172-8
The metabolic regulator PGC-1α links hepatitis C virus infection to hepatic insulin resistance.
Shlomai A, Rechtman MM, Burdelova EO, Zilberberg A, Hoffman S, Solar I, Fishman S, Halpern Z, Sklan EH.J Hepatol. 2012 Oct;57(4):867-7
Perinephric and epididymal fat affect hepatic metabolism in rats.
Ben-Shlomo S, Einstein FH, Zvibel I, Atias D, Shlomai A, Halpern Z, Barzilai N, Fishman S.Obesity (Silver Spring). 2012 Jan;20(1):151-6.
Curcumin inhibits hepatitis B virus via down-regulation of the metabolic coactivator PGC-1alpha.
Rechtman MM, Har-Noy O, Bar-Yishay I, Fishman S, Adamovich Y, Shaul Y, Halpern Z, Shlomai A.FEBS Lett. 2010 Jun 3;584(11):2485-90