Senior Investigator
George
Kunos,
M.D., Ph.D.
Dr. Kunos received his M.D. degree in 1966 from Semmelweis University in Budapest and his Ph.D. in 1973 from McGill University in Montreal where he worked with Mark Nickerson on adrenergic receptors. In 1974 he joined the faculty in Pharmacology and Medicine at McGill University and then in 1987 joined the NIAAA as Chief of the Laboratory of Physiologic and Pharmacologic Studies. Dr. Kunos moved to the Medical College of Virginia in 1992 to Chair the Department of Pharmacology & Toxicology. In 2000 he returned to NIH as Scientific Director of NIAAA. He is an elected fellow of the High Blood Pressure Research Council of the American Heart Association and a foreign member of the Hungarian Academy of Sciences. He is recipient of the Mechoulam Award of the Intl. Cannabinoid Research Society and the NIH Director's Award. Dr. Kunos' laboratory is studying the role of endocannabinoids in neuroendocrine, metabolic and cardiovascular regulation.
Our laboratory is interested in the biology of the endocannabinoid system, with particular focus on its role in cardiovascular and metabolic regulation and the related therapeutic implications.
Endocannabinoids (ECs) are lipid mediators that interact with the same cannabinoid receptors - CB1 or CB2 - that recognize the psychoactive ingredient of marijuana and produce similar biological effects. We discovered that macrophage-derived ECs acting via vascular and cardiac CB1 receptors contribute to the hypotension in various forms of shock and advanced liver cirrhosis, and also act as a compensatory mechanism in hypertension. We have also identified a novel, nonCB1/nonCB2 GPCR that mediates the vasodilator effect of ECs in certain vascular beds. We use physiological approaches in whole animals, including genetically altered mice, as well as cell and molecular biological techniques.
We discovered that ECs acting via CB1 receptors regulate appetite in a leptin-dependent manner and also regulate the desire to drink alcohol. Our more recent findings indicate that ECs also regulate peripheral fat metabolism via CB1 receptors in liver and adipose tissue, and these peripheral effects contribute to diet-related obesity (DIO) and its hormonal/metabolic consequences. Endocannabinoids acting via hepatic CB1 receptors also play a key role in alcoholic liver disease and in liver regeneration. The emerging role of peripheral CB1 receptors led us to develop and test novel CB1 blockers - both neutral antagonists and inverse agonists - that do not penetrate the brain. We found that such compounds reverse DIO and the associated fatty liver, dyslipidemia and insulin and leptin resistance without causing unwanted behavioral effects that limit the therapeutic potential of brai-penetrant CB1 antagonists. A novel, peripheral CB1 inverse agonist is currently undergoing toxicological screening in preparation to its clinical testing.
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Resat Cinar, Ph.D.
Visiting Fellow
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Grzegorz Godlewski, Ph.D.
Visiting Fellow
(301) 496-6777
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Judy Harvey-White, B.S.
Senior Research Assistant
(301) 496-6777
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Tony Jourdan, Ph.D.
Visiting Fellow
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Jie Liu, M.D.
Staff Scientist
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Bani Mukhopadhyay, Ph.D.
Research Fellow
(301) 496-6777
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Gergo Szanda
Visiting Fellow
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Joseph Tam, Ph.D.
Staff Scientist
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Keming Xiong
Research Technician
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1) Liu J, Zhou L, Xiong K, Godlewski G, Mukhopadhyay B, Tam J, Yin S, Gao P, Shan X, Pickel J, Bataller R, O'Hare J, Scherer T, Buettner C, Kunos G (InPress) (2013)
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Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice
- Gastroenterology
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2) Mukhopadhyay B, Cinar R, Yin S, Liu J, Tam J, Godlewski G, Harvey-White J, Mordi I, Cravatt BF, Lotersztajn S, Gao B, Yuan Q, Schuebel K, Goldman D, Kunos G (2011)
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Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver
- Proc Natl Acad Sci USA, 108, 6323-6328
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3) Mukhopadhyay B, Liu J, Osei-Hyiaman D, Godlewski G, Mukhopadhyay P, Wang L, Jeong WI, Gao B, Duester G, Mackie K, Kojima S, Kunos G (2010)
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Transcriptional regulation of cannabinoid receptor-1 expression in the liver by retinoic acid receptor-gamma
- Journal of Biological Chemistry, 285, 19002-11
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4) Tam J, Vemuri VK, Liu J, Batkai S, Mukhopadhyay B, Godlewski G, Osei-Hyiaman D, Ohnuma S, Ambudkar SV, Pickel J, Makriyannis A, Kunos G (2010)
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Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity
- Journal of Clinical Investigation, 120, 2953-2966
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5) Godlewski G, Alapafuja SO, Batkai S, Nikas SP, Cinar R, Offertaler L, Osei-Hyiaman D, Liu J, Mukhopadhyay B, Harvey-WhiteJ, Tam J, Pacak K, Blankman JL, Cravatt BF, Makriyannis A, Kunos G (2010)
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Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects
- Chemistry & Biology, 17, 1256-1266
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6) Jeong WI, Osei-Hyiaman D, Liu J, Batkai S, Mukhopadhyay P, Horiguchi N, Perk O, Harvey-White J, Marsicano G, Lutz B, Gao B, Kunos G (2008)
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Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediate alcoholic fatty liver.
- Cell Metabolism, 7, 227-235
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7) • Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Batkai S, Marsicano G, Lutz B, Kunos G (2008)
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Hepatic CB1 receptor involvement in diet-induced steatosis, altered lipid profile, and insulin and leptin resistance.
- J. Clin. Invest.
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8) • Jeong WI, Osei-Hyiaman D, Liu J, Batkai S, Mukhopadhyay P, Horiguchi N, Perk O, Harvey-White J, Marsicano G, Lutz B, Gao B, Kunos G (2008)
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Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediate alcoholic fatty liver.
- Cell Metabolism, 7, 227-235
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9) • Osei-Hyiaman D, Depetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, Harvey-White J, Offertaler L, Wang L, Kunos G (2005)
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Endocannabinoid acting at hepatic CB1 receptors regulates fatty acid synthesis: role in diet-induced obesity.
- J. Clin. Invest. , 115, 1298-1305
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10) Wang L, Liu J, Harvey-White J, Zimmer A, Kunos G (2003)
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Endocannabinoid signaling via CB1 receptors is involved in ethanol preference and its age-dependent decline in mice.
- Proc Natl Acad Sci , 100, 1393-1398
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11) Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G (2001)
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Leptin-regulated endocannabinoids acting at CB1 receptors are involved in maintaining food intake
- Nature (London), 410, 822-825
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12) Batkai S, Jarai Z, Wagner JA, Goparaju SK, Varga K, Liu J, Wang L, Mirshahi S, Khanolkar AD, Makriyannis A, Urbaschek R, Garcia N, Sanyal AJ, Kunos G (2001)
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Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis
- Nature Medicine, 7, 827-832
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13) Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G (1999)
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Cannabinoid-induced mesenteric vasodilation via a novel endothelial site of action
- Proc Natl Acad Sci USA, 96, 14136-14141
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14) Varga K, Wagner JA, Bridgen DT, Kunos G (1998)
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Macrophage- and platelet-derived endogenous cannabinoids are involved in endotoxin-induced hypotension
- FASEB Journal, 12, 1035-1044
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15) Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G (1997)
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Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock
- Nature (London), 390, 518-521
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