Long JZ, Roche AM, Berdan CA, Louie SM, Roberts AJ, Svensson KJ, Dou FY, Bateman LA, Mina AI, Deng Z, Jedrychowski MP, Lin H, Kamenecka TM, Asara JM, Griffin PR, Banks AS, Nomura DK, Spiegelman BM. Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception.
Proc Natl Acad Sci U S A. 2018 [in press]
Bioactive lipids control a wide variety of physiologic processes. We have recently identified a branch of bioactive lipid signaling mediated by the N-acyl amino acids and the circulating enzyme PM20D1. Here, we generated and characterized mice globally deficient in PM20D1. These knockout animals have bidirectional changes to endogenous N-acyl amino acids and a variety of metabolic and nociceptive phenotypes. Our studies establish PM20D1 as the principal N-acyl amino acid synthase/hydrolase in vivo and illuminate control of metabolic homeostasis and nociceptive behaviors by N-acyl amino acid signaling.
Lin H*, Long JZ*, Roche AM, Svensson KJ, Dou FY, Chang MR, Strutzenberg T, Ruiz C, Cameron MD, Novick SJ, Berdan CA, Louie SM, Nomura DK, Spiegelman BM, Griffin PR, Kamenecka TM. Discovery of hydrolysis resistant isoindoline N-acyl amino acid analogs that stimulate mitochondrial respiration.
J. Med. Chem. 2018 Apr 12;61(7):3224-3230. *equal contribution
Palmer CJ, Bruckner RJ, Paulo JA, Kazak L, Long JZ, Mina AI, Deng Z, LeClaire KB, Hall JA, Hong S, Zushin PH, Smith KL, Gygi SP, Hagen S, Cohen DE, Banks AS. Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue.
Mol. Metab. 2017 Oct;6(10):1212-1225.
Vishvanath L, Long JZ, Spiegelman BM, Gupta RK. Do Adipocytes Emerge from Mural Progenitors?
Cell Stem Cell. 2017 May;20(5):585-586.
Sylow L, Long JZ, Lokurkar IA, Zeng X, Richter EA, Spiegelman BM. The Cancer Drug Dasatinib Increases PGC-1α in Adipose Tissue but Has Adverse Effects on Glucose Tolerance in Obese Mice.
Endocrinology. 2016 Nov;157(11):4184-4191.
Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MR, Jedrychowski MP, Paulo JA, Gygi SP, Griffin PR, Nomura DK, Spiegelman BM. The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria.
Cell. 2016 Jul 14;166(2):424-35.
Here we identify a class of lipid metabolites, the N-acyl amino acids, that function as endogenous uncouplers of mitochondrial respiration. These lipids are regulated in vivo by a previously mis-characterized circulating enzyme hormone, peptidase M20 domain containing 1 (PM20D1). In vitro, PM20D1 is a bi-directional N-acyl amino acid hydrolase and synthase. In mice, increased circulating PM20D1, or injection of N-acyl amino acids, increases respiration and energy expenditure. This discovery directly links a new enzyme-metabolite pathway to mammalian energy homeostasis and assigns a new bioactivity to a class of endogenous lipids.
Svensson KJ, Long JZ, Jedrychowski MP, Cohen P, Lo JC, Serag S, Kir S, Shinoda K, Tartaglia JA, Rao RR, Chédotal A, Kajimura S, Gygi SP, Spiegelman BM. A Secreted Slit2 Fragment Regulates Adipose Tissue Thermogenesis and Metabolic Function.
Cell Metab. 2016 Mar 8;23(3):454-66.
Nass SR, Long JZ, Schlosburg JE, Cravatt BF, Lichtman AH, Kinsey SG. Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge.
J Neuroimmune Pharmacol. 2015 Jun;10(2):364-70.
Zhang Z, Wang W, Zhong P, Liu SJ, Long JZ, Zhao L, Gao HQ, Cravatt BF, Liu QS. Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity.
Hippocampus. 2015 Jan;25(1):16-26.
Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, Jedrychowski MP, Ruas JL, Wrann CD, Lo JC, Camera DM, Lachey J, Gygi S, Seehra J, Hawley JA, Spiegelman BM. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis.
Cell. 2014 Jun 5;157(6):1279-91.
Schlosburg JE, Kinsey SG, Ignatowska-Jankowska B, Ramesh D, Abdullah RA, Tao Q, Booker L, Long JZ, Selley DE, Cravatt BF, Lichtman AH. Prolonged monoacylglycerol lipase blockade causes equivalent cannabinoid receptor type 1 receptor-mediated adaptations in fatty acid amide hydrolase wild-type and knockout mice.
J Pharmacol Exp Ther. 2014 Aug;350(2):196-204.
Long JZ, Svensson KJ, Tsai L, Zeng X, Roh HC, Kong X, Rao RR, Lou J, Lokurkar I, Baur W, Castellot JJ Jr, Rosen ED, Spiegelman BM. A smooth muscle-like origin for beige adipocytes.
Cell Metab. 2014 May 6;19(5):810-20.
Here, we used a genetic strategy to tag populations of UCP1+ thermogenic fat directly in heterogeneous adipose tissues. We used this mouse model to generate comprehensive gene expression profiles from thermogenic brown and beige adipocytes in vivo. Our dataset demonstrated striking similarities and important differences between beige and brown adipocytes, including a smooth muscle-like gene expression pattern in beige, but not brown fat cells in vivo. Fate mapping using inducible and constitutive smooth muscle reporters demonstrated that at least a subset of beige fat arises from vascular smooth muscle-like precursors. Our study therefore clarifies the cellular origin of beige fat cells and also establishes a portrait of adipocyte gene expression in vivo.
Zhong P, Wang W, Pan B, Liu X, Zhang Z, Long JZ, Zhang HT, Cravatt BF, Liu QS. Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling.
Neuropsychopharmacology. 2014 Jun;39(7):1763-76.
Pryce G, Cabranes A, Fernández-Ruiz J, Bisogno T, Di Marzo V, Long JZ, Cravatt BF, Giovannoni G, Baker D. Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors.
Mult Scler. 2013 Dec;19(14):1896-904.
Blankman JL, Long JZ, Trauger SA, Siuzdak G, Cravatt BF. ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC.
Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1500-5.
Wise LE, Long KA, Abdullah RA, Long JZ, Cravatt BF, Lichtman AH. Dual fatty acid amide hydrolase and monoacylglycerol lipase blockade produces THC-like Morris water maze deficits in mice.
ACS Chem Neurosci. 2012 May 16;3(5):369-78.
Booker L, Kinsey SG, Abdullah RA, Blankman JL, Long JZ, Ezzili C, Boger DL, Cravatt BF, Lichtman AH. The fatty acid amide hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice.
Br J Pharmacol. 2012 Apr;165(8):2485-96.
Sticht MA, Long JZ, Rock EM, Limebeer CL, Mechoulam R, Cravatt BF, Parker LA. Inhibition of monoacylglycerol lipase attenuates vomiting in Suncus murinus and 2-arachidonoyl glycerol attenuates nausea in rats.
Br J Pharmacol. 2012 Apr;165(8):2425-35.
Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.
Nature. 2012 Jan 11;481(7382):463-8.
Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MC, Ward AM, Hahn YK, Lichtman AH, Conti B, Cravatt BF. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation.
Science. 2011 Nov 11;334(6057):809-13.
Long JZ, Cravatt BF. The metabolic serine hydrolases and their functions in mammalian physiology and disease.
Chem Rev. 2011 Oct 12;111(10):6022-63.
In this review, Ben and I provide an overview of the metabolic serine hydrolase family. This family of enzymes, characterized by an active site serine residue, has >100 members in mammals and is involved in nearly all aspects of mammalian physiology, including neurotransmission, diabetes, nociception, and inflammation. Notable examples of serine hydrolase family members include DPP4, ACHE, FAAH, and MGLL. We go enzyme by enzyme through the mammalian serine hydrolases and provide a summary of the knowledge to date regarding their enzymatic activities in vivo and physiologic functions.
Long JZ, Cisar JS, Milliken D, Niessen S, Wang C, Trauger SA, Siuzdak G, Cravatt BF. Metabolomics annotates ABHD3 as a physiologic regulator of medium-chain phospholipids.
Nat Chem Biol. 2011 Sep 18;7(11):763-5.
In this paper we report a cell-based metabolomics pipeline for the annotation of physiologic substrates and products for previously uncharacterized enzymes, without a priori knowledge of the enzyme, reactants, or products. Using this platform, we identify that the transmembrane enzyme alpha/beta hydrolase domain containing 3 (ABHD3) is a regulator of medium-chain phospholipids. In vitro, ABHD3 shows striking specificity for medium (<C16), but not long chain substrates. ABHD3-KO mice have dysregulated medium-chain phospholipids, including the bioactive myristoyl-lysophosphatidyl choline, confirming the physiologic relevance of our metabolite assignments. This general platform might be useful for the large-scale annotation of uncharacterized enzymes in the mammalian genome.
Nomura DK, Lombardi DP, Chang JW, Niessen S, Ward AM, Long JZ, Hoover HH, Cravatt BF. Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer.
Chem Biol. 2011 Jul 29;18(7):846-56.
Ramesh D, Ross GR, Schlosburg JE, Owens RA, Abdullah RA, Kinsey SG, Long JZ, Nomura DK, Sim-Selley LJ, Cravatt BF, Akbarali HI, Lichtman AH. Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice.
J Pharmacol Exp Ther. 2011 Oct;339(1):173-85.
Kinsey SG, Nomura DK, O'Neal ST, Long JZ, Mahadevan A, Cravatt BF, Grider JR, Lichtman AH. Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice.
J Pharmacol Exp Ther. 2011 Sep;338(3):795-802.
Ezzili C, Mileni M, McGlinchey N, Long JZ, Kinsey SG, Hochstatter DG, Stevens RC, Lichtman AH, Cravatt BF, Bilsky EJ, Boger DL. Reversible competitive α-ketoheterocycle inhibitors of fatty acid amide hydrolase containing additional conformational constraints in the acyl side chain: orally active, long-acting analgesics.
J Med Chem. 2011 Apr 28;54(8):2805-22.
Kinsey SG, O'Neal ST, Long JZ, Cravatt BF, Lichtman AH. Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay.
Pharmacol Biochem Behav. 2011 Mar;98(1):21-7.
Long JZ, LaCava M, Jin X, Cravatt BF. An anatomical and temporal portrait of physiological substrates for fatty acid amide hydrolase.
J Lipid Res. 2011 Feb;52(2):337-44.
Fatty acid amide hydrolase (FAAH), an enzyme Ben cloned in 1996, is the major regulator of the N-acyl ethanolamine and N-acyl taurine classes of bioactive lipids in vivo. We profiled the metabolite changes following pharmacologic and genetic disruption of FAAH in mice. These studies elucidated distinct biosynthetic pathways for the N-acyl ethanolamine and taurine lipids which could be distinguished both temporally and anatomically. This paper highlights how in vivo substrate-product relationships for signaling metabolites can be established through targeted mass spectrometry measurements of endogenous lipids.
Schlosburg JE, Blankman JL, Long JZ, Nomura DK, Pan B, Kinsey SG, Nguyen PT, Ramesh D, Booker L, Burston JJ, Thomas EA, Selley DE, Sim-Selley LJ, Liu QS, Lichtman AH, Cravatt BF. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system.
Nat Neurosci. 2010 Sep;13(9):1113-9.
Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH, Coy J, Bodor AL, Muccioli GG, Hu SS, Woodruff G, Fung S, Lafourcade M, Alexander JP, Long JZ, Li W, Xu C, Möller T, Mackie K, Manzoni OJ, Cravatt BF, Stella N. The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors.
Nat Neurosci. 2010 Aug;13(8):951-7.
Kinsey SG, Long JZ, Cravatt BF, Lichtman AH. Fatty acid amide hydrolase and monoacylglycerol lipase inhibitors produce anti-allodynic effects in mice through distinct cannabinoid receptor mechanisms.
J Pain. 2010 Dec;11(12):1420-8.
Long JZ, Jin X, Adibekian A, Li W, Cravatt BF. Characterization of tunable piperidine and piperazine carbamates as inhibitors of endocannabinoid hydrolases.
J Med Chem. 2010 Feb 25;53(4):1830-42.
The serine hydrolase family of enzymes can be inhibited by carbamate electrophiles. Such compounds are relatively selective and in vivo active pharmacologic tools that can be used to perturb serine hydrolase function. Here we disclose the full account of the synthesis, structure-activity relationships, and inhibitory activities of piperidine/piperazine carbamates against members of the serine hydrolase family. This paper describes the full efforts leading to the generation of the MAGL inhibitor JZL184 and the dual MAGL/FAAH inhibitor JZL195. These compounds can be now purchased through Sigma Aldrich to perturb the function of MAGL and/or FAAH in cells and in mice.
Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis.
Cell. 2010 Jan 8;140(1):49-61.
Long JZ, Nomura DK, Vann RE, Walentiny DM, Booker L, Jin X, Burston JJ, Sim-Selley LJ, Lichtman AH, Wiley JL, Cravatt BF. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo.
Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20270-5.
The endogenous cannabinoid system (endocannabinoids) consists of two distinct lipid ligand agonists, anandamide and 2-arachidonoyl glycerol, that act at two distinct GPCRs, CB1 and CB2. This paper addresses the major question of how the various ligands and receptors interact to regulate physiology. Using newly developed pharmacologic tools to inhibit the degradative enzymes for the two endocannabinoids either separately or concurrently, we find evidence for synergistic interaction of endocannabinoid signaling in vivo. This paper therefore elucidates how diversification at the ligand level, rather than the receptor level, can be used as a mechanism to fine-tune neuromodulatory lipid signaling.
Straiker A, Hu SS, Long JZ, Arnold A, Wager-Miller J, Cravatt BF, Mackie K. Monoacylglycerol lipase limits the duration of endocannabinoid-mediated depolarization-induced suppression of excitation in autaptic hippocampal neurons.
Mol Pharmacol. 2009 Dec;76(6):1220-7.
Pan B, Wang W, Long JZ, Sun D, Hillard CJ, Cravatt BF, Liu QS. Blockade of 2-arachidonoylglycerol hydrolysis by selective monoacylglycerol lipase inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) Enhances retrograde endocannabinoid signaling.
J Pharmacol Exp Ther. 2009 Nov;331(2):591-7.
Long JZ, Nomura DK, Cravatt BF. Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism.
Chem Biol. 2009 Jul 31;16(7):744-53.
McQuaid KM, Long JZ, Sames D. C-H bond functionalization via hydride transfer: synthesis of dihydrobenzopyrans from ortho-vinylaryl akyl ethers.
Org Lett. 2009 Jul 16;11(14):2972-5.
Kinsey SG, Long JZ, O'Neal ST, Abdullah RA, Poklis JL, Boger DL, Cravatt BF, Lichtman AH. Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain.
J Pharmacol Exp Ther. 2009 Sep;330(3):902-10.
Schlosburg JE, Carlson BL, Ramesh D, Abdullah RA, Long JZ, Cravatt BF, Lichtman AH. Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice.
AAPS J. 2009 Jun;11(2):342-52.
Ahn K, Johnson DS, Mileni M, Beidler D, Long JZ, McKinney MK, Weerapana E, Sadagopan N, Liimatta M, Smith SE, Lazerwith S, Stiff C, Kamtekar S, Bhattacharya K, Zhang Y, Swaney S, Van Becelaere K, Stevens RC, Cravatt BF. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain.
Chem Biol. 2009 Apr 24;16(4):411-20.
Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.
Nat Chem Biol. 2009 Jan;5(1):37-44.
This paper describes JZL184, the first in vivo active and selective inhibitor of an uncharacterized enzyme, monoacylglycerol lipase (MAGL). Using this tool compound, we demonstrate that MAGL is the major degradative enzyme for a brain neuromodulatory lipid, 2-arachidonoyl glycerol (2-AG). Blockade of MAGL in vivo leads to accumulation of 2-AG, reductions in brain arachidonate, and multiple cannabinoid receptor-dependent behaviors including anti-nociception. These data establish MAGL as a major enzymatic hub in the mammalian brain for arachidonoyl signaling lipids, and suggest targeting MAGL may be a therapeutic strategy to dissociate the beneficial and untoward effects of cannabinoid receptor agonists.
Rhee JM, Pirity MK, Lackan CS, Long JZ, Kondoh G, Takeda J, Hadjantonakis AK. In vivo imaging and differential localization of lipid-modified GFP-variant fusions in embryonic stem cells and mice.
Genesis. 2006 Apr;44(4):202-18.
Long JZ, Lackan CS, Hadjantonakis AK. Genetic and spectrally distinct in vivo imaging: embryonic stem cells and mice with widespread expression of a monomeric red fluorescent protein.
BMC Biotechnol. 2005 Jul 4;5:20.