Cannabinoid Receptor 2 as Antiobesity Target: Inflammation, Fat Storage, and Browning Modulation.
Obesity is associated with a low-grade inflammatory state and adipocyte (ADP) hyperplasia/hypertrophy. Obesity inhibits the "browning" of white adipose tissue. Cannabinoid receptor 2 (CB2) agonists reduce food intake and induce antiobesity effect in mice. A common missense CB2 variant, Q63R, causes CB2-reduced function.



To evaluate the influence of CB2 receptor on the modulation of childhood obesity and of ADP activity and morphology.



CB2-Q63R variant was analyzed in obese Italian children. The effects of an inflammatory stimulus and those of drugs selectively acting on CB2 were investigated on in vitro ADPs obtained from mesenchymal stem cells of adult healthy donors or from sc adipose biopsies of adult nonobese and obese subjects.



Department of Women, Child and General and Specialist Surgery of the Second University of Naples.



A total of 501 obese Italian children (age 11 ± 2.75). Twelve healthy bone marrow donors (age 36.5 ± 15); and 17 subjects, 7 lean (age 42 ± 10) and 10 obese (age 37.8 ± 12) underwent sc adipose tissue biopsies.



Effects of CB2 stimulation on adipokine, perilipin, and uncoupling protein-1 expression.



The less-functional CB2-R63 variant was significantly associated with a high z-score body mass index. CB2 blockade with AM630 reverse agonist increased inflammatory adipokine release and fat storage and reduced browning. CB2 stimulation with JWH-133 agonist reversed all of the obesity-related effects.



CB2 receptor is a novel pharmacological target that should be considered for obesity.
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Francesca
F
Rossi
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Giulia
G
Bellini
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Livio
L
Luongo
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Iolanda
I
Manzo
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Salvatore
S
Tolone
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Chiara
C
Tortora
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Maria Ester
ME
Bernardo
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Anna
A
Grandone
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Antonella
A
Conforti
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Ludovico
L
Docimo
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Bruno
B
Nobili
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Laura
L
Perrone
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Franco
F
Locatelli
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Sabatino
S
Maione
Department of Women, Child and General and Specialist Surgery (F.R., I.M., A.G., B.N., L.P., E.M.d.G.) and Department of Experimental Medicine (G.B., L.L., I.M., C.T., S.M.), Division of Pharmacology Leonardo Donatelli, The Second University of Naples, 80138 Naples, Italy; The Endocannabinoid Research Group (L.L., S.M.), 80078 Pozzuoli, Naples, Italy; Division of General and Obesity Surgery (S.T., L.D.), The Second University of Naples, 80131 Naples, Italy; Department of Onco-Hematology (M.E.B., A.C., F.L.), Istituto di Ricovero e Cura a Caarattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy; and University of Pavia (F.L.), 27100 Pavia, Italy.
Emanuele Miraglia
EM
Del Giudice
D052437:Adipocytes, Brown / Q000276:immunology / Q000473:pathology*; D000273:Adipose Tissue / Q000276:immunology / Q000473:pathology*; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D007558:Italy; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009765:Obesity / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics*
D015415:Biomarkers; D043885:Receptor, Cannabinoid, CB2