title: High-fat diet-induced insulin resistance does not increase plasma anandamide levels or potentiate anandamide insulinotropic effect in isolated canine islets.
abstract: BACKGROUND
  Obesity has been associated with elevated plasma anandamide levels. In addition, anandamide has been shown to stimulate insulin secretion in vitro, suggesting that anandamide might be linked to hyperinsulinemia.
  
  
  OBJECTIVE
  To determine whether high-fat diet-induced insulin resistance increases anandamide levels and potentiates the insulinotropic effect of anandamide in isolated pancreatic islets.
  
  
  METHODS
  Dogs were fed a high-fat diet (n = 9) for 22 weeks. Abdominal fat depot was quantified by MRI. Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp. Fasting plasma endocannabinoid levels were analyzed by liquid chromatography-mass spectrometry. All metabolic assessments were performed before and after fat diet regimen. At the end of the study, pancreatic islets were isolated prior to euthanasia to test the in vitro effect of anandamide on islet hormones. mRNA expression of cannabinoid receptors was determined in intact islets. The findings in vitro were compared with those from animals fed a control diet (n = 7).
  
  
  RESULTS
  Prolonged fat feeding increased abdominal fat content by 81.3±21.6% (mean±S.E.M, P<0.01). In vivo insulin sensitivity decreased by 31.3±12.1% (P<0.05), concomitant with a decrease in plasma 2-arachidonoyl glycerol (from 39.1±5.2 to 15.7±2.0 nmol/L) but not anandamide, oleoyl ethanolamide, linoleoyl ethanolamide, or palmitoyl ethanolamide. In control-diet animals (body weight: 28.8±1.0 kg), islets incubated with anandamide had a higher basal and glucose-stimulated insulin secretion as compared with no treatment. Islets from fat-fed animals (34.5±1.3 kg; P<0.05 versus control) did not exhibit further potentiation of anandamide-induced insulin secretion as compared with control-diet animals. Glucagon but not somatostatin secretion in vitro was also increased in response to anandamide, but there was no difference between groups (P = 0.705). No differences in gene expression of CB1R or CB2R between groups were found.
  
  
  CONCLUSIONS
  In canines, high-fat diet-induced insulin resistance does not alter plasma anandamide levels or further potentiate the insulinotropic effect of anandamide in vitro.
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors: Orison O
authors: OO
authors: Woolcott
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Joyce M
authors: JM
authors: Richey
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors: Morvarid
authors: M
authors: Kabir
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Robert H
authors: RH
authors: Chow
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors: Malini S
authors: MS
authors: Iyer
authors: Department of Animal Resources, University of Southern California, Los Angeles, California, United States of America.
authors: Erlinda L
authors: EL
authors: Kirkman
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors: Darko
authors: D
authors: Stefanovski
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Maya
authors: M
authors: Lottati
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors: Stella P
authors: SP
authors: Kim
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: L Nicole
authors: LN
authors: Harrison
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors: Viorica
authors: V
authors: Ionut
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Dan
authors: D
authors: Zheng
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Isabel R
authors: IR
authors: Hsu
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Karyn J
authors: KJ
authors: Catalano
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Jenny D
authors: JD
authors: Chiu
authors: Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.
authors: Heather
authors: H
authors: Bradshaw
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors: Qiang
authors: Q
authors: Wu
authors: Cathryn M
authors: CM
authors: Kolka
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors: Richard N
authors: RN
authors: Bergman
mesh_terms: D050153:Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis; D001095:Arachidonic Acids / Q000097:blood / Q000235:genetics*; D001786:Blood Glucose; D001835:Body Weight; D059305:Diet, High-Fat / Q000009:adverse effects; D004285:Dogs; D063388:Endocannabinoids / Q000097:blood / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000097:blood* / Q000473:pathology; D053284:Polyunsaturated Alkamides / Q000097:blood; D043885:Receptor, Cannabinoid, CB2 / Q000096:biosynthesis
chemical_list: D023181:Antimicrobial Cationic Peptides; D001095:Arachidonic Acids; D001786:Blood Glucose; C000598900:CB1a protein; D063388:Endocannabinoids; D007328:Insulin; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; C078814:anandamide