title: AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin.
abstract: In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo.
  
  
  
  Six-week-old male C57BL/6J wild-type and Adipoq-/-mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 μg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50 kg/m2) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry.
  
  
  
  AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8+T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p < 0.05), urinary H2O2(p < 0.05) and renal superoxide levels (p < 0.01) in both wild-type and Adipoq-/-mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq-/-mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients.
  
  
  
  AICAR may promote metabolic health and protect against obesity-induced systemic diseases in an adiponectin-independent manner. Furthermore, AICAR reduced inflammation in human adipose tissue explants, suggesting by proof-of-principle that the drug may reduce obesity-induced complications in humans.
  
  
  
  ClinicalTrials.gov NCT02322073.
authors.affiliation: The Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, S-413 45, Gothenburg, Sweden. borgesonlab@gmail.com.|Centre for Renal Translational Medicine, Institute of Metabolomic Medicine, UC San Diego Health Sciences, San Diego VA HealthCare System, Stein Clinical Research Building, Room 406, mail code 0711, 9500 Gilman Drive, La Jolla, CA, 92093, USA. borgesonlab@gmail.com.|Veteran's Affairs (VA), San Diego VA HealthCare System, Veterans Medical Research Foundation, San Diego, CA, USA. borgesonlab@gmail.com.
authors.forename: Emma
authors.initials: E
authors.lastname: Börgeson
authors.affiliation: Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ville
authors.initials: V
authors.lastname: Wallenius
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of California, San Diego, CA, USA.
authors.forename: Gulam H
authors.initials: GH
authors.lastname: Syed
authors.affiliation: Centre for Renal Translational Medicine, Institute of Metabolomic Medicine, UC San Diego Health Sciences, San Diego VA HealthCare System, Stein Clinical Research Building, Room 406, mail code 0711, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Darshi
authors.affiliation: The Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, S-413 45, Gothenburg, Sweden.
authors.forename: Juan
authors.initials: J
authors.lastname: Lantero Rodriguez
authors.affiliation: Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Biörserud
authors.affiliation: Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Ragnmark Ek
authors.affiliation: Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Björklund
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Quiding-Järbrink
authors.affiliation: Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Fändriks
authors.affiliation: University College Dublin (UCD) Diabetes Complications Research Centre, UCD Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.affiliation: Centre for Renal Translational Medicine, Institute of Metabolomic Medicine, UC San Diego Health Sciences, San Diego VA HealthCare System, Stein Clinical Research Building, Room 406, mail code 0711, 9500 Gilman Drive, La Jolla, CA, 92093, USA. kumarsharma@ucsd.edu.|Veteran's Affairs (VA), San Diego VA HealthCare System, Veterans Medical Research Foundation, San Diego, CA, USA. kumarsharma@ucsd.edu.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007674:Kidney Diseases / Q000276:immunology / Q000378:metabolism; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000276:immunology / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse
keywords: AICAR; Adiponectin; Inflammation; Kidney disease; Liver disease; Macrophages; Obesity