Therapeutic Potential of AICAR in Attenuating Obesity‐Induced Metabolic, Liver and Kidney Disease

Abstract

Study ObjectiveObesity is a risk factor for organ inflammation, diabetes, and kidney disease. Here we evaluated the therapeutic potential of AICAR (an AMPK activator) in obesity‐induced metabolic, kidney and liver disease with High‐Fat‐Diet (HFD) in wild type and adiponectin‐deficient mice. We also correlate our findings to human pathophysiology, by examining human tissue responses to AICAR ex vivo in a proof of concept study.MethodMale C57BL/6 or Adiponectin−/− mice were fed a standard (10% fat) or HFD (60% fat) diet for 12 wks. HFD induced obesity and CKD, as evident by increased albuminuria. Vehicle or AICAR (500 mg/g) was given intraperitoneal as interventional therapeutics 3 times weekly, between wk 5–12. Furthermore, omental adipose tissue biopsies were isolated from obese (BMI 35–50), non‐diabetic female bariatric surgery patients (n=4). The adipose explants were incubated ex vivo with vehicle or AICAR (1 mM) for 6 hours at 37 °C, after which leukocytes were characterized by flow cytometry.ResultsInterventional AICAR treatment protected against obesity‐induced kidney disease, liver steatosis and improved insulin sensitivity in mice. Adipose inflammation is a key driver of obesity‐induced pathophysiology. AICAR attenuated adipose inflammation, by shifting MΦ phenotype from pro‐inflammatory M1 (CD11c+) to anti‐inflammatory M2 (CD206+), while reducing the percentage of CD8+ T‐cells, which correlated with reduced TNF‐α production and increasing adipose pAMPK levels. Interestingly, AICAR reduced interstitial adipose fibrosis, but enhanced omental capsular fibrosis. AICAR‐mediated protection was adiponectin independent, as protection was observed in both obese wild‐type and adiponectin−/− mice. In omental adipose tissue explants isolated from obese patients, AICAR promoted a ‘pro‐inflammatory’ to ‘anti‐inflammatory’ MΦ phenotype switch, which correlated with a reduction in TNF‐α.ConclusionIn conclusion, these data support a novel therapeutic paradigm for using AICAR to promote metabolic health and protect against obesity‐induced systemic pathophysiology, e.g. liver and kidney disease.Support or Funding InformationFinancial support was obtained from the National Institute of Health and Science Foundation Ireland, and EB is a recipient of grants from the Marie Curie International Outgoing fellowship (IOF‐GA‐2011‐301803) and the Swedish Research Council.