title: The full capacity of AICAR to reduce obesity-induced inflammation and insulin resistance requires myeloid SIRT1.
abstract: Chronic Inflammation is a key link between obesity and insulin resistance. We previously showed that two nutrient sensors AMP-activated protein kinase (AMPK) and SIRT1 interact to regulate macrophage inflammation. AMPK is also a molecular target of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), which has been shown to reduce insulin resistance in various animal models. Here we aim to determine whether the therapeutic effects of AICAR against insulin resistance involve its anti-inflammatory function, which requires macrophage SIRT1. Long-term administration of low-dose AICAR significantly suppressed adipose inflammation in established diet-induced obese mice. This was associated with improved glucose homeostasis and insulin sensitivity without changes of body weight. In contrast, SIRT1 deletion in myeloid SIRT1 knockout (MSKO) mice increased infiltration of classically activated M1 macrophages and decreased alternatively activated M2 macrophages in adipose tissue. As a result, MSKO mice on high fat (HF) diets exhibited impaired insulin signaling in skeletal muscle, fat, and liver, and developed systemic insulin resistance in glucose tolerance tests, insulin tolerance tests, and hyperinsulinemic-euglycemic clamp experiments. Interestingly, the beneficial effects of AICAR on adipose inflammation and insulin sensitivity were absent in MSKO mice fed HF diets, suggesting that the full capacity of AICAR to antagonize obesity-induced inflammation and insulin resistance requires myeloid SIRT1. In summary, AICAR negatively regulates HF diet-induced inflammation, which requires myeloid SIRT1, thereby contributing to the protection against insulin resistance. Myeloid SIRT1 is a therapeutic target of the anti-inflammatory and insulin-sensitizing effects of AICAR.
authors.affiliation: Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Yang
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Wang
authors.forename: Yin
authors.initials: Y
authors.lastname: He
authors.forename: Ling
authors.initials: L
authors.lastname: Qi
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xue
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D012265:Ribonucleotides / Q000008:administration & dosage*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D016177:Macrophage-1 Antigen; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C031143:AICA ribonucleotide; D005947:Glucose