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.