The Full Capacity of AICAR to Reduce Obesity-Induced Inflammation and Insulin Resistance Requires Myeloid SIRT1

Zhenggang Yang,Ling Qi,Liqing Yu,Xianfeng Wang,Hang Shi,Bingzhong Xue,Yin He,Andrea Cignarella

doi:10.1371/journal.pone.0049935

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.

Highlights

Chronic Inflammation is a key link between obesity and insulin resistance/type 2 diabetes [1]
We first determined whether activation of AMPactivated protein kinase (AMPK) pathway by the AMPK agonist AICAR protects against obesity-induced inflammation and insulin resistance
Mice on the high fat (HF) diet received either saline or the low-dose 150 mg/kg AICAR i.p. daily for 5 weeks, whereas mice on the chow diet received only saline, because we have shown that low dose of AICAR had no effects on glucose homeostasis and insulin sensitivity in lean mice (Fig. S1)

Summary

Introduction

Chronic Inflammation is a key link between obesity and insulin resistance/type 2 diabetes [1]. The role of AMPK in regulation of obesity-induced inflammation and insulin resistance were first reported in an elegant genetic study by Galic et al [12]. They convincingly demonstrated that disruption of AMPK signaling in hematopoietic derived cells including macrophages via bone marrow transplantation increased adipose macrophage inflammation and hepatic insulin resistance [12]. Our observations raise an interesting question as to whether the therapeutic effects of the AMPK agonist AICAR to reduce insulin resistance in various animal models [13,14,15] may depend on reduction of obesity-induced inflammation

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