Deficiency in AIM2 induces inflammation and adipogenesis in white adipose tissue leading to obesity and insulin resistance
Absent in melanoma 2 (AIM2) is a cytosolic sensor for double-stranded DNA and a tumour suppressor. Binding of double-stranded DNA to AIM2 forms the AIM2 inflammasome, leading to activation of caspase-1 and production of IL-1β and IL-18. Although inflammasome-independent effects of AIM2 have been reported, its role in energy metabolism is unknown. We aimed to evaluate the effect of AIM2 in energy metabolism and glucose homeostasis.
Male and female whole body Aim2 knockout (Aim2−/−) mice were used in the current study. Body weight, food intake, body composition, energy expenditure, fasting blood glucose levels, GTT and body temperature were measured at indicated time points. RNA sequencing was carried out on gonadal white adipose tissue (gWAT) in 14-month-old female mice. mRNA and protein levels in tissues were analysed by quantitative real-time PCR and immunoblot. Immune cell infiltration in gWAT was examined by flow cytometry. Stromal vascular fractions isolated from gWAT were used to investigate adipocyte differentiation.
Male and female Aim2−/− mice were obese compared with wild-type controls from 7 weeks of age until 51 weeks of age, with increased adiposity in both subcutaneous and visceral fat depots. While there were no differences in food intake, Aim2−/− mice demonstrated decreased energy expenditure and impaired brown adipose tissue function compared with wild-type controls. Fasting glucose and insulin levels were elevated, and Aim2−/− mice were glucose intolerant on intraperitoneal GTT. RNA sequencing revealed marked upregulation of the IFN-inducible gene Ifi202b, which encodes protein 202 (p202) and elevated inflammatory signalling in gWAT of Aim2−/− mice. Increased infiltration of total and Ly6Clow monocytes was noted at 8 weeks of age in gWAT, before the onset of obesity and insulin resistance. Ifi202b knockdown blocked adipogenesis in stromal vascular fractions and reduced inflammation in bone marrow-derived macrophages, demonstrating a key role of p202 in mediating the increased adipogenesis and inflammation in Aim2−/− mice.
These results demonstrate a fundamental role for AIM2 in energy metabolism, inflammation and insulin resistance. Our studies establish a novel link between the innate immunity proteins, AIM2 and p202, and metabolism.
KeywordsAdipogenesis AIM2 CX3CL1 Ifi202b Inflammasome Monocyte infiltration p202
Absent in melanoma 2
Apoptosis-associated speck-like protein containing a caspase activation and recruitment domain
Brown adipose tissue
Bone marrow-derived macrophage
CCAAT/enhancer binding protein
Comprehensive Lab Animal Monitoring System
Fatty acid oxidation
Gonadal white adipose tissue
Granulocyte-macrophage colony-stimulating factor
Ingenuity pathway analysis
Lean body mass
Monocyte chemoattractant protein 1
New Zealand Obese
Peroxisome proliferator activated receptor γ
Respiratory exchange ratio
Small interfering RNA
Stromal vascular fraction
Tris-buffered saline with Tween 20
Uncoupling protein 1
White adipose tissue
ZG and RM designed the experiments, performed statistical analysis and composed the manuscript. ZG, XZ, KS, RJ, EF, ESG, JW, HHD and PD conducted experiments, acquired and analysed data, and edited the manuscript. ZS and WC analysed the RNAseq data, conducted the bioinformatics analysis and edited the manuscript. All listed authors approved the final version of the manuscript. ZG and RM are the guarantors of this work.
This work was supported in part by grants from Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center Health System (RM), CHP Foundation grants (to ZG and RM) and National Institutes of Health R00HL12076, 1R01HL143967 (to PD), 1K08HL125666 (to EF), R01HL113655 (to JW) and R01DK090242 (to ESG).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
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