Deficiency in AIM2 induces inflammation and adipogenesis in white adipose tissue leading to obesity and insulin resistance

Abstract

Aims/hypothesis 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. Methods 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. Results 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 Ly6C low 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. Conclusions/interpretation 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.

Circulating apelin, chemerin and omentin levels in patients with gestational diabetes mellitus: a systematic review and meta-analysis

“…We found that the year of publication, geographic region, study sample size, BMI, and gestational age were not sources of heterogeneity across the included studies. The binding of chemerin to its receptors can promote the recruitment of macrophages and dendritic cells, and neutrophil activation to produce inflammation [39], and chronic low-grade inflammation has been associated with increased IR [40]. A reduction in chemerin levels may be associated with the development of GDM through decreased insulin sensitivity and attenuated anti-inflammatory capacity [25].…”

Lipids, inflammasomes, metabolism, and disease

“…In contrast to the NLRP3 function, deficiency in AIM2 increases inflammation and adipogenesis leading to spontaneous obesity and insulin resistance. 195 Correspondingly, Aim2 −/− mice were more obese than their WT counterparts and exhibited reduced energy expenditure and higher glucose intolerance. 195 196 AIM2 is also a regulator of hepatic fat levels.…”

“…195 Correspondingly, Aim2 −/− mice were more obese than their WT counterparts and exhibited reduced energy expenditure and higher glucose intolerance. 195 196 AIM2 is also a regulator of hepatic fat levels. Deficiency in Aim2 resulted in liver enlargement with increased lipid deposition.…”

The Emerging Relevance of AIM2 in Liver Disease

“…Together, these studies suggest that AIM2 inflammasome activation might contribute to inflammation and the progression of NAFLD to NASH. On the other hand, AIM2-deficient ( Aim −/− ) mice showed spontaneous increase in body weight, fasting glucose, and insulin levels compared with wild type (WT) controls [ 50 ]. This was coincident with increased macrophage infiltration and pro-inflammatory markers in the white adipose tissue.…”