Obesity development in caspase-1-deficient mice

Abstract

Caspase-1 is a member of the intracellular cysteine protease family that mediates inflammation through the activation of the cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). As mice lacking IL-18 become obese and insulin resistant, and both IL-18 and IL-1β have a role in overall energy balance, we sought to determine whether caspase-1 deficiency also causes obesity. Male and female caspase-1-deficient (caspase-1-/-) and control (wild-type (WT)) mice were fed either a high-fat (HF, 45% of kcal) or a low-fat (LF, 10% of kcal) synthetic diet starting at 6 weeks of age. Caspase-1-/- mice maintained lower but detectable levels of IL-18 compared with WT mice. Plasma IL-1β levels were below the detection limit for both KO and WT mice. Male caspase-1-/- mice gained extra fat mass by 16 weeks on the HF diet, but not until 40 weeks on the LF diet. Female capase-1-/- mice gained more fat by 28 weeks but only on the HF diet. These data indicate that caspase-1-/- mice develop obesity with an age and sex-dependent differences, and only male mice display obesity on LF diet. Overall, this study suggests that the lower level of IL-18 in caspase-1-/- mice might be causing obesity development similarly to IL-18-deficient mice.

Inflammasomes: Molecular Regulation and Implications for Metabolic and Cognitive Diseases

“…Also, pancreatic β-cell death and insulin resistance in T2DM have been associated with IL-1β secretion mediated by the ROS-TXNIP axis, thereby enhancing NLRP3 activation (Zhou et al, 2010). This involvement of ROSTXNIP in T2DM is consistent with the requirement for ROS in the NLRP3 inflammasome pathway (Wang et al, 2014a). Therefore, the NLRP3 inflammasome may contribute to the pathogenesis of T2DM via the TXNIP protein (Wang et al, 2014a).…”

“…This involvement of ROSTXNIP in T2DM is consistent with the requirement for ROS in the NLRP3 inflammasome pathway (Wang et al, 2014a). Therefore, the NLRP3 inflammasome may contribute to the pathogenesis of T2DM via the TXNIP protein (Wang et al, 2014a). However, the mechanisms that induce ROS generation in response to metabolic stress, such as chronic hyperglycemia, remain incompletely understood.…”

“…For example, pro-inflammatory cytokines, TNF-α, IL-1β and IFNγ, activate signaling pathways that result in pancreatic β-cell death and dysfunction (Eizirik et al, 2012; Feve et al, 2009; Mraz et al, 2011). As a result, elevated IL-1β levels and limited β-cell function are two primary predictors for the development of T2DM through inhibition of insulin signaling (Wang et al, 2014a). Additionally, recent studies have shown that inhibition of IL-1β production reduced T2DM prevalence in animal models (Emanuela et al, 2012; Mandrup-Poulsen et al, 2010).…”

Inflammasomes: mechanism of action, role in disease, and therapeutics

“…Similarly, it was also observed that NLRP3, ASC, and caspase-1 deficiency protected from HFD-induced obesity 106 . However, a recent study reported contradictory results that mice lacking Casp1 were more obese than control mice including having increased fat mass compared with controls 121 . The difference may be due to the variation in intestinal microbiota in mice raised in different animal facilities, as intestinal microbiota has been demonstrated to play a significant role in metabolic diseases 122 .…”

NALP3 inflammasome activation in protein misfolding diseases

“…It is characterized by a reduction in the ability of insulin to stimulate glucose utilization, insulin resistance and inadequate pancreatic β-cell insulin secretion in response to hyperglycemia [7,10]. Elevated level of IL-1β and limited beta-cell function are two primary predictors for the development of T2DM [75]. Pioneering studies have demonstrated the contribution of NALP3 inflammasome in the pathogenesis of T2DM.…”