Maternal high-fat diet exaggerates diet-induced insulin resistance in adult offspring by enhancing inflammasome activation through noncanonical pathway of caspase-11

• Main Authors: Naotoshi Wada, Hiroyuki Yamada, Shinichiro Motoyama, Makoto Saburi, Takeshi Sugimoto, Hiroshi Kubota, Daisuke Miyawaki, Noriyuki Wakana, Daisuke Kami, Takehiro Ogata, Satoaki Matoba
• Format: Article
• Language: English
• Published: Elsevier 2020-07-01
• Series: Molecular Metabolism
• Subjects: Maternal high-fat diet; Insulin resistance; Inflammasome; Interleukin-1β; Caspase-1; Caspase-11
• Online Access: http://www.sciencedirect.com/science/article/pii/S2212877820300624

Objective: Maternal high-fat diet (HFD) has been shown to promote the development of insulin resistance (IR) in adult offspring; however, the underlying mechanisms remain unclear. Methods: Eight-week-old female wild-type mice (C57BL/6) were fed either an HFD or a normal diet (ND), one week prior to mating, and the diet was continued throughout gestation and lactation. Eight-week-old male offspring of both groups were fed an HFD for 8 weeks. Results: Offspring of HFD-fed dams (O-HFD) exhibited significantly impaired insulin sensitivity compared with the offspring of ND-fed dams (O-ND). The adipocyte size of the eWAT increased significantly in O-HFD and was accompanied by abundant crown-like structures (CLSs), as well as a higher concentration of interleukin 1β (IL-1β) in the eWAT. Treatment with an inflammasome inhibitor, MCC950, completely abrogated the enhanced IR in O-HFD. However, ex vivo caspase-1 activity in eWAT revealed no difference between the two groups. In contrast, noncanonical inflammasome activation of caspase-11 was significantly augmented in O-HFD compared with O-ND, suggesting that membrane pore formation, but not cleavage of pro-IL-1β by caspase-1, is augmented in O-HFD. To examine the membrane pore formation, we performed metabolic activation of bone marrow-derived macrophages (BMDMs). The percentage of pore formation assessed by ethidium bromide staining was significantly higher in BMDMs of O-HFD, accompanied by an enhanced active caspase-11 expression. Consistently, the concentration of IL-1β in culture supernatants was significantly higher in the BMDMs from O-HFD than those from O-ND. Conclusions: These findings demonstrate that maternal HFD exaggerates diet-induced IR in adult offspring by enhancing noncanonical caspase-11-mediated inflammasome activation.