Joost M. Lambooij1,2, Hendrik J.P. van der Zande1, Frank Otto1, Martin Giera3, Arnaud Zaldumbide2, Bruno Guigas1
1.Leiden University Center for Infectious Diseases, 2.Department of Cell & Chemical Biology, and 2.Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden.
j.m.lambooij@lumc.nl
Weight loss (WL) through caloric restriction has been shown to have beneficial effects on the metabolic profile of obese individuals and has been suggested to reduce inflammation. However, whether WL improves the immunometabolic profile of metabolic organs, especially through remodeling of the tissue-resident immune landscape, remains unclear. Here we investigate the impact of WL through dietary reversion on the immunometabolic remodeling of the white adipose tissue (WAT) and liver of obese mice.
Male C57Bl6/J mice were fed a high-fat diet (HFD) in addition to sucrose-containing drinking water (10% w/v) for 12 weeks, followed or not by dietary switch to low-fat diet (LFD) for 4 weeks. Bodyweight/composition and whole-body metabolic homeostasis, assessed by glucose/insulin tolerance tests (GTT/ITT), were monitored. The immunometabolic profile of the WAT and liver were studied using a multiomics-based approach including transcriptomics, lipidomics and spectral flow cytometry.
Weight loss significantly lowered bodyweight and fat mass in obese mice, and reduced plasma glucose, insulin, cholesterol and ALT levels to those of LFD controls. Whole-body insulin sensitivity and glucose homeostasis, assessed by ITT and GTT, were completely normalized. Hepatic transcriptome and lipidome, as well as MASLD activity score, resembled those of LFD-fed control mice, indicating healthy liver restoration. Importantly, WL strongly reduced HFD-induced hepatic Kupffer cell activation and death, monocyte infiltration and accumulation of monocyte-derived pro-inflammatory CD11c+ macrophages. The WAT immune profile remained similar to HFD-fed mice characterized by increased monocyte infiltration and CD11c+ macrophage accumulation further supported by sustained transcriptional upregulation of obesity-associated genes involved in inflammation and immune cell activation.
In conclusion, WL rapidly normalizes metabolic parameters, yet fails to fully revert the immune profile in WAT. This pervasive inflammatory immune activation could contribute to exacerbated symptoms following weight gain and these insights might assist the improvement of novel dietary intervention strategies.