2011-P: Totum-63 Lowers Adipose Tissue Inflammation and Reverses Both Hepatic Steatosis and Insulin Resistance in High-Fat Diet-Induced Obese Mice

Abstract

The worldwide prevalence of obesity, metabolic syndrome and type 2 diabetes (T2D) is reaching epidemic proportions that urge the development of new therapeutic strategies. Obesity-associated meta-inflammation contributes to nonalcoholic fatty liver disease (NAFLD) and plays a central role in the development of insulin resistance and T2D. Totum-63 has recently been developed for the management of prediabetes and shown to prevent high-fat diet (HFD)-induced metabolic disorders in mice. In the present study, we investigated whether Totum-63 could also improve metabolic homeostasis in insulin-resistant obese mice. For this purpose, C57Bl6/J male mice were fed a low- (LFD) or HFD for 12 weeks followed by supplementation with or without Totum-63 (2.7% w/w) for 4 additional weeks. Although no metabolic phenotype was observed in LFD-fed mice, Totum-63 decreased body weight in HFD-fed mice, an effect exclusively due to reduced fat mass and associated with a transient reduction in food intake confined to the first days of supplementation. The liver and brown adipose tissue weights were significantly reduced, whereas adipose tissue (AT) mass and adipocyte size distribution were not affected. Totum-63 markedly reduced hepatic macrovesicular steatosis and liver triglyceride content. Furthermore, potent decreases in fasting plasma glucose, insulin and leptin levels, and improvements in systemic insulin sensitivity and glucose tolerance were observed. Remarkably, a significant reduction in AT M1-like pro-inflammatory macrophages was found, indicating that Totum-63 can modulate macrophage recruitment/polarization and lower HFD-induced AT inflammation. Altogether, our results strongly suggest that Totum-63 reverses hepatic steatosis and insulin resistance in obese mice at least partly by dampening meta-inflammation, constituting a promising new approach for alleviating NAFLD and metabolic dysfunctions in established T2D. Disclosure H.J. van der Zande: None. A. Zawistowska-Deniziak: None. F. Otto: None. V. Chavanelle: Employee; Self; Valbiotis. S. Peltier: Board Member; Self; Valbiotis. P. Sirvent: Board Member; Self; Valbiotis. B. Guigas: Advisory Panel; Self; Valbiotis. Research Support; Self; Valbiotis.