Drug‐like sphingolipid SH‐BC‐893 opposes ceramide‐induced mitochondrial fission and corrects diet‐induced obesity

Vaishali Jayashankar,Selma Masri,Brianna M Hoover,Karina S Cramer,Elizabeth Selwan,Giedre Milinkeviciute,Amandine Verlande,Maggie O Goodson,Kazumi H Eckenstein,Nigel Turner,Aimee L Edinger,Bin Chen,Angela G Fleischman,Sarah E Hancock,Stephen Hanessian

doi:10.15252/emmm.202013086

Abstract

Ceramide‐induced mitochondrial fission drives high‐fat diet (HFD)‐induced obesity. However, molecules targeting mitochondrial dynamics have shown limited benefits in murine obesity models. Here, we reveal that these compounds are either unable to block ceramide‐induced mitochondrial fission or require extended incubation periods to be effective. In contrast, targeting endolysosomal trafficking events important for mitochondrial fission rapidly and robustly prevented ceramide‐induced disruptions in mitochondrial form and function. By simultaneously inhibiting ARF6‐ and PIKfyve‐dependent trafficking events, the synthetic sphingolipid SH‐BC‐893 blocked palmitate‐ and ceramide‐induced mitochondrial fission, preserved mitochondrial function, and prevented ER stress in vitro. Similar benefits were observed in the tissues of HFD‐fed mice. Within 4 h of oral administration, SH‐BC‐893 normalized mitochondrial morphology in the livers and brains of HFD‐fed mice, improved mitochondrial function in white adipose tissue, and corrected aberrant plasma leptin and adiponectin levels. As an interventional agent, SH‐BC‐893 restored normal body weight, glucose disposal, and hepatic lipid levels in mice consuming a HFD. In sum, the sphingolipid analog SH‐BC‐893 robustly and acutely blocks ceramide‐induced mitochondrial dysfunction, correcting diet‐induced obesity and its metabolic sequelae.

Highlights

Obesity has emerged as a serious epidemic
In mice consuming a high-fat diet (HFD), increased circulating palmitate is converted to C16:0 ceramide, triggering fragmentation of the mitochondrial network and the negative metabolic consequences associated with obesity (Jheng et al, 2012; Sebastian et al, 2012; Schneeberger et al, 2013; Smith et al, 2013; Wang et al, 2015; Filippi et al, 2017; Hammerschmidt et al, 2019)
Compelling evidence suggests that the limited benefits of mdivi-1 in obesity models stem from mitochondrial complex I inhibition rather than direct inhibition of DRP1 (Bordt et al, 2017); the type 2 diabetes mellitus therapy metformin is a complex I inhibitor

Summary

Introduction

Obesity has emerged as a serious epidemic. While the drivers of the growing obesity epidemic are multi-factorial, over-consumption of calorie dense, high-fat foods clearly contributes (Swinburn et al, 2011). These hypercaloric diets synergize with environmental and genetic factors to create a chronic positive energy balance that leads to excessive adiposity and metabolic dysfunction. While dietary modification and increasing exercise are an integral part of any interventional program, lifestyle changes alone have proven insufficient to resolve obesity in most patients. There is a critical unmet need for medical therapies that can complement dietary and lifestyle interventions and help individuals overcome the barriers to successful long-term weight loss

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Results

Conclusion