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

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.

Liraglutide Counteracts Endoplasmic Reticulum Stress in Palmitate-Treated Hypothalamic Neurons without Restoring Mitochondrial Homeostasis

“…In Sim1/MC4R neurons of the PVN, loss of MC4R is concomitant with fragmentation of mitochondrial network [7]. In vitro experiments have found that direct exposure to elevated palmitate induces fragmentation of mitochondria in insulinoma cells [46], podocytes [28], epithelial cells [67], and fibroblasts [68]. Similarly, we find here that direct exposure to elevated palmitate is sufficient to induce mitochondrial fragmentation and depolarization in hypothalamic neurons.…”

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

“…Lysosomal storage disorders are characterized by the lysosomal accumulation of the unique glycerophospholid bis(monoacylglycerol) phosphate (BMP), also called lysobisphosphatidic acid (LBPA), which may deplete phosphatidylglycerol levels, decreasing the rate of synthesis of mitochondrial cardiolipin, which is required for ETC function. Lysosomal dysfunction also interferes with the normal subcellular distribution of ceramide and cholesterol to mitochondria and other organelles, altering mitochondrial function [ 269 ] and dynamics [ 270 ] and contributing to cellular dysfunction in PD.…”

Disentangling Mitochondria in Alzheimer’s Disease

“…These studies indicate an important role for ceramide in inducing Aβ-mediated toxicity across various AD models and in patients with AD. Recently, the synthetic sphingolipid SH-BC-893 was shown to be a rapid and effective inhibitor of ceramide-induced mitochondrial fission, which works by potentially influencing the recruitment of Drp1 to the OMM ([ 253 ], commentary in: [ 254 ]). Treatment with SH-BC-893 preserved mitochondrial function in ceramide-treated cells and protected against ER stress induced by ceramide-mediated mitochondrial fission.…”

“…Treatment with SH-BC-893 preserved mitochondrial function in ceramide-treated cells and protected against ER stress induced by ceramide-mediated mitochondrial fission. Additionally, SH-BC-893 mimics the effects of caloric restriction by reducing food intake and thereby producing weight loss [ 253 ]. Although the above-mentioned beneficial effects were seen in diet-induced obesity, SH-BC-893 seems to be of great potential and needs to be tested urgently for the treatment of AD.…”