Journal
EMBO MOLECULAR MEDICINE
Volume 13, Issue 8, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202013086
Keywords
ceramide; high-fat diet; leptin resistance; mitochondrial fission; obesity
Categories
Funding
- NIH [R01 CA254360]
- Beall Applied Innovation
- National Center for Research Resources
- National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR001414]
- National Health and Medical Research Council of Australia [1126135]
- National Institutes of Health [P30CA062203]
- Concern Foundation for Cancer Research
- V Foundation for Cancer Research
- National Cancer Institute of the National Institutes of Health [P30CA062203, T32CA009054]
- Graduate Assistance in Areas of National Need (GAANN) [P200A120207]
- Hitachi-Nomura postdoctoral fellowship
- Chao Family Comprehensive Cancer Center Optical Biology Center
- NSERC Canada
- National Health and Medical Research Council of Australia [1126135] Funding Source: NHMRC
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Compounds targeting mitochondrial dynamics are ineffective at blocking ceramide-induced fission, while targeting endolysosomal trafficking events can rapidly and effectively prevent disruptions in mitochondrial form and function caused by ceramide.
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 PlKfyve-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.
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