CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity

Abstract

Highlights d CerS6, but not CerS5, deficiency protects from obesityassociated insulin resistance d CerS6, but not CerS5, regulates C 16:0 ceramides in mitochondria and MAMs d CerS6-derived C 16:0 sphingolipids interact with Mff d CerS6 and Mff regulate mitochondrial dynamics and insulin resistance in obesity

A tissue‐specific screen of ceramide expression in aged mice identifies ceramide synthase‐1 and ceramide synthase‐5 as potential regulators of fiber size and strength in skeletal muscle

“…Previous publications implicated CerS5 and CerS6 in obesity and glucose intolerance (Gosejacob et al, ; Hammerschmidt et al, ). We, therefore, scrutinized the data for possible co‐founding effects of body mass index (BMI) and type 2 diabetes.…”

“…As a metabolic organ, skeletal muscle is closely linked to glucose homeostasis. Indeed, previous publications implicated CerS1 and CerS5 in obesity and glucose intolerance (Hammerschmidt et al, ; Turpin et al, ; Turpin‐Nolan et al, ) (Gosejacob et al, ) Specifically, CerS1‐derived C18‐ceramide in skeletal muscle was shown to enhance whole‐body glucose metabolism in obesity by increasing the muscle‐derived adipokine Fgf21 (Turpin‐Nolan et al, ). The impact of CerS5 is controversial.…”

The integrative biology of type 2 diabetes

“…In this context, lowering cellular ceramide by ablating dihydroceramide desaturase 1 increased mitochondrial oxygen flux and improved steatosis and glucose metabolism in insulin-resistant mice 63 . Conversely, mitochondrial C16:0 ceramide, generated by overexpression of ceramide synthase 6 (CerS6), interacts with mitochondrial fission factor (MFF) to promote mitochondrial fragmentation, insulin resistance and steatosis 64 . Silencing of MFF prevented CerS6-dependent metabolic abnormalities despite elevated C16:0 ceramide.…”

Ceramides: A Cause of Insulin Resistance in Nonalcoholic Fatty Liver Disease in Both Murine Models and Humans

“…Of these, CerS5 and CerS6 add SFA C 16:0 to the sphingoid backbone. Liver‐specific CerS6, but not CerS5, knockout mice are protected against SFA‐induced IR and steatosis . This difference was recently attributed to the ability of CerS6‐derived sphingolipids to bind mitochondrial fission factors and promote FA‐induced mitochondrial fragmentation on subcellular pools of C 16:0 ceramides …”

“…Liver-specific CerS6, but not CerS5, knockout mice are protected against SFA-induced IR and steatosis. (6,7) This difference was recently attributed to the ability of CerS6-derived sphingolipids to bind mitochondrial fission factors and promote FA-induced mitochondrial fragmentation on subcellular pools of C 16:0 ceramides. (7) The final step of ceramide formation involves insertion of a single double bond to dihydroceramide (DH-Cer) by the enzyme dihydroceramide desaturase 1 (DEGS1).…”