Targeting ceramide metabolism in obesity

Abstract

Obesity is a major health concern that increases the risk for insulin resistance, type 2 diabetes (T2D), and cardiovascular disease. Thus, an enormous research effort has been invested into understanding how obesity-associated dyslipidemia and obesity-induced alterations in lipid metabolism increase the risk for these diseases. Accordingly, it has been proposed that the accumulation of lipid metabolites in organs such as the liver, skeletal muscle, and heart is critical to these obesity-induced pathologies. Ceramide is one such lipid metabolite that accumulates in tissues in response to obesity, and both pharmacological and genetic strategies that reduce tissue ceramide levels yield salutary actions on overall metabolic health. We will review herein why ceramide accumulates in tissues during obesity and how an increase in intracellular ceramide impacts cellular signaling and function as well as potential mechanisms by which reducing intracellular ceramide levels improves insulin resistance, T2D, atherosclerosis, and heart failure. Because a reduction in skeletal muscle ceramide levels is frequently associated with improvements in insulin sensitivity in humans, the beneficial findings reported for reducing ceramides in preclinical studies may have clinical application in humans. Therefore, modulating ceramide metabolism may be a novel, exciting target for preventing and/or treating obesity-related diseases.

Mechanistic interplay between ceramide and insulin resistance

“…In agreement with Prieur et al 10,. this can be the cause of the obesity-induced insulin resistance1112, which is stronger at 16 weeks than at 5 weeks, leading to severe insulin resistance and glucose intolerance.…”

Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance

“…The mechanistic picture for ceramides is somewhat more blurred. An AKT-centric mechanism has long been favored; newer mechanisms involving hepatocellular lipid oxidation, VLDL export, CD36 activation, and mitochondrial dysfunction are intriguing but are indirect [61,68,69,100]. One commonality of these latter mechanisms is the conclusion that ceramides drive hepatosteatosis.…”

Fenretinide treatment accelerates atherosclerosis development in apoE‐deficient mice in spite of beneficial metabolic effects

“…Additionally, fenretinide prevents ceramide accumulation by inhibiting dihydroceramide desaturase, which catalyses the final step of de novo ceramide synthesis (Bikman et al, 2012). Given the emerging role of ceramides in promoting insulin resistance and other obesity-induced metabolic alterations (Aburasayn, Al Batran, & Ussher, 2016;Petersen & Shulman, 2018), this mechanism may account for the favourable metabolic effects of fenretinide treatment (Bikman et al, 2012;Mody & Mcilroy, 2014). Further, fenretinide administration to high-fat fed mice has been shown to significantly reduce hepatic steatosis (Koh et al, 2012;Preitner, Mody, Graham, Peroni, & Kahn, 2009) and to moderately lower plasma lipids, possibly by increasing liver fatty acid oxidation (Koh et al, 2012).…”