Abstract
Metabolic dysfunction is intertwined with the pathophysiology of both diabetes and cardiovascular disease. Recently, one particular lipid class has been shown to influence the development and sustainment of these diseases: ceramides. As a subtype of sphingolipids, these species are particularly central to many sphingolipid pathways. Increased levels of ceramides are known to correlate with impaired cardiovascular and metabolic health. Furthermore, the interaction between ceramides and adipokines, most notably adiponectin and leptin, appears to play a role in the pathophysiology of these conditions. Adiponectin appears to counteract the detrimental effects of elevated ceramides, largely through activation of the ceramidase activity of its receptors. Elevated ceramides appear to worsen leptin resistance, which is an important phenomenon in the pathophysiology of obesity and metabolic syndrome.
Highlights
Sphingolipids are by far the most structurally diverse class of lipid molecules
We found that increased fibroblast growth factor 21 (FGF21), in mice and cell culture, lowered circulating ceramides, and that mice lacking FGF21 have impaired adiponectin production and increased circulating ceramides
Myriocin treatment had no effect on SOCS3 expression in leptin-deficient ob/ob mice, but it decreased SOCS3 expression in diet-induced obesity (DIO) mice. These results indicate that lowering ceramide levels increases leptin sensitivity and that this increased sensitivity cannot occur in the absence of leptin signaling
Summary
Ceramides constitute a simple subtype of sphingolipids composed of a variable-length fatty acid and an amino group (a sphingoid base, usually sphingosine). When adiponectin was overexpressed in adipocytes of DIO mice, the animals remained insulin sensitive with low plasma ceramide levels, despite their increased adiposity. Adiponectin receptors lower a larger variety of ceramide species, including deoxyceramides, which are possibly more cytotoxic because of the limited pathways for metabolizing these alanine (rather than serine) derived sphingolipids, than does AC [137] Leptin is another major adipokine that plays a prominent role in feeding and adipose homeostasis, as well as in reproduction, maintenance of bone mass, immunity, etc. One study showed that administration of myriocin, an inhibitor of de novo ceramide synthesis, to obese mice (both DIO and ob/ob) led to reduced levels of leptin expression in epididymal fat. It is unclear whether ER stress is the true mediator of ceramides’ effect on leptin sensitivity
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