A role for sphingolipids in the pathophysiology of obesity-induced inflammation

Abstract

Following the initial discovery that adipose tissue actively synthesizes and secretes cytokines, obesity-induced inflammation has been implicated in the etiology of a host of disease states related to obesity, including cardiovascular disease and type II diabetes. Interestingly, a growing body of evidence similarly implicates sphingolipids as prime instigators in these same diseases. From the recent discovery that obesity-related inflammatory pathways modulate sphingolipid metabolism comes a novel perspective—sphingolipids may act as the dominant mediators of deleterious events stemming from obesity-induced inflammation. This paradigm may identify sphingolipids as an effective target for future therapeutics aimed at ameliorating diseases associated with chronic inflammation.

Fig. 1

Adipocyte expansion, leading to obesity, is associated with reduced adiponectin levels and elevated TNFα and ceramide

Fig. 2

The TLR4-induced activation of ceramide biosynthesis represents a common pathway between lipotoxicity- and inflammation-induced insulin resistance. Saturated fatty acids (SFA); lipopolysaccharide (LPS); tumor necrosis factor (TNF) α; inhibitor of κB kinase (IKK) β; sphingomyelinase (SMAase)

Fig. 3

TNFα induces ceramide biosynthesis and accrual through multiple mechanisms, whereas adiponectin activates ceramide degradation and eventual formation of S1P. Ceramide (Cer); sphingosine 1-phosphoate (S1P)

Fig. 4

Ceramide has been shown to cause virtually all of the pathological states elicited by obesity-induced inflammation

Fig. 5

Several sphingolipids elicit metabolically deleterious results, similar to ceramide. However, only ceramide formation (red pathways) has been shown to mediate inflammation-induced disturbances. Inhibition of the indicated enzymes invites the indicated results. Serine palmitoyltransferase (SPT); dihydroceramide desaturase 1 (Des1); sphingomyelinase synthase (SMS); sphingomyelinase (SMase); glucosylceramide synthase (GCS); sphingosine kinase (SK)