Diabetes and Obesity Drug Discovery & Therapy (Track)




Targeting de novo ceramide biosynthesis ameliorates multiple features of the metabolic syndrome in diet induced obesity

Fahumiya Samad
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA

Abstract:

Although obesity is associated with multiple features of the metabolic syndrome (insulin resistance, leptin resistance, hepatic steatosis, chronic inflammation etc), the molecular changes that promote these conditions are not completely understood. The adipose tissue has become a central focus in the pathogenesis of obesityassociated metabolic and cardiovascular complications. In both mice and humans, obesity is characterized by a state of chronic inflammation initiating primarily in the adipose tissue, which produces a number of proinflammatory cytokines, chemokines, hormones, coagulation and fibrinolytic proteins etc (collectively termed “adipokines”), that affect multiple cellular processes including energy homeostasis, insulin sensitivity and cardiovascular risk. Thus, identification of crucial pathways that link adipose inflammation and the metabolic syndrome may prove useful to develop therapeutic strategies that reduce the complications associated with weight gain in humans. Ceramide is the central molecule in sphingolipid metabolism and the common precursor in the generation of complex sphingolipids. We show that in high fat diet (HFD) induced obese mice, ceramide levels were significantly increased in adipose tissues and plasma via induction of enzymes that synthesize ceramide (serine palmitoyl transferase: SPT; acid or neutral sphingomyelinase: ASMase, NSMase). We next tested the hypothesis that elevated ceramide may provide a mechanistic link between the intake of excess nutrients, inflammation and the metabolic syndrome. Chronic treatment for 8 weeks of HFD-induced obese mice with myriocin, an inhibitor of de novo ceramide synthesis, decreased circulating ceramides. Decreased ceramide was associated with reduced weight, enhanced metabolism and energy expenditure, decreased hepatic steatosis and improved glucose hemostasis via enhancement of insulin signaling in the liver and muscle. Inhibition of de novo ceramide biosynthesis decreased adipose expression of the insulin resistance mediator, suppressor of cytokine signaling-3 (SOCS-3) and induced adipose uncoupling protein 3 (UCP-3), a key regulator of mitochondrial energy expenditure and metabolism. Moreover, ceramide directly induced SOCS-3 and inhibited UCP-3 mRNA in cultured adipocytes suggesting a direct role for ceramide in regulation of metabolism and energy expenditure. Inhibition of de novo ceramide synthesis had no effect on adipose tumor necrosis factor-α (TNF-α) expression, but dramatically reduced adipose expression of the cardiovascular risk factor, plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattactant protein 1 (MCP-1). This study highlights mechanisms for ceramide downstream of TNF-α and upstream of targets of leptin and insulin resistance (SOCS-3), energy uncoupling (UCP-3) and inflammatory cardiovascular risk genes (PAI-1, MCP-1) and defines a novel role for ceramide in whole body energy expenditure and the metabolic syndrome. Furthermore, these studies not only contribute to our empirical understanding of the biochemical events underlying obesity-associated pathologies, but have also uncovered novel targets for development of therapeutic interventions designed to treat or reverse the major health-related complications of obesity.