Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome.
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. Here, we tested the hypothesis that elevated ceramide biosynthesis contributes to the pathogenesis of obesity and the metabolic syndrome. Chronic treatment for 8 wk of genetically obese (ob/ob), and, high-fat diet-induced obese (DIO) 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 suppressor of cytokine signaling-3 (SOCS-3) and induced adipose uncoupling protein-3 (UCP3). Moreover, ceramide directly induced SOCS-3 and inhibited UCP3 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-alpha (TNF-alpha) expression but dramatically reduced adipose plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattactant protein-1 (MCP-1). This study highlights a novel role for ceramide biosynthesis in body weight regulation, energy expenditure, and the metabolic syndrome.
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA.
Guang
G
Yang
Leylla
L
Badeanlou
Jacek
J
Bielawski
Amanda J
AJ
Roberts
Yusuf A
YA
Hannun
Fahumiya
F
Samad
D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000502:physiology*; D002518:Ceramides / Q000096:biosynthesis* / Q000097:blood / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism; D008246:Lysophospholipids / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D000071247:Uncoupling Protein 3
D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D007473:Ion Channels; D008246:Lysophospholipids; D024101:Mitochondrial Proteins; C491411:Socs3 protein, mouse; D013107:Sphingolipids; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; C060506:sphingosine 1-phosphate; D013110:Sphingosine; C001996:thermozymocidin