Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance.
Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.
Holland
William L
WL
Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA.
Brozinick
Joseph T
JT
Wang
Li-Ping
LP
Hawkins
Eric D
ED
Sargent
Katherine M
KM
Liu
Yanqi
Y
Narra
Krishna
K
Hoehn
Kyle L
KL
Knotts
Trina A
TA
Siesky
Angela
A
Nelson
Don H
DH
Karathanasis
Sotirios K
SK
Fontenot
Greg K
GK
Birnbaum
Morris J
MJ
Summers
Scott A
SA
D000818:Animals; D002518:Ceramides / Q000096:biosynthesis / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005224:Fats, Unsaturated / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D010088:Oxidoreductases / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013107:Sphingolipids / Q000378:metabolism
D002518:Ceramides; D005224:Fats, Unsaturated; D005227:Fatty Acids; D005938:Glucocorticoids; D013107:Sphingolipids; D010088:Oxidoreductases; C108138:dihydroceramide desaturase