Abstract
Dietary saturated fats have often been implicated in the promotion of obesity and related disorders. It has been shown recently that saturated fats act through the transcription factor SREBP-1c (sterol regulatory element-binding protein-1c) and its requisite coactivator, peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta), to exert their pro-lipogenic effects. We show here that a diet high in the saturated fat stearate induces lipogenic genes in wild-type mice, with the induction of the Scd1 (stearoyl-CoA desaturase-1) gene preceding that of other lipogenic genes. However, in Scd1-/- mice, stearate does not induce lipogenesis, and Srebp-1c and Pgc-1beta levels are markedly reduced. Instead, genes of fatty acid oxidation such as Cpt-1 (carnitine palmitoyltransferase-1) as well as Pgc-1alpha are induced. Mitochondrial fatty acid oxidation is increased, and white adipose tissue and hepatic glycogen stores are depleted in stearate-fed Scd1-/- mice. Furthermore, AMP-activated protein kinase is also induced by stearate feeding in Scd1-/- mice. These results indicate that the desaturation of saturated fats such as stearate by SCD is an essential step mediating their induction of lipogenesis. In the absence of SCD1, stearate promotes oxidation, leading to protection from saturated fat-induced obesity. SCD1 thus serves as a molecular switch in the promotion or prevention of lipid-induced disorders brought on by consumption of excess saturated fat.
Highlights
Introductionstearoyl-CoA desaturase (SCD) is the key enzyme involved in the synthesis of monounsaturated fatty acids and catalyzes the insertion of a double bond between carbons 9 and 10 of long chain saturated fatty acids [9]
A High Triolein Diet Causes Greater Weight Gain and Adiposity than a High Tristearin Diet— saturated fats such as stearate have been implicated in the development of obesity and induction of lipogenesis [4], oleate is the preferred substrate for triglyceride synthesis, and mice unable to synthesize oleate from stearate are protected from dietinduced obesity [14]
The use of the Scd1Ϫ/Ϫ mouse model circumvents this pathway to examine the molecular effects of saturated fats
Summary
SCD is the key enzyme involved in the synthesis of monounsaturated fatty acids and catalyzes the insertion of a double bond between carbons 9 and 10 of long chain saturated fatty acids [9] This enzyme displays specificity for palmitoyl- and stearoyl-CoA as substrates, converting them to palmitoleoyl- and oleoyl-CoA, respectively. Scd1Ϫ/Ϫ mice are lean and protected from diet-induced obesity and insulin resistance (7, 14 –18) They accumulate very little hepatic and whole body lipids compared with wild-type (WT) animals. Given the fact that oleate, the product of SCD, is a preferred substrate for complex lipid synthesis, we hypothesized that intracellular oleate generated by SCD1 is directly involved in the development of obesity and in the induction of lipogenesis previously attributed to saturated fat. In the Scd1Ϫ/Ϫ, mouse which is unable to carry out this desaturation process, dietary stearate does not promote lipogenesis or weight gain but instead promotes oxidation, leaving the animal protected from saturated fat-induced obesity
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