Combined deletion of SCD1 from adipose tissue and liver does not protect mice from obesity

Abstract

This article is available online at http://www.jlr.org occurring Scd1 mutations and those with global deletion of Scd1 (GKO mice) ( 1-3 ). These mice display a remarkable hypermetabolic phenotype that protects them from obesity, insulin resistance, and hepatic steatosis. To determine which tissue or tissues are primarily responsible for these metabolic changes, we have employed the Crelox system to explore the tissue-specifi c contributions of SCD1.We previously found that mice with a liver-specifi c deletion of Scd1 (LKO mice) are protected from high-carbohydrate, but not high-fat, diet-induced obesity (DIO), unlike GKO mice that are resistant to both high-fat and highcarbohydrate DIO ( 4 ). This indicates that inhibition of liver SCD1 alone is insuffi cient to elicit the hypermetabolism and increased energy expenditure necessary to compensate for the increased energy intake associated with high-fat feeding. The reduced high-carbohydrate dietinduced adiposity in LKO and GKO mice was associated with a block in carbohydrate-induced increases in hepatic sterol regulatory element binding protein-1c (SREBP-1c) proteolytic processing, expression of FA synthesis genes, and hepatic triglyceride (TG) accumulation. We recently reported that mice with a skin-specifi c deletion of Scd1 (SKO mice) recapitulated the hypermetabolic phenotype observed in GKO mice, indicating that the skin is a major contributor to the altered energy metabolism observed in GKO mice ( 5 ). In contrast, SKO mice had normal carbohydrate-induced increase in SREBP-1c maturation and FA synthesis genes. These hepatic observations highlight that not all of the phenotypes of the SCD1 GKO mice can be attributed to SCD1 deletion in the skin.Interestingly, mice intraperitoneally injected with Scd1 -targeted antisense oligonucleotides (ASO) are also protected from the development of high-fat DIO and insulin -DK-062388 (to J.M.N.), ; and by an American Heart Association postdoctoral fellowship (to M.T.F.) Abbreviations: a/a, non-agouti; A y /a, agouti; AKO, adipose SCD1 knockout; ASO, antisense oligonucleotide; DIO, diet-induced obesity; GKO, global SCD1 knockout; LAKO, liver/adipose SCD1 knockout; LKO, liver SCD1 knockout; Lox, Scd1 fl ox/fl ox ; SCD1, stearoyl-CoA desaturase-1; SKO, skin SCD1 knockout; SREBP1c, sterol regulatory element binding protein-1c; TG, triglyceride.

SCD1 activity in muscle increases triglyceride PUFA content, exercise capacity, and PPARΔ expression in mice

“…However, we have recently shown that the antiobesity phenotype in SCD1-null animals is due to loss of SCD1 in the skin ( 18 ), which may be preventing the accumulation of SFA due to increased energy expenditure. In fact, recent studies examining the effect of tissuespecifi c deletion of SCD1 in liver and adipose have shown no protection from obesity and may even increase infl ammation when skin expression is normal ( 13,21,22 ).…”

Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation

“…Hepatic microsomes were prepared by sequential centrifugation as previously described ( 21 ). SCD activity assays were performed using 100 g liver microsomal protein.…”

“…Liver, adipose tissue, and plasma fatty acid analyses were carried out as previously described ( 21 ). Lipids were extracted following a modifi ed Folch method ( 22 ).…”

Elucidating the roles of stearoyl-CoA desaturase 1 in adipocyte fatty acid metabolism and cellular function

“…Discrepancies between AKO and Scd1-/-mice have therefore created some uncertainty regarding the influence of SCD1 activity in AT. Adding further to this ambiguity, mice with a combined knockout of Scd1 in the liver and AT (i.e., LAKO mice) were not protected from diet-induced adiposity, unlike Scd1-/-and LKO mice, but similar to AKO mice [160]. The high expression of Scd1 in AT and the significant changes in AT metabolism that occur in models of Scd1 deficiency (e.g., Scd1-/-, LKO, AKO, LAKO, and mice treated with antisense oligonucleotides), emphasize the importance of understanding exactly how Scd1 evokes changes in AT metabolism.…”

“…However, models entailing whole-body SCD1 deficiency (i.e., Scd1-/-mice or antisense oligonucleotide injections) are limited in their ability to deduce if the observed metabolic changes are AT-specific, or due to other underlying mechanisms in another tissue. For instance, when whole-body Scd1 is reduced, any changes occurring in the liver and skeletal muscle could influence adipocyte metabolism 32 through the secretion of signalling molecules (e.g., cytokines or lipids) [160] which in turn could confound conclusions made about AT.…”