De novo lipogenesis (DNL) is a complex yet highly regulated metabolic pathway, and transcription factors such as liver X receptor (LXR), sterol regulatory element-binding protein-1c (SREBP-1c), and carbohydrate response element binding protein (ChREBP) exert significant control over the de novo synthesis of fatty acids.

Stearoyl CoA desaturase 1 (SCD1) catalyzes the rate-limiting step in the production of MUFA that are major components of tissue lipids. Alteration in SCD1 expression changes the fatty acid profile of these lipids and produces diverse effects on cellular function. High SCD1 expression is correlated with metabolic diseases such as obesity and insulin resistance, whereas low levels are protective against these metabolic disturbances. However, SCD1 is also involved in the regulation of inflammation and stress in distinct cell types, including β-cells, adipocytes, macrophages, endothelial cells, and myocytes. Furthermore, complete loss of SCD1 expression has been implicated in liver dysfunction and several inflammatory diseases such as dermatitis, atherosclerosis, and intestinal colitis. Thus, normal cellular function requires the expression of SCD1 to be tightly controlled. This review summarizes the current understanding of the role of SCD1 in modulating inflammation and stress.

Stearoyl-CoA desaturase 1 (SCD1) deficiency protects mice from diet-induced obesity and insulin resistance. To understand the tissue-specific role of SCD1 in energy homeostasis, we have generated mice with an adipose-specific knockout of Scd1 (AKO), and report here that SCD1 deficiency increases GLUT1 expression in adipose tissue of AKO mice, but not global SCD1 knockout (GKO) mice. In 3T3-L1 adipocytes treated with a SCD inhibitor, basal glucose uptake and the cellular expression of GLUT1 were significantly increased while GLUT4 expression remained unchanged. Consistently, adipose-specific SCD1 knockout (AKO) mice had significantly elevated GLUT1 expression, but not GLUT4, in white adipose tissue compared to Lox counterparts. Concurrently, adiponectin expression was significantly diminished, whereas TNF-α expression was elevated. In contrast, in adipose tissue of GKO mice, GLUT4 and adiponectin expression were significantly elevated with lowered TNF-α expression and little change in GLUT1 expression, suggesting a differential responsiveness of adipose tissue to globalor adipose-specific SCD1 deletion. Taken together, these results indicate that adipose-specific deletion of SCD1 induces GLUT1 up-regulation in adipose tissue, associated with decreased adiponectin and increased TNF-α production, and suggest that GLUT1 may play a critical role in controlling glucose homeostasis of adipose tissue in adipose-specific SCD1-deficient conditions.

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.

We report the first high precision characterization of molecular and intramolecular δ15N of nucleosides derived from mammalian DNA. The influence of dietary protein level on brain amino acids and deoxyribonucleosides was determined to investigate whether high protein turnover would alter amino acid 15N or 13C. Pregnant guinea pig dams were fed control diets, or high or low levels of dietary protein throughout gestation, and all pups were fed control diets. Cerebellar DNA of offspring was extracted at 2 and 120 days of life, nucleosides isolated and δ15N and δ13C characterized. Mean diet δ15N = 0.45±0.33‰, compared to cerebellar whole tissue and DNA δ15N = +4.1±0.7‰ and −4.5±0.4‰, respectively. Cerebellar deoxythymidine (dT), deoxycytidine (dC), deoxyadenosine (dA), and deoxyguanosine (dG) δ15N were +1.4±0.4, −2.1±0.9, −7.2±0.3, and −10.4±0.5‰, respectively. There were no changes in amino acid or deoxyribonucleoside δ15N due to dietary protein level. Using known metabolic relationships, we developed equations to calculate the intramolecular δ15N originating from aspartate (asp) in purines (pur) or pyrimidines (pyr), glutamine (glu), and glycine (gly) to be δ15NASP-PUR, δ15NASP-PYR, δ15NGLN, and δ15NGLY +11.9±2.3‰, +7.0±2.0‰, −9.1±2.4‰, and −31.8±8.9‰, respectively. A subset of twelve amino acids from food and brain had mean δ15N of 4.3±3.2‰ and 13.8±3.1‰, respectively, and δ15N for gly and asp were 12.6±2.2‰ and 15.2±0.8‰, respectively. A separate isotope tracer study detected no significant turnover of cerebellar DNA in the first six months of life. The large negative δ15N difference between gly and cerebellar purine N at the gly (7) position implies either that there is a major isotope effect during DNA synthesis, or that in utero gly has a different isotope ratio during rapid growth and metabolism than in adult life. Our data show that cerebellar nucleoside intramolecular δ15N vary over more than 40‰ and are not influenced by dietary protein level or age.