Combined deletion of SCD1 from adipose tissue and liver does not protect mice from obesity.
ABSTRACT: Stearoyl-CoA desaturase 1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated FA. Mice with whole-body or skin-specific deletion of SCD1 are resistant to obesity. Here, we show that mice lacking SCD1 in adipose and/or liver are not protected from either genetic- (agouti; A(y)/a) or diet-induced obesity (DIO) despite a robust reduction in SCD1 MUFA products in both subcutaneous and epididymal white adipose tissue. Adipose SCD1 deletion had no effect on glucose or insulin tolerance or on hepatic triglyceride (TG) accumulation. Interestingly, lack of SCD1 from liver lowered the MUFA levels of adipose tissue and vice versa, as reflected by the changes in FA composition. Simultaneous deletion of SCD1 from liver and adipose resulted in a synergistic lowering of tissue MUFA levels, especially in the A(y)/a model in which glucose tolerance was also improved. Lastly, we found that liver and plasma TG show nearly identical genotype-dependent differences in FA composition, indicating that FA composition of plasma TG is predictive for hepatic SCD1 activity and TG FA composition. The current study suggests that SCD1 deletion from adipose and/or liver is insufficient to elicit protection from obesity, but it supports the existence of extensive lipid cross-talk between liver and adipose tissue.
Project description:BACKGROUND:The fatty acid (FA) composition of adipose tissue influences the nutritional quality of meat products. The unsaturation level of FAs is determined by fatty acid desaturases such as stearoyl-CoA desaturases (SCDs), which are under control of the transcription factor sterol regulatory element-binding protein (SREBP). Differences in SCD genotype may thus confer variations in lipid metabolism and FA content among cattle breeds. This study investigated correlations between FA composition and lipogenic gene expression levels in the subcutaneous adipose tissue of beef cattle breeds of different gender from the Basque region of northern Spain. Pirenaica is the most important beef cattle breed in northern Spain, while Salers cattle and Holstein-Friesian cull cows are also an integral part of the regional beef supply. RESULTS:Pirenaica heifers showed higher monounsaturated FA (MUFA) and conjugated linoleic acid (CLA) contents in subcutaneous adipose tissue than other breeds (P?<?0.001). Alternatively, Salers bulls produced the highest oleic acid content, followed by Pirenaica heifers (P?<?0.001). There was substantial variability in SCD gene expression among breeds, consistent with these differences in MUFA and CLA content. Correlations between SCD1 expression and most FA desaturation indexes (DIs) were positive in Salers (P?<?0.05) and Pirenaica bulls, while, in general, SCD5 expression showed few significant correlations with DIs. There was a significant linear correlation between SCD1 and SRBEP1 in all breeds, suggesting strong regulation of SCD1 expression by SRBEP1. Pirenaica heifers showed a stronger correlation between SCD1 and SREBP1 than Pirenaica bulls. We also observed a opposite relationship between SCD1 and SCD5 expression levels and opposite associations of isoform expression levels with the ?9 desaturation indexes. CONCLUSIONS:These results suggest that the relationships between FA composition and lipogenic gene expression are influenced by breed and sex. The opposite relationship between SCD isoforms suggests a compensatory regulation of total SCD activity, while opposite relationships between SCD isoforms and desaturation indexes, specially 9c-14:1 DI, previously reported as an indicator of SCD activity, may reflect distinct activities of SCD1 and SCD5 in regulation of FA content. These findings may be useful for beef/dairy breeding and feeding programs to supply nutritionally favorable products.
Project description:Growth hormone (GH) transgenic Amago (Oncorhynchus masou ishikawae), containing the sockeye GH1 gene fused with metallothionein-B promoter from the same species, were generated and the physiological condition through lipid metabolism compared among homozygous (Tg/Tg) and heterozygous GH transgenic (Tg/+) Amago and the wild type control (+/+). Previously, we have reported that the adipose tissue was generally smaller in GH transgenic fish compared to the control, and that the ?-6 fatty acyl desaturase gene was down-regulated in the Tg/+ fish. However, fatty acid (FA) compositions have not been measured previously in these fish. In this study we compared the FAs composition and content in the liver using gas chromatography. Eleven kinds of FA were detected. The composition of saturated and monounsaturated fatty acids (SFA and MUFA) such as myristic acid (14:0), palmitoleic acid (16:1n-7), and cis-vaccenic acid (cis-18:1n-7) was significantly (P<0.05) decreased in GH transgenic Amago. On the other hand, the composition of polyunsaturated fatty acids (PUFAs) such as linoleic acid (18:2n-6), arachidonic acid (20:4n-6), and docosapentaenoic acid (22:5n-3) was significantly (P<0.05) increased. Levels of serum glucose and triacylglycerol were significantly (P<0.05) decreased in the GH transgenics compared with +/+ fish. Furthermore, 3'-tag digital gene expression profiling was performed using liver tissues from Tg/Tg and +/+ fish, and showed that Mid1 interacting protein 1 (Mid1ip1), which is an important factor to activate Acetyl-CoA carboxylase (ACC), was down-regulated in Tg/Tg fish, while genes involved in FA catabolism were up-regulated, including long-chain-fatty-acid-CoA ligase 1 (ACSL1) and acyl-coenzyme A oxidase 3 (ACOX3). These data suggest that liver tissue from GH transgenic Amago showed starvation by alteration in glucose and lipid metabolism due to GH overexpression. The decrease of serum glucose suppressed Mid1ip1, and caused a decrease of de novo FA synthesis, resulting in a decrease of SFA and MUFA. This induced expression of ACSL1 and ACOX3 to produce energy through ?-oxidation in the GH transgenic Amago.
Project description:The non-essential fatty acids, C18:1n9, C16:0, C16:1n7, C18:0 and C18:1n7 account for over 75% of fatty acids in white adipose (WAT) triacylglycerol (TAG). The relative composition of these fatty acids (FA) is influenced by the desaturases, SCD1-4 and the elongase, ELOVL6. In knock-out models, loss of SCD1 or ELOVL6 results in reduced ?9 desaturated and reduced 18-carbon non-essential FA respectively. Both Elovl6 KO and SCD1 KO mice exhibit improved insulin sensitivity. Here we describe the relationship between WAT TAG composition in obese mouse models and obese humans stratified for insulin resistance. In mouse models with increasing obesity and insulin resistance, there was an increase in scWAT ?9 desaturated FAs (SCD ratio) and FAs with 18-carbons (Elovl6 ratio) in mice. Data from mouse models discordant for obesity and insulin resistance (AKT2 KO, Adiponectin aP2-transgenic), suggested that scWAT TAG Elovl6 ratio was associated with insulin sensitivity, whereas SCD1 ratio was associated with fat mass. In humans, a greater SCD1 and Elovl6 ratio was found in metabolically more harmful visceral adipose tissue when compared to subcutaneous adipose tissue.
Project description:The response to overfeeding is sex dependent, and metabolic syndrome is more likely associated to obesity in men or postmenopausal women than in young fertile women. We hypothesized that obesity-induced metabolic syndrome is sex dependent due to a sex-specific regulation of the fatty acid (FA) synthesis pathways in liver and white adipose depots. We aimed to identify distinctive molecular signatures between sexes using a lipidomics approach to characterize lipid species in liver, perigonadal adipose tissue, and inguinal adipose tissue and correlate them to the physiopathological responses observed. Males had less total fat but lower subcutaneous on visceral fat ratio together with higher liver weight and higher liver and serum triglyceride (TG) levels. Males were insulin resistant compared to females. Fatty acid (FA) and TG profiles differed between sexes in both fat pads, with longer chain FAs and TGs in males compared to that in females. Remarkably, hepatic phospholipid composition was sex dependent with more abundant lipotoxic FAs in males than in females. This may contribute to the sexual dimorphism in response to obesity towards more metaflammation in males. Our work presents an exhaustive novel description of a sex-specific lipid signature in the pathophysiology of metabolic disorders associated with obesity in ob/ob mice. These data could settle the basis for future pharmacological treatment in obesity.
Project description:2,3,7,8-tetrachlorodibenzo-?-dioxin (TCDD) induces hepatic dyslipidemia mediated by the aryl hydrocarbon receptor (AhR). Stearoyl-CoA desaturase 1 (Scd1) performs the rate-limiting step in monounsaturated fatty acid (MUFA) synthesis, desaturating 16:0 and 18:0 into 16:1n7 and 18:1n9, respectively. To further examine the role of Scd1 in TCDD-induced hepatotoxicity, comparative studies were performed in Scd1(+/+) and Scd1(-/-) mice treated with 30 ?g/kg TCDD. TCDD induced Scd1 activity, protein, and messenger RNA (mRNA) levels approximately twofold. In Scd1(+/+) mice, hepatic effects were marked by increased vacuolization and inflammation and a 3.5-fold increase in serum alanine aminotransferase (ALT) levels. Hepatic triglycerides (TRGs) were induced 3.9-fold and lipid profiling by gas chromatography-mass spectroscopy measured a 1.9-fold increase in fatty acid (FA) levels, consistent with the induction of lipid transport genes. Induction of Scd1 altered FA composition by decreasing saturated fatty acid (SFA) molar ratios 8% and increasing MUFA molar ratios 9%. Furthermore, ChIP-chip analysis revealed AhR enrichment (up to 5.7-fold), and computational analysis identified 16 putative functional dioxin response elements (DREs) within Scd1 genomic loci. Band shift assays confirmed AhR binding with select DREs. In Scd1(-/-) mice, TCDD induced minimal hepatic vacuolization and inflammation, while serum ALT levels remained unchanged. Although Scd1 deficiency attenuated TCDD-induced TRG accumulation, overall FA levels remained unchanged compared with Scd1(+/+) mice. In Scd1(-/-) mice, TCDD induced SFA ratios 8%, reduced MUFA ratios 13%, and induced polyunsaturated fatty acid ratios 5% relative to treated Scd1(+/+) mice. Collectively, these results suggest that AhR regulation of Scd1 not only alters lipid composition but also contributes to the hepatotoxicity of TCDD.
Project description:Hepatic steatosis is associated with detrimental metabolic phenotypes including enhanced risk for diabetes. Stearoyl-CoA desaturases (SCDs) catalyze the synthesis of MUFAs. In mice, genetic ablation of SCDs reduces hepatic de novo lipogenesis (DNL) and protects against diet-induced hepatic steatosis and adiposity. To understand the mechanism by which hepatic MUFA production influences adipose tissue stores, we created two liver-specific transgenic mouse models in the SCD1 knockout that express either human SCD5 or mouse SCD3, that synthesize oleate and palmitoleate, respectively. We demonstrate that hepatic de novo synthesized oleate, but not palmitoleate, stimulate hepatic lipid accumulation and adiposity, reversing the protective effect of the global SCD1 knockout under lipogenic conditions. Unexpectedly, the accumulation of hepatic lipid occurred without induction of the hepatic DNL program. Changes in hepatic lipid composition were reflected in plasma and in adipose tissue. Importantly, endogenously synthesized hepatic oleate was associated with suppressed DNL and fatty acid oxidation in white adipose tissue. Regression analysis revealed a strong correlation between adipose tissue lipid fuel utilization and hepatic and adipose tissue lipid storage. These data suggest an extrahepatic mechanism where endogenous hepatic oleate regulates lipid homeostasis in adipose tissues.
Project description:This study compared the long-term effects of EY consumption under two diet conditions: normal (ND?+?EY) and high fat diet (HFD?+?EY), on lipid metabolism in mice. ND?+?EY did not increase serum triglycerides, total cholesterol hepatic triglyceride concentrations, adipose tissue accumulation and glucose impairment, not leading to fatty liver. HFD?+?EY markedly decreased adipose tissue accumulation, the triglyceride and total cholesterol, and improved serum HDL-C and blood glucose impairment compared with HFD. PLS-DA analyzes showed both ND?+?EY and HFD?+?EY could decrease serum C18:1 and MUFA. HFD?+?EY could further decrease hepatic C18:2 and PUFA and increase C18:1 and MUFA excretion, which were associated with lower expression of Elovl6 and higher expression of Scd1 in liver. These results suggest that HFD?+?EY significantly improved dyslipidemia caused by HFD through modifying lipid metabolism, and ND?+?EY did not adversely affect the biomarkers associated with dyslipidemia risk, but showed less obvious regulation of lipid metabolism than HFD?+?EY.
Project description:The aim of this study was to characterize the responses of individual tissues to high-fat feeding as a function of mass, fat composition, and transcript abundance. We examined a panel of eight tissues [5 white adipose tissues (WAT), brown adipose tissue (BAT), liver, muscle] obtained from DBA/2J mice on either a standard breeding diet (SBD) or a high-fat diet (HFD). HFD led to weight gain, decreased insulin sensitivity, and tissue-specific responses, including inflammation, in these mice. The dietary fatty acids were partially metabolized and converted in both liver and fat tissues. Saturated fatty acids (SFA) were converted in the liver to monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), and oleic acid (C18:1) was the preferred MUFA for storage of excess energy in all tissues of HFD-fed mice. Transcriptional changes largely reflected the tissue-specific fat deposition. SFA were negatively correlated with genes in the collagen family and processes involving the extracellular matrix. We propose a novel role of the tryptophan hydroxylase 2 (Tph2) gene in adipose tissues of diet-induced obesity. Tissue-specific responses to HFD were identified. Liver steatosis was evident in HFD-fed mice. Gonadal, retroperitoneal and subcutaneous adipose tissue and BAT exhibited severe inflammatory and immune responses. Mesenteric adipose tissue was the most metabolically active adipose tissue. Gluteal adipose tissue had the highest mass gain but was sluggish in its metabolism. In HFD conditions, BAT functioned largely like WAT in its role as a depot for excess energy, whereas WAT played a role in thermogenesis.
Project description:Secreted frizzled-related protein (SFRP) 4 is an extracellular antagonist of Wnt signalling that regulates adipogenesis, and is highly in the visceral adipose tissue of obese individuals. However, it is still unclear how exactly SFRP4 regulates the secretion of adipokines in the adipose tissue in vivo, an event that is closely related to the pathogenesis of obesity and insulin resistance. In this study, we generated transgenic (Tg) mice overexpressing SFRP4 in the liver and investigated SFRP4 role in adipokine secretion in mice on a regular normal diet. In Tg mice, SFRP4 protein was overexpressed in the liver, as compared to wild-type littermates (non-Tg), and released into the blood. Moreover, the size of adipocytes was smaller in the visceral adipose tissue of Tg mice compared to controls. Additionally, SFRP4 overexpression affected the expression of genes related to adipocyte differentiation, causing the upregulation of adiponectin and glucose transporter 4, and the downregulation of CCAAT/enhancer-binding protein-?, in both visceral and subcutaneous adipose tissue. However, there was no difference in body weight or body composition between Tg and non-Tg mice. In summary, our data showed that SFRP4 overexpression altered adipocyte size and adipokine secretion, possibly affecting adipocyte differentiation, obesity, and glucose metabolism.
Project description:Obesity and dyslipidemia are major risk factors for the development of cardiovascular diseases (CVD). Quercetin, a natural flavonoid, lowers plasma triglycerides (TG) in human intervention studies, and its intake is associated with lower CVD risk. The aim of this study was to elucidate the mechanism by which quercetin lowers plasma TG levels in diet-induced obesity. C57Bl/6J mice received a high-fat diet (45% of calories derived from fat) with or without quercetin (0.1% <i>w</i>/<i>w</i>) for 12 weeks. Quercetin decreased plasma TG levels from nine weeks onwards (?19%, <i>p</i> < 0.05), without affecting food intake, body composition, or energy expenditure. Mechanistically, quercetin did not reduce intestinal fatty acid (FA) absorption. Rather, quercetin induced a slight reduction in liver <i>Apob</i> expression (?13%, <i>p</i> < 0.05), which suggests decreased very-low density lipoprotein-TG production. Interestingly, quercetin also markedly increased the uptake of [³H]oleate, which was derived from glycerol tri[³H]oleate-labeled lipoprotein-like particles by subcutaneous white adipose tissue (sWAT, +60%, <i>p</i> < 0.05). Furthermore, quercetin also markedly increased mRNA expression of <i>Ucp1</i> (+229%, <i>p</i> < 0.05) and <i>Elovl3</i> (+138%, <i>p</i> < 0.05), specifically in sWAT. Accordingly, only quercetin-treated animals showed uncoupling protein-1 protein-positive cells in sWAT, which is fully compatible with increased browning. Taken together, the TG-lowering effect of quercetin may, at least in part, be due to increased TG-derived FA uptake by sWAT as a consequence of browning.