Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase–1

Jiang, Guoqiang; Li, Zhihua; Liu, Franklin; Ellsworth, Kenneth; Dallas-Yang, Qing; Wu, Margaret; Ronan, John; Esau, Christine; Murphy, Cain; Szalkowski, Deborah; Bergeron, Raynald; Doebber, Thomas W.; Zhang, Bei B.

doi:10.1172/jci23962

Cited by 137 publications

(130 citation statements)

References 37 publications

(41 reference statements)

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“…Whereas short-term treatment with an antisense inhibitor of Scd1 is sufficient to improve hepatic insulin sensitivity (46), longer treatment additionally prevents diet-induced obesity and is associated with lowered plasma glucose and insulin (47). For the first time, using the hyperinsulinemic-euglycemic clamp technique, we show that insulin-stimulated whole-body, heart, and soleus muscle glucose uptake are increased in Scd1 Ϫ/Ϫ mice.…”

Section: Scd1 Deficiency In Obese Micementioning

confidence: 80%

Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Flowers

Rabaglia²,

Schueler³

et al. 2007

Diabetes

134

122

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The lipogenic gene stearoyl-CoA desaturase (SCD)1 appears to be a promising new target for obesity-related diabetes, as mice deficient in this enzyme are resistant to diet-and leptin deficiency-induced obesity. The BTBR mouse strain replicates many features of insulin resistance found in humans with excess visceral adiposity. Using the hyperinsulinemic-euglycemic clamp technique, we determined that insulin sensitivity was improved in heart, soleus muscle, adipose tissue, and liver of BTBR SCD1-deficient mice. We next determined whether SCD1 deficiency could prevent diabetes in leptin-deficient BTBR mice. Loss of SCD1 in leptin ob/ob mice unexpectedly accelerated the progression to severe diabetes; 6-week fasting glucose increased ϳ70%. In response to a glucose challenge, Scd1 Ϫ/Ϫ leptin ob/ob mice had insufficient insulin secretion, resulting in glucose intolerance. A morphologically distinct class of islets isolated from the Scd1 Ϫ/Ϫ leptin ob/ob mice had reduced insulin content and increased triglycerides, free fatty acids, esterified cholesterol, and free cholesterol and also a much higher content of saturated fatty acids. We believe the accumulation of lipid is due to an upregulation of lipoprotein lipase (20-fold) and Cd36 (167-fold) and downregulation of lipid oxidation genes in this class of islets. Therefore, although loss of Scd1 has beneficial effects on adiposity, this benefit may come at the expense of ␤-cells, resulting in an increased risk of diabetes. Diabetes 56:1228-1239, 2007 S tearoyl-CoA desaturase (SCD) catalyzes the synthesis of monounsaturated fatty acids by introducing a cis double bond in the ⌬9 position of saturated 16-and 18-carbon fatty acyl-CoA substrates. The products of SCD, palmitoleoyl-CoA and oleoylCoA, are the most abundant monounsaturated fatty acids of phospholipids, triglycerides, cholesterol esters, and wax esters (1). Various diseases, including cancer, obesity, diabetes, and atherosclerosis, are associated with an imbalance in the ratio of saturated to monounsaturated fatty acids (2). Two human and four mouse isoforms of SCD have been characterized. SCD1 is the primary isoform found in lipogenic tissues.Loss of Scd1 is protective against obesity (3-5). The decreased adiposity in the Scd1 Ϫ/Ϫ mice is due to reduced lipid synthesis and increased energy expenditure through enhanced fatty acid oxidation (3). Scd1 Ϫ/Ϫ mice have an increase in insulin signaling and glucose uptake in muscle and brown adipose tissue (6,7).Leptin-deficient BTBR leptin ob/ob mice are a particularly useful animal model for studying obesity-related diabetes. Unlike the B6 leptin ob/ob mice, which develop only moderate hyperglycemia, BTBR leptin ob/ob mice become severely diabetic (8 -10). The diabetic BTBR leptin ob/ob mice have increased Scd1 expression in muscle and decreased expression in adipose tissue and liver, compared with nondiabetic B6 leptin ob/ob mice (10). Insulin resistance is often correlated with abdominal obesity. The BTBR mouse strain has excess abdominal obesity associated with ins...

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Section: Scd1 Deficiency In Obese Micementioning

confidence: 80%

Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Flowers

Rabaglia²,

Schueler³

et al. 2007

Diabetes

134

122

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“…There is strong evidence that downregulation of SCD1 prevents or reduces the development of NAFLD, obesity and insulin resistance [29][30][31][32]. Elevated hepatic transcription of Scd1 has been reported in fat-fed mice of the 129S6 [13] and C57BL/6J [13,23] strains.…”

Section: Discussionmentioning

confidence: 99%

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

et al. 2007

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Aims/hypothesis Complex changes in gene expression are associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD) promoted by feeding a high-fat diet (HFD). We used functional genomic technologies to document molecular mechanisms associated with dietinduced NAFLD. Materials and Methods Male 129S6 mice were fed a diet containing 40% fat (high-fat diet, HFD) for 15 weeks. Glucose tolerance, in vivo insulin secretion, plasma lipid profile and adiposity were determined. Plasma metabonomics and liver transcriptomics were used to identify changes in gene expression associated with HFD-induced NAFLD.Results In HFD-fed mice, NAFLD and impaired glucose and lipid homeostasis were associated with increased hepatic transcription of genes involved in fatty acid uptake, intracellular transport, modification and elongation, whilst genes involved in beta-oxidation and lipoprotein secretion were, paradoxically, also upregulated. NAFLD developed despite strong and sustained downregulation of transcription of the gene encoding stearoyl-coenzyme A desaturase 1 (Scd1) and uncoordinated regulation of transcription of Scd1 and the gene encoding sterol regulatory element binding factor 1c (Srebf1c) transcription. Inflammatory mechanisms appeared to be stimulated by HFD. Conclusions/interpretation Our results provide an accurate representation of subtle changes in metabolic and gene expression regulation underlying disease-promoting and compensatory mechanisms, collectively contributing to dietinduced insulin resistance and NAFLD. They suggest that proposed models of NAFLD pathogenesis can be enriched with novel diet-reactive genes and disease mechanisms.

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“…Therefore, although thiazolidinediones enhanced adipocyte conversion, they concomitantly caused a dramatic decrease in cell size and lipid droplet compared with the control 3T3-L1 cells. SCD1 inhibition has been suggested as a new target for the treatment of obesity and related metabolic disorders (32)(33)(34). SCD1 is a key rate-limiting enzyme in the synthesis of unsaturated fatty acids, major components of triacylglycerols, from long-chain saturated fatty acids.…”

Section: Discussionmentioning

confidence: 99%

Identification of Mouse Prp19p as a Lipid Droplet-associated Protein and Its Possible Involvement in the Biogenesis of Lipid Droplets

Cho

Shin

Park

et al. 2007

Journal of Biological Chemistry

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Prp19p is an integral component of the heteromeric protein complex (the NineTeen complex) in the nucleus, and it is essential for the structural integrity of NineTeen complex and its subsequent activation of the spliceosome. We identified Prp19p, which has never been reported in relation to any function outside of the nucleus, as a member of proteins associated with lipid droplets. Down-regulation of Prp19p expression with RNA interference in 3T3-L1 cells repressed lipid droplet formation with the reduction in the level of expression of perilipin and S3-12. The levels of expression of SCD1 (stearoyl-CoA desaturase-1), DGAT-1 (acyl-CoA diacylglycerol acyltransferase-1), and glycerol-3-phosphate acyltransferase were also reduced in Prp19p down-regulated cells, and a significant decrease in triglycerides was observed. Unlike perilipin, which is one of the most extensively studied lipid droplet-associated proteins, Prp19p is not essential for cAMP-and hormone-sensitive lipasedependent lipolysis pathways, even though Prp19p is a component of the lipid droplet phospholipid monolayer, and downregulation of Prp19p represses fat accretion significantly. These results suggest that Prp19p or Prp19-interacting proteins during lipid droplet biogenesis in adipocytes may be considered as another class of potential targets for attacking obesity and obesity-related problems.Lipid droplets are subcellular organelles that function as major energy depots by storing neutral lipids, mainly triacylglycerols (1, 2). Therefore, the biogenesis of a lipid droplet is central to whole body energy homeostasis. In addition to their function as energy depots, lipid droplets appear to have important roles in lipid trafficking in adipocytes, cell signaling, and several important human diseases (3-7). It is thus important to understand the mechanism of deposition and mobilization of cellular neutral lipids. Although the mechanisms of lipid droplet biogenesis are still not entirely clear, it is expected that a set of proteins involved in lipid droplet biogenesis could comprise effective targets for the regulation of the whole body energy homeostasis. Lipid droplets are surrounded by a phospholipid monolayer into which many proteins are embedded (8). These surface proteins on adipocyte lipid droplets include structural proteins, such as PAT (perilripin/ADRP/TIP47) family proteins, S3-12, vimentin, and caveolin-1, and enzymes involved in many aspects of lipid metabolism, such as hormone-sensitive lipase (HSL)-, acyl-CoA synthetase-, lanosterol synthase-, CGI-58-, and NAD(P)-dependent steroid dehydrogenase-like protein and members of the Rab family of GTPases. Some of these lipid droplet-associated proteins are reported to play important roles in the functions of the lipid droplets (7, 9 -13).In this study, in order to explore proteins that are involved in lipid droplet biogenesis, we investigated the protein composition of lipid droplets isolated from cultured 3T3-L1 adipocytes, and we identified several more lipid droplet-associated proteins using ...

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Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase–1

Cited by 137 publications

References 37 publications

Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

Identification of Mouse Prp19p as a Lipid Droplet-associated Protein and Its Possible Involvement in the Biogenesis of Lipid Droplets

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