Role for Stearoyl-CoA Desaturase-1 in Leptin-Mediated Weight Loss

Cohen, Paul; Miyazaki, Masaru; Socci, Nicholas D.; Hagge-Greenberg, Aaron; Liedtke, Wolfgang; Soukas, Alexander A.; Sharma, Ratnendra; Hudgins, Lisa C.; Ntambi, James M.; Friedman, Jeffrey M.

doi:10.1126/science.1071527

Cited by 763 publications

(605 citation statements)

References 25 publications

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“…Our results suggest a correlation of high ∆9-desaturase activity with obesity, muscle insulin resistance and possibly diabetes. Our data add to the recent discovery of the key role of ∆9-desaturase in metabolism and energy balance [51].…”

Section: Discussionsupporting

confidence: 67%

Glucose oversupply increases Δ9-desaturase expression and its metabolites in rat skeletal muscle

et al. 2003

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Aim/hypothesis. Previous studies have shown that prolonged glucose infusion causes insulin resistance and triglyceride accumulation in rat skeletal muscle. In this study, we investigated a possible relationship between insulin resistance and the composition of different accumulated lipid fractions in rat skeletal muscle. Methods. Continuous glucose infusion was carried out in rats for 7 days. Lipids were extracted from skeletal muscle, separated by thin layer chromatography and fatty acid composition of phospholipids, triglycerides, diglycerides, free fatty acids and cholesterol esters fractions was analysed by gas chromatography. ∆9-Desaturase mRNA was measured by real time polymerase chain reaction. The enzyme activity was measured in the microsomal fractions. Results. Prolonged glucose infusion (5 days) increased the relative content of palmitoleic acid (16:1 N7) several-fold (2.3-to 5.8-fold) in four out of five lipid fractions and enhanced oleic acid (18:1 N9) two-fold in three lipid fractions suggesting increased ∆9-desaturase activity while the content of several polyunsaturated fatty acids was reduced. In parallel, ∆9-Desaturase mRNA contents and enzyme activities in skeletal muscle were increased 10-fold, 75-fold, 2.6-fold and 7.7-fold after 2 and 5 days of glucose infusion, respectively. Conclusion/interpretation. Our results suggest that long-term glucose oversupply induces a rapid increase in ∆9-desaturase expression and enzyme activity in skeletal muscle which leads to fast and specific changes in fatty acid metabolism possibly contributing to the insulin resistance in this animal model. [Diabetologia (2003) 46:203-212]

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Section: Discussionsupporting

confidence: 67%

Glucose oversupply increases Δ9-desaturase expression and its metabolites in rat skeletal muscle

et al. 2003

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“…While the starvation-induced decrease in the mRNA levels of SOCS-3 was evidenced in both strains, the hypothalamic content of this transcript was greater in starved Lou/C than in starved Wistar rats. In addition, stearoyl-coenzyme A desaturase 1 (SCD-1), another target gene known to be specifically repressed by leptin, 28 was clearly downregulated in Lou/C rats ( Table 3). The mRNA content of STAT3, JAK2, the protein tyrosine phosphatase-1B (PTP1B) and SCD-2 was not modified in both strains whatever the nutritional state (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…44 Our results in Lou/C rats are consistent with the proposed 'hypothalamic fatty acid sensing hypothesis', 45,46 which involves hormone-mediated lack of AMPK activation during starvation, thus preventing subsequent ACC phosphorylation and inactivation, which in turn would maintain elevated intrahypothalamic malonyl-CoA and/or LCFA-CoA content and inhibits feeding (Figure 4). In addition, we propose that a decrease in SCD-1 expression, a rate-limiting enzyme catalyzing the synthesis of monounsaturated fatty acids from LCFA-CoA, [47][48][49] which is known to be specifically repressed by leptin, 28 could also participate in the higher intrahypothalamic level of malonyl-CoA and/or LCFA-CoA by decreasing triglycerides and phospholipid synthesis.…”

Section: Discussionmentioning

confidence: 99%

Lack of starvation-induced activation of AMP-activated protein kinase in the hypothalamus of the Lou/C rats resistant to obesity

et al. 2007

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Objective: The AMP-activated protein kinase (AMPK) is involved in the control of food intake by the hypothalamus. The aim of this work was to investigate if modification of hypothalamic AMPK regulation could be related to the spontaneous food restriction of Lou/C rats, a strain resistant to obesity exhibiting a 40% reduction in caloric intake compared with their lean Wistar counterparts. Design: Three-month-old male Lou/C rats were compared with age-matched male Wistar rats in both fed ad libitum and 24-h food deprivation state. Measurements and results: We first confirmed that starvation activated both isoforms of AMPK catalytic a subunits and enhanced the phosphorylation state of its downstream targets acetyl-CoA carboxylase and elongation factor 2 in the hypothalamus of Wistar rats. These changes were not observed in the hypothalamus of Lou/C rats. Interestingly, the starvationinduced changes in hypothalamic mRNA levels of the main orexigenic and anorexigenic neuropeptides were also blunted in the Lou/C rats. Analysis of the concentrations of circulating substrates and hormones known to regulate hypothalamic AMPK indicated that the starvation-induced changes in ghrelin, adiponectin and leptin were not observed in Lou/C rats. Furthermore, an increased phosphorylation state of signal transducer and activator of transcription 3 (STAT3), which admittedly mediates leptin signaling, was evidenced in the hypothalamus of the starved Lou/C rats, as well as modifications of expression of the leptin-sensitive genes suppressor of cytokine signaling-3 and stearoyl-coenzyme A desaturase 1. In addition, despite reduced leptin level in fed Lou/C rats, the phosphorylation state of hypothalamic STAT3 remained similar to that found in fed Wistar rats, an adaptation that could be explained by the concomitant increase in ObRb leptin receptor mRNA expression. Conclusion: Activation of hypothalamic AMPK by starvation, which stimulates food intake through changes in (an)orexigenic neuropeptides in the normal rats, was not observed in the spontaneously hypophagic Lou/C rats.

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“…On the other hand, mice with a targeted disruption of Scd1 gene exhibit increased insulin sensitivity and fatty acid metabolism [34]. The activity and expression of Scd1 were highly elevated in ob/ob mice and were normalised by leptin treatment [35]. Also, the hepatic Scd1 mRNA level was significantly increased in leptin-resistant fa/fa ZDF rats [36].…”

Section: Discussionmentioning

confidence: 99%

Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

et al. 2006

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Aims/hypothesis: We used oestrogen receptor-α (ERα) knockout (ERKO) and receptor-β (ERβ) knockout (BERKO) mice to investigate the mechanism(s) behind the effects of oestrogens on glucose homeostasis. Methods: Endogenous glucose production (EGP) was measured in ERKO mice using a euglycaemic-hyperinsulinaemic clamp. Insulin secretion was determined from isolated islets. In isolated muscles, glucose uptake was assayed by using radiolabelled isotopes. Genome-wide expression profiles were analysed by high-density oligonucleotide microarray assay, and the expression of the genes encoding stearoyl-CoA desaturase 1 and the Leptin receptor (Scd1 and Lepr, respectively) was confirmed by RT-PCR. Results: ERKO mice had higher fasting blood glucose, plasma insulin levels and IGT. The plasma leptin level was increased, while the adiponectin concentration was decreased in ERKO mice. Levels of both glucose-and arginine-induced insulin secretion from isolated islets were similar in ERKO and wild-type mice. The euglycaemichyperinsulinaemic clamp revealed that suppression of EGP by increased insulin levels was blunted in ERKO mice, which suggests a pronounced hepatic insulin resistance. Microarray analysis revealed that in ERKO mice, the genes involved in hepatic lipid biosynthesis were upregulated, while genes involved in lipid transport were downregulated. Notably, hepatic Lepr expression was decreased in ERKO mice. In vitro studies showed a modest decrease in insulin-mediated glucose uptake in soleus and extensor digitorum longus (EDL) muscles of ERKO mice. BERKO mice demonstrated normal glucose tolerance and insulin release. Conclusions/interpretation: We conclude that oestrogens, acting via ERα, regulate glucose homeostasis mainly by modulating hepatic insulin sensitivity, which can be due to the upregulation of lipogenic genes via the suppression of Lepr expression.

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Role for Stearoyl-CoA Desaturase-1 in Leptin-Mediated Weight Loss

Cited by 763 publications

References 25 publications

Glucose oversupply increases Δ9-desaturase expression and its metabolites in rat skeletal muscle

Glucose oversupply increases Δ9-desaturase expression and its metabolites in rat skeletal muscle

Lack of starvation-induced activation of AMP-activated protein kinase in the hypothalamus of the Lou/C rats resistant to obesity

Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

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