The Role of Stearoyl-CoA Desaturase in Body Weight Regulation

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Abstract

Obesity is a significant health problem due to its serious medical complications that include hypertension, insulin resistance, diabetes, coronary artery disease, and heart failure. This review addresses the hypothesis that stearoyl-CoA desaturase (SCD) is an important metabolic control point in body weight regulation. SCD is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids. These products are the most abundant fatty acids found in triglycerides, cholesterol esters, wax esters, and phospholipids. Mice with a disruption in the scd1 gene (scd1−/−) have increased energy expenditure, reduced body adiposity, and increased insulin sensitivity, and are resistant to diet-induced obesity. The expression of several genes encoding enzymes of lipid oxidation is upregulated, whereas genes encoding enzymes of lipid synthesis are downregulated in the scd1-deficient mice. scd1 is also a component of the novel metabolic response to the hormone leptin. SCD therefore appears to be an important metabolic control point, and inhibition of its expression could be of benefit in the treatment of obesity, diabetes, cardiovascular disease, and other metabolic diseases.

Section snippets

Role of SCD in Lipid Metabolism

Studies on scd1−/− mice have shown that loss of SCD function decreases the content of tissue triglycerides, cholesterol esters, wax esters, and alkyldiacylglycerols (Miyazaki et al. 2000 and 2001a). Additionally, scd1−/− mice have very low levels of triglycerides in the very low-density lipoprotein (VLDL) and low-density lipoprotein fractions, relative to normal animals (Miyazaki et al. 2000). The expression of scd2 in the liver of scd1−/− mice does not compensate for the scd1 deficiency, nor

SCD1 Deficiency Reduces Obesity of ob/ob Mice

Leptin is an adipocyte-derived liporegulatory hormone that controls lipid homeostasis in nonadipose tissues and was recently found to specifically repress scd1 gene expression and enzymatic activity of hepatic SCD (Cohen et al. 2002). In rodents, mutations in the ob gene can cause leptin deficiency. The ob/ob mice exhibit the full metabolic syndrome of obesity early in life, including hyperlipidemia; elevated free fatty acid levels; and steatosis of liver, heart, skeletal muscle, and pancreatic

SCD and Insulin Signaling

Obesity is often associated with resistance to insulin-stimulated glucose transport in muscles and adipose tissue and to insulin-stimulated suppression of glucose production in the liver (Haffner 2003). These events can, to some extent, be reversed by modest weight loss, which improves insulin signaling and protects pancreatic β cells. Therefore, why is obesity associated with insulin resistance and weight loss with improved insulin signaling? One of the proposed reasons is that excess lipids,

Conclusion

As outlined in this article, the recent studies on SCD provided many new insights into the biology of lipid metabolism and body weight regulation. SCD has been shown to be a critical enzyme in the synthesis of triglycerides, cholesterol esters, and wax esters. Mice with a targeted disruption of scd1 gene are considerably leaner and accumulate less fat than do their wild-type counterparts. Evidence points to direct antisteatotic effects of SCD deficiency on tissues, leading to a reduction in

Acknowledgements

The authors thank Pawel Dobrzyn, Harini Sampath, Seong-Ho Lee, and Makoto Miyazaki for their useful comments during the preparation of this review. This work has been supported by National Institutes of Health grant NIDDK-RO162388 (JMN) and American Heart Association Postdoctoral Fellowship 040051Z (AD).

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