Obesity has reached epidemic proportions globally and is a major contributor to the global burden of chronic disease and disability. Often coexisting in developing countries with under-nutrition, obesity is a complex condition, with serious social and psychological dimensions, affecting virtually all ages and socioeconomic groups. We now know that obesity is a multifactorial condition stemming from a combination of genetic, dietary and lifestyle factors and the interaction between these components. The microsomal enzyme stearoyl-CoA desaturase-1 (SCD1) is a critical control point in the development of metabolic diseases, including obesity and insulin resistance. SCD1 catalyzes the biosynthesis of monounsaturated fatty acids (MUFA) palmitoleate (16:1n-7) and oleate (18:1n-9) from saturated fatty acids palmitate (16:0) and stearate (18:0), respectively, that are either synthesized de novo or derived from the diet. These MUFAs (mainly 18:1n-9) are abundant in various kinds of tissue lipids, including phospholipids, triglycerides, cholesterol esters, wax esters and alkyldiacylglycerols. Apart from being components of lipids, MUFA also serve as mediators of signal transduction, cellular differentiation and metabolism. Palmitoleate (16:1n-7) recently has been found to be an important lipokine that controls energy homeostasis and insulin resistance in mice.
Mice lacking the SCD1 enzyme globally (GKO) are lean and protected from diet-induced and leptin deficiency-induced obesity. Because SCD1 is expressed in multiple tissues, including liver, brown and white adipose tissue, skeletal muscle and skin, it has been difficult to determine the relative contributions of the various tissues to the dramatically altered metabolic phenotypes of global SCD1 knockout mice. Using Cre recombinase-mediated inhibition of hepatic Scd1, we reported that chronic deletion of SCD1 specifically in liver protects mice from high carbohydrate-induced weight gain but does not protect against high fat diet-induced obesity, suggesting that extrahepatic tissues may play a more prominent role in mediating the lean phenotype.
Given the changes in skin lipids of the sebaceous glands of the GKO mice that we had reported previously, we generated mice with a skin-specific deletion of SCD1 (SKO). We found that a major part of the hypermetabolic phenotype and protection against diet-induced obesity and insulin resistance of global SCD1 deletion in mice is mediated by loss of SCD1 in the skin. To the best of our knowledge, these mice represent the first model of skin-specific deletion of a lipogenic enzyme resulting in global changes in energy homeostasis.
Although the mechanisms of protection against high fat-induced obesity and insulin resistance because of SCD1 deficiency in skin are yet to be determined, it is tempting to speculate at this time that SCD1 deficiency leads to secondary elevations in skin-derived circulating factor(s) that interact with peripheral tissues that alter systemic energy homeostasis. Numerous studies have always focused on liver and adipose tissue as the primary sites of lipid metabolism and regulation of obesity. Our studies of skin SCD1 illustrate an example of cross talk between the skin and peripheral organs and resurrect the importance of skin lipids in the regulation of whole body energy metabolism.
James M. Ntambi (email@example.com) is Katherine Berns Von Donk Steenbock professor in the department of biochemistry at the University of Wisconsin-Madison.