Abstract
Stearoyl-CoA desaturase-1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids and is an important regulator of whole body energy homeostasis. Severe cutaneous changes in mice globally deficient in SCD1 also indicate a role for SCD1 in maintaining skin lipids. We have generated mice with a skin-specific deletion of SCD1 (SKO) and report here that SKO mice display marked sebaceous gland hypoplasia and depletion of sebaceous lipids. In addition, SKO mice have significantly increased energy expenditure and are protected from high fat diet-induced obesity, thereby recapitulating the hypermetabolic phenotype of global SCD1 deficiency. Genes of fat oxidation, lipolysis, and thermogenesis, including uncoupling proteins and peroxisome proliferator-activated receptor-gamma co-activator-1alpha, are up-regulated in peripheral tissues of SKO mice. However, unlike mice globally deficient in SCD1, SKO mice have an intact hepatic lipogenic response to acute high carbohydrate feeding. Despite increased basal thermogenesis, SKO mice display severe cold intolerance because of rapid depletion of fuel substrates, including hepatic glycogen, to maintain core body temperature. These data collectively indicate that SKO mice have increased cold perception because of loss of insulating factors in the skin. This results in up-regulation of thermogenic processes for temperature maintenance at the expense of fuel economy, illustrating cross-talk between the skin and peripheral tissues in maintaining energy homeostasis.
Highlights
Because Stearoyl-CoA desaturase-1 (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 these tissues to the dramatically altered metabolic phenotypes of GKO mice
Using Cre recombinase-mediated inhibition of hepatic Scd1, we recently reported that chronic deletion of SCD1 in liver does not protect mice from high fat diet-induced obesity [16], suggesting that extra-hepatic tissues may play a more prominent role in the increased energy expenditure phenotype of global SCD1 deficiency [16]
The results of our present study indicate that the cutaneous phenotypes resulting from global SCD1 deletion are a direct result of the loss of SCD1 and local ⌬-9 MUFA synthesis in the skin
Summary
Animals and Diets—The generation of mice having the third exon of the Scd gene flanked by loxP sites (Scd1flox/flox) has been described previously [16]. SCD1 protein levels were significantly decreased only in skin of SKO mice (Fig. 1B). In addition to the sebaceous gland hypgenerate skin-specific SCD1 knock-out mice (SKO), we crossed oplasia, the skin of SKO mice exhibited other histologic female Scd1lox/lox mice to male mice expressing Cre recombi- changes previously described in a model of global SCD1 definase under a keratin-14 promoter [19]. The ⌬-9 desaturation index of skin surface lipids was significantly lowered in both the TG Skin surface lipids were extracted from Lox and SKO mice as described under “Experimental Procedures” and separated by thin layer chromatography. Apart from these large reductions in sebaceous lipids, we observed a generalized increase in lipids likely to be of epidermal ori-
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