Metabolic Changes in Skin Caused by Scd1 Deficiency: A Focus on Retinol Metabolism

Abstract

We previously reported that mice with skin-specific deletion of stearoyl-CoA desaturase-1 (Scd1) recapitulated the skin phenotype and hypermetabolism observed in mice with a whole-body deletion of Scd1. In this study, we first performed a diet-induced obesity experiment at thermoneutral temperature (33°C) and found that skin-specific Scd1 knockout (SKO) mice still remain resistant to obesity. To elucidate the metabolic changes in the skin that contribute to the obesity resistance and skin phenotype, we performed microarray analysis of skin gene expression in male SKO and control mice fed a standard rodent diet. We identified an extraordinary number of differentially expressed genes that support the previously documented histological observations of sebaceous gland hypoplasia, inflammation and epidermal hyperplasia in SKO mice. Additionally, transcript levels were reduced in skin of SKO mice for genes involved in fatty acid synthesis, elongation and desaturation, which may be attributed to decreased abundance of key transcription factors including SREBP1c, ChREBP and LXRα. Conversely, genes involved in cholesterol synthesis were increased, suggesting an imbalance between skin fatty acid and cholesterol synthesis. Unexpectedly, we observed a robust elevation in skin retinol, retinoic acid and retinoic acid-induced genes in SKO mice. Furthermore, SEB-1 sebocytes treated with retinol and SCD inhibitor also display an elevation in retinoic acid-induced genes. These results highlight the importance of monounsaturated fatty acid synthesis for maintaining retinol homeostasis and point to disturbed retinol metabolism as a novel contributor to the Scd1 deficiency-induced skin phenotype.

Role of Stearoyl-CoA Desaturase-1 in Skin Integrity and Whole Body Energy Balance

“…Surprisingly, SKO mice still consumed more food than WT counterparts but were resistant to weight gain during the feeding period (36). Interestingly, although SKO mice were almost completely protected from weight gain on a HFD even when maintained at 33°C for the duration of feeding, hyperphagia in SKO mice appeared to be less pronounced at 33°C compared with mice housed in conventional rooms at 25°C (34,36). When housed at 25°C, SKO mice ate over 50% more HFD by weight compared with WT counterparts (34).…”

“…Although it was clear from studies in the global Scd1 Ϫ/Ϫ model that SCD1 regulates skin integrity, the generation of a skin-specific Scd1 Ϫ/Ϫ animal model (SKO mouse) has revealed surprising connections between skin-specific expression of SCD1, maintenance of the integrity of the skin, and whole body energy metabolism (34,36).…”

“…Indeed, markers of cold exposure, including ␤ 3 -adrenergic receptor signaling in brown adipose tissue, were elevated in SKO mice, suggesting increased cold perception in these mice even at room temperature (34). To follow up on this hypothesis, WT and SKO mice were housed at 33°C, and food intake and body weight gain on a HFD were measured (36). Surprisingly, SKO mice still consumed more food than WT counterparts but were resistant to weight gain during the feeding period (36).…”

“…To follow up on this hypothesis, WT and SKO mice were housed at 33°C, and food intake and body weight gain on a HFD were measured (36). Surprisingly, SKO mice still consumed more food than WT counterparts but were resistant to weight gain during the feeding period (36). Interestingly, although SKO mice were almost completely protected from weight gain on a HFD even when maintained at 33°C for the duration of feeding, hyperphagia in SKO mice appeared to be less pronounced at 33°C compared with mice housed in conventional rooms at 25°C (34,36).…”

Elucidating the roles of stearoyl-CoA desaturase 1 in adipocyte fatty acid metabolism and cellular function

“…SCD1 inhibition in mice using antisense oligonucleotide injections has also been shown to elicit a pro-inflammatory response in isolated macrophages, which can promote atherosclerosis [19]. AKO mice also have elevated tumor necrosis factor α (Tnfα) expression in AT and reduced plasma adiponectin levels [27], while skin-specific Scd1 knockout (SKO) mice exhibit increased cutaneous inflammation [116]. Furthermore, the development of inflammatory conditions such as ulcerative colitis was shown to involve the down-regulation of Scd1 expression in mice [117].…”