Despite their ability to similarly catalyze TG synthesis, DGAT1 and DGAT2 belong to two separate gene families, share neither DNA nor protein sequence homology and differ in their biochemical, cellular, and physiological functions (Yen et al. 2008). DGAT1 belongs to a large family of membrane-bound O-acyltransferases known as the MBOAT family. The genes encoding human and murine DGAT1 were identified by their sequence homology to acyl-CoA:cholesterol acyltransferase enzymes but were shown to encode a protein having DGAT activity (Cases et al. 1998). In humans, the DGAT1 gene is located on chromosome 8 and comprises 17 exons spanning 10.62 kb. In most species, the encoded protein has a predicated molecular weight of ~ 55 kDa and consists of about 500 amino acids. In humans, DGAT1 is ubiquitously expressed, with the highest mRNA expression in tissues that make considerable amounts of TG, such as the small intestine, liver, and adipose tissue (Cases et al. 1998). In mice, the expression pattern is similar to that of humans, except in that mRNA levels are relatively low in liver (Cases et al. 1998). As for the mRNA expression of DGAT specifically in the skin, it is scarcely detectable in the epidermis or dermis of neonatal mice (Stone et al. 2004). Although it is expressed at very low levels in the epidermis of adult mice, it is highly expressed in sebaceous glands (Chen et al. 2002a).

Regarding biochemical function, DGAT1 not only catalyzes the synthesis of TGs, but also the synthesis of diacyalglcyerols, retinyl esters, and wax esters via its acyl-CoA:monoacylglycerol acyltransferase (MGAT), acyl-CoA:retinol acyltransferase (ARAT) and wax synthase activities, respectively (Yen et al. 2005a). In effect, studies in vivo show that its ARAT and wax synthase activities play an important role in skin and hair physiology (Chen et al. 2002a; Shih et al. 2009). Furthermore, DGAT1 functions as such a potent ARAT that it may have been named differently had it been initially identified to possess this activity (Yen et al. 2005a).

DGAT2 belongs to the DGAT2/MGAT gene family (Cases et al. 2001). In addition to DGAT2 and MGATs 1, 2, and 3 (Yen et al. 2002; Yen and Farese 2003; Cheng et al. 2003), this family also consists of wax monoester synthases (Cheng and Russell 2004; Turkish et al. 2005) and a multifunctional O-acyltransferase (Yen et al. 2005b). Interestingly, this multifunctional enzyme catalyzes the synthesis of diacyalglcyerols, retinyl esters, and wax esters (Yen et al. 2005b) similarly to the multiple enzymatic activities of DGAT1.The fact that members of the DGAT2/MGAT gene family comprise enzymes that possess wax synthase activity highlights the overlapping similarities between the gene families of DGAT1 and DGAT2.

In humans, the DGAT2 gene is located on chromosome 11 and comprises eight exons spanning 42.03 kb. In most species, the encoded protein has a predicated molecular weight ranging from 40 to 44 kDa and consists of 350–400 amino acids. Like DGAT1, DGAT2 is expressed in most mammalian tissues, with the highest mRNA levels in organs that make considerable amounts of TG (small intestine, liver, and adipose tissue; Cases et al. 2001). In mice, DGAT2 mRNA is more widely expressed than humans with less variation in levels across tissues (Cases et al. 2001). As for the mRNA expression of DGAT2 specifically in the skin, it is expressed at higher levels in the epidermis than dermis of neonatal mice (Stone et al. 2004). In the epidermis of adult mice, DGAT2 mRNA expression is much more robust than DGAT1 and the majority of its expression is accounted for in the basal layer (Stone et al. 2004).

Although Dgat1 ^−/− mice have been primarily studied in regards to whole-body energy metabolism, important observations have been made in respect to DGAT1 function in skin and fur (Chen et al. 2002a; Shih et al. 2009). Adult Dgat1 ^−/− mice develop dry fur and hair loss, which are associated with atrophic sebaceous glands and fur lipid abnormalities. Young Dgat1 ^−/− mice exhibit normal fur appearance at weaning. However, after puberty (6–8 weeks of age) the fur of Dgat1 ^−/− mice appears dry and less sheen compared to that of wild-type mice and subsequent hair loss is observed (Chen et al. 2002a). The hair loss phenotype is more prominent in young males than in females (Chen et al. 2002a) but is similar regardless of gender as it worsens with age (unpublished).

In a wild-type mouse, the sheen appearance of the fur is due to lipids (sebum) secreted from the sebaceous glands associated with hair follicles. In 6-week-old Dgat1 ^−/− mice, the sebaceous glands are normal in appearance and located in a typical association with normal hair follicles. However, in 3-month-old Dgat1 ^−/− mice, sebaceous glands are atrophied along the ventral and dorsal surfaces and few are associated with hair follicles. Although fur lipids from both wild-type and Dgat1 ^−/− mice are composed of similar levels of sterol esters, free cholesterol, and surprisingly, triglycerides, Dgat1 ^−/− mice lack several fur lipids, with the most prominent of these being type II wax diesters. Like the hair loss phenotype, the difference in fur lipid composition is also age-dependent where the differences are less striking in young mice but more pronounced in adults. Of note, the fur of heterozygous (Dgat1 ^+/−) mice is normal in appearance throughout their lifespan.

As a result of atrophied sebaceous glands and decreased fur lipids, Dgat1 ^−/− mice exhibit impaired water repulsion and hypothermia following water immersion. The fur of Dgat1 ^−/− mice retains significantly more water compared to wild-type controls, which are almost completely dry, 5 min after water immersion (Chen et al. 2002a). Consequently, Dgat1 ^−/− mice become hypothermic and this persists for an hour following immersion.

Farese and colleagues found the skin and fur phenotypes of Dgat1 ^−/− mice to be unexpectedly modulated by the adipocyte-secreted hormone, leptin (Chen et al. 2002a). Leptin is a peptide hormone known to reduce food intake and enhance energy expenditure through its receptors in the central nervous system (specifically in the hypothalamus; Morton and Schwartz 2011) but also functions to regulate energy metabolism directly through its receptors in peripheral tissues, including the skin (Frank et al. 2000; Poeggeler et al. 2010). When DGAT1 deficiency is introduced into mice with a spontaneous mutant in the leptin gene (Dgat1 ^−/− ob/ob), the hair loss, water repulsion, and sebaceous gland abnormalities are almost absent. However, it is important to note that the sebaceous gland size and fur lipid levels are slightly decreased in Dgat1 ^−/− ob/ob mice compared to controls (Dgat1 ^+/+ ob/ob). Following 2 weeks of peripheral or central leptin infusion, the size of sebaceous glands and fur lipid levels are slightly reduced in controls but both are markedly reduced in Dgat1 ^−/− ob/ob mice. Furthermore, these changes are reverted to pretreatment states 2 weeks after leptin administration is withdrawn. Since both peripheral and central administrations of leptin have similar effects on sebaceous glands and fur lipid composition, it is reasonable that these observations can be mediated entirely through the hypothalamus. One plausible mechanism by which leptin centrally modulates the skin and fur phenotypes of Dgat1 ^−/− mice is by activation of the sympathetic nervous system to suppress the expression of DGAT2. Indeed, mice deficient in DGAT1 are known to exhibit enhanced leptin sensitivity (Chen et al. 2002b) and DGAT2 mRNA is significantly decreased in the skin of these mice (Chen et al. 2002a). Moreover, compared to wild-type controls, DGAT2 mRNA expression is increased at similar levels in the skin of leptin-deficient mice despite the presence or absence of DGAT1.

Upon further investigation of the hair loss observed in Dgat1 ^−/− mice, Farese and colleagues discovered this phenotype to also be, in part, due to impaired retinoid (retinol and its derivatives) homeostasis and that the ARAT activity of DGAT1 plays an important role in murine skin (Shih et al. 2009). As mentioned above, DGAT1 not only catalyzes the synthesis of TGs, but also functions as a potent ARAT synthesizing retinyl esters through the esterification of retinol (vitamin A) with fatty acyl-CoA substrates (Yen et al. 2005a). Retinol is obtained through the diet and mostly stored in the form of retinyl esters in the cytosolic lipid droplets of cells providing then a local source of retinol. Retinol is the precursor for retinoic acids (all-trans and 9-cis-retinoic acid), which are ligands for nuclear hormone receptors (retinoic acid receptor and retinoid-x receptor) and are known to affect sebaceous gland function (Zouboulis et al. 1991; Strauss et al. 1987) and hair growth (Bazzano et al. 1993). In whole skin of Dgat1 ^−/− mice compared to controls, ARAT activity is significantly reduced by ~ 90 % and levels of unesterified retinol and all-trans retinoic acid are increased by ~ 22 and 40 %, respectively (Shih et al. 2009). Studies from Dgat1 ^−/− mice suggest that when dietary retinol is sufficient, DGAT1 deficiency results in retinoic acid toxicity in the skin, which subsequently leads to cyclical hair loss. Consistent with retinoic acid toxicity, genes regulated by the retinoic acid receptor are also elevated in the skin of these mice. When dietary retinol is deficient however, neither retinoic acid toxicity nor hair loss is observed in Dgat1 ^−/− mice. Moreover, mice deficient of DGAT1 specifically in the skin exhibit cyclical hair loss and increased expression of retinoic acid receptor target genes indicating that dysregulation of retinoid homeostasis is due loss of the enzyme in the skin rather than systemic changes in metabolism (Shih et al. 2009). Collectively, these findings reveal DGAT1 to be a major ARAT in murine skin and therefore essential for maintaining retinoid homeostasis and preventing retinoic acid toxicity-induced hair loss. Of note, it remains to be determined if the sebaceous gland and fur lipid phenotypes of Dgat1 ^−/− mice are also due to the dysregulation of retinoid homeostasis.