Mice homozygous for the Dgat1tm1Far targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities however, homozygous mutant females exhibit a complete absence of milk production, necessitating the use of foster mothers. Dgat1 mRNA is undetectable by Northern blot analysis, and DGAT enzyme activity in a variety of tissues is either absent or shows only residual levels. Surprisingly, in DGAT deficient mice triglyceride levels and fasting serum triglycerides levels are similar to wildtype controls. Although homozygotes do not differ in body weight compared to age- and sex-matched controls, total fat pad weight is reduced. Tissue triglyceride levels are reduced 30-40% in white adipose tissue and muscle. Liver triglyceride levels tend to be lower in chow-fed DGAT-deficient mice, but high-fat feeding leads to significantly lower liver triglycerides. Changes in tissue triglyceride levels are associated with increased sensitivity to insulin and leptin. Additionally, infusion of leptin suppresses weight gain significantly more in DGAT-deficient mice compared to controls. Dry fur and hair loss in mutant mice are evident by 6-8 weeks, resulting from sebaceous gland atrophy and abnormal fur lipid production (especially type 2 wax diesters). DGAT-deficient mice also exhibit impaired water repulsion and hypothermia after water immersion. Interestingly, leptin modulates the fur and skin effects seen with DGAT deficiency. Homozygotes that are maintained on a high fat diet (21% fat by weight) are resistant to obesity. Resistance to diet-induced obesity is attributed to increased energy expenditure in Dgat1-null mice. This mutant strain is a suitable tool for use in studies examining mechanisms of triglyceride synthesis and the relationship between triglyceride synthesis and obesity, leptin, and insulin resistance. DGAT-deficient mice also provide a useful model to study the role of DGAT in fur and sebaceous gland physiology.
