HORMONAL AND NUTRITIONAL CONTROL OF THE FATTY-ACID SYNTHASE PROMOTER IN TRANSGENIC MICE

To study the molecular basis of tissue-specific and hormonally regulat ed expression of the fatty acid synthase (FAS) gene in vivo, we genera ted lines of transgenic mice carrying 2.1 kilobases of the 5'-flanking region (-2100 to +67) of the rat FAS gene fused to a chloramphenicol acetyltransferase (CAT) reporter gene. This reporter gene construct wa s strongly expressed in tissues that normally express high levels of F AS mRNA, which include liver and white adipose tissues, In contrast, C AT reporter activity was not detected in appreciable levels in lung, h eart, kidney, and muscle tissues, which do not normally show significa nt levels of FAS activity, The relative levels of the CAT mRNA driven by the rat FAS promoter in various tissues of the transgenic animals a pproximated those of the endogenous mouse FAS mRNA, We also examined t he hormonal and nutritional regulation of the FAS(2.1)-CAT reporter ge ne in transgenic mice, CAT activity was increased in both liver and wh ite adipose tissue when fasted animals were refed a high carbohydrate, fat-free diet, These changes in CAT activity and CAT mRNA levels occu rred in parallel to the changes in endogenous mouse FAS mRNA levels, O n the other hand, fasting/refeeding did not change CAT activity apprec iably in other tissues, such as muscle and brown adipose tissue, Admin istration of dibutyryl cAMP at the start of refeeding prevented an inc rease in CAT activity in liver, However, the cAMP effect was tissue-sp ecific as cAMP treatment did not bring about change in CAT activity in adipose tissue, Next, to examine the effect of insulin, we made the t ransgenic mice insulin-deficient by streptozotocin treatment, Insulin treatment of the streptozotocin-diabetic mice increased both the CAT a ctivity and CAT mRNA levels driven by the rat FAS promoter in liver an d white adipose tissue, These changes in CAT expression by insulin par alleled those in endogenous FAS mRNA levels, Administration of glucoco rticoids increased CAT activity in all tissues examined: liver, white and brown adipose tissues, lung, heart, and spleen, Overall, the first 2.1 kilobases of the 5'-flanking region of the rat FAS gene appear to contain sequence elements necessary to confer tissue-specific and hor monally regulated expression characteristic of the endogenous FAS gene .