Apolipoprotein (APO) C1 is a 6.6-kDa protein present in plasma and associated with lipoproteins. Using hyperinsulinemic-euglycemic clamp tests, we previously found that in APOC1 transgenic mice, the whole-body insulin-mediated glucose uptake is increased concomitant with a decreased fatty acid uptake. These latter results are confirmed in the present study, showing that APOC1 transgenic mice exhibit a 50% reduction in the uptake of the fatty acid analog 15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid in white adipose tissue stores. We next investigated whether APOC1 overexpression can modulate the initiation and/or development of obesity and insulin resistance. When crossbred on the genetically obese ob/ob background, APOC1 transgenic mice were fully protected from the development of obesity compared with ob/ob only mice, as reflected by a strong reduction in body weight (21 ؎ 4 vs. 44 ؎ 7 g), total adipose tissue stores (15 ؎ 3 vs. 25 ؎ 3% body wt), and average adipocyte size (7,689 ؎ 624 vs. 15,295 ؎ 1,289 m 2 ). Although less pronounced, APOC1 overexpression also reduced body weight on a wild-type background, solely due to a reduction in adipose tissue. Furthermore, despite elevated plasma free fatty acid and triglyceride levels, APOC1 overexpression significantly improved insulin sensitivity in ob/ob mice, as demonstrated by a strong reduction in plasma glucose and insulin levels, as well as a better performance in the glucose tolerance test. In conclusion, a marked reduction in the uptake of fatty acids into adipocytes may underlie the protection from obesity and insulin resistance in transgenic mice overexpressing human APOC1. Diabetes 50: 2779 -2785, 2001 T he human Apolipoprotein (APO) C1 gene is located ϳ5 kb downstream of the human APOE gene on chromosome 19 and is primarily expressed in the liver with low expression in lung, skin, and spleen (1). ApoC1 is subsequently synthesized and secreted as a 6.6-kDa protein in plasma, where it resides on chylomicrons, VLDL, and HDL (2). To elucidate the role of apoC1 in lipid metabolism, we generated transgenic mice overexpressing human APOC1 (3). Human APOC1 transgenic mice have elevated levels of plasma cholesterol and triglycerides as a result of an inhibitory action of apoC1 on VLDL uptake via hepatic receptors, in particular the LDL receptor-related protein (3,4).In addition to the increased levels of plasma cholesterol and triglycerides, APOC1 transgenic mice exhibit elevated plasma concentrations of free fatty acids (FFA) (5). These increased lipid levels are not associated with insulin resistance, because hyperinsulinemic-euglycemic clamp studies revealed an increase in the insulin-mediated glucose uptake in APOC1 transgenic mice compared with their wild-type littermates (6). In contrast, whole-body fatty acid uptake was strongly decreased in APOC1 transgenic mice (6), which suggests that apoC1 somehow inhibits the uptake of FFA by peripheral tissues. To explore further these findings, we aimed 1) to identify the tissues in APOC1 transgenic mice e...