Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.
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 microm(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.
Jong
M C
MC
TNO-Prevention and Health, Gaubius Laboratory, Leiden, the Netherlands.
Voshol
P J
PJ
Muurling
M
M
Dahlmans
V E
VE
Romijn
J A
JA
Pijl
H
H
Havekes
L M
LM
D017667:Adipocytes / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D053302:Apolipoprotein C-I; D001056:Apolipoproteins C / Q000235:genetics* / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D048429:Cell Size; D002784:Cholesterol / Q000097:blood; D003433:Crosses, Genetic; D005227:Fatty Acids / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015870:Gene Expression; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D007457:Iodine Radioisotopes; D007462:Iodobenzenes / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D009929:Organ Size; D014280:Triglycerides / Q000097:blood; D015431:Weight Loss / Q000235:genetics
D053302:Apolipoprotein C-I; D001056:Apolipoproteins C; D001786:Blood Glucose; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D007457:Iodine Radioisotopes; D007462:Iodobenzenes; D014280:Triglycerides; C049338:iodofiltic acid; D002784:Cholesterol