Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance.
Adipose tissue glyceroneogenesis generates glycerol 3-phosphate, which could be used for fatty acid esterification during starvation. To determine whether increased glyceroneogenesis leads to increased fat mass and to explore the role of obesity in the development of insulin resistance, we overexpressed PEPCK, a regulatory enzyme of glyceroneogenesis in adipose tissue. Transgenic mice showed a chronic increase in PEPCK activity, which led to increased glyceroneogenesis, re-esterification of free fatty acids (FFAs), increased adipocyte size and fat mass, and higher body weight. In spite of increased fat mass, transgenic mice showed decreased circulating FFAs and normal leptin levels. Moreover, glucose tolerance and whole-body insulin sensitivity were preserved. Skeletal muscle basal and insulin-stimulated glucose uptake and glycogen content were not affected, suggesting that skeletal muscle insulin sensitivity is normal in transgenic obese mice. Our results indicate the key role of PEPCK in the control of FFA re-esterification in adipose tissue and, thus, the contribution of glyceroneogenesis to fat accumulation. Moreover, they suggest that higher fat mass without increased circulating FFAs does not lead to insulin resistance or type 2 diabetes in these mice.
Franckhauser
Sylvie
S
Department of Biochemistry and Molecular Biology, School of Veterinary Medicine and Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Spain.
Muñoz
Sergio
S
Pujol
Anna
A
Casellas
Alba
A
Riu
Efren
E
Otaegui
Pedro
P
Su
Benli
B
Bosch
Fatima
F
D017667:Adipocytes / Q000473:pathology; D000273:Adipose Tissue / Q000201:enzymology*; D000818:Animals; D002250:Carbon Radioisotopes; D003847:Deoxyglucose / Q000378:metabolism; D004951:Esterification; D005227:Fatty Acids / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism; D015870:Gene Expression; D005990:Glycerol / Q000378:metabolism; D005994:Glycerophosphates / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006984:Hypertrophy; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000201:enzymology*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D002250:Carbon Radioisotopes; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D005994:Glycerophosphates; D020738:Leptin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003847:Deoxyglucose; C029620:alpha-glycerophosphoric acid; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005990:Glycerol