Adipose overexpression of phosphoenolpyruvate carboxykinase leads to high susceptibility to diet-induced insulin resistance and obesity.
Obesity and insulin resistance are associated with increased serum free fatty acids (FFAs). Thus, a reduction in circulating FFAs may increase insulin sensitivity. This could be achieved by increasing FFA reesterification in adipose tissue. Transgenic mice with increased adipose tissue glyceroneogenesis, caused by overexpression of phosphoenolpyruvate carboxykinase (PEPCK), show increased FFA reesterification and develop obesity but are insulin sensitive. Here, we examined whether these transgenic mice were protected from diet-induced insulin resistance. Surprisingly, when fed a high-fat diet for a short period (6 weeks), transgenic mice developed severe obesity and were more hyperinsulinemic, glucose intolerant, and insulin resistant than controls. The high triglyceride accumulation prevented white adipose tissue from buffering the flux of lipids in circulation and led to increased serum triglyceride levels and fat deposition in liver. Furthermore, circulating leptin and FFA concentrations increased to similar levels in transgenic and control mice, while adiponectin levels decreased in transgenic mice compared with controls. In addition, transgenic mice showed fat accumulation in brown adipose tissue, which decreased uncoupling protein-1 expression, suggesting that these mice had impaired diet-induced thermogenesis. These results indicate that increased PEPCK expression in the presence of high-fat feeding may have deleterious effects and lead to severe insulin resistance and type 2 diabetes.
Franckhauser
Sylvie
S
Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Muñoz
Sergio
S
Elias
Ivet
I
Ferre
Tura
T
Bosch
Fatima
F
D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000201:enzymology*; D000818:Animals; D004032:Diet; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015971:Gene Expression Regulation, Enzymologic; D006946:Hyperinsulinism; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000139:chemically induced* / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism*
D052242:Adiponectin; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D010729:Phosphoenolpyruvate Carboxykinase (GTP)