Sources of plasma glucose and liver glycogen in fasted ob/ob mice.
Alterations in intrahepatic carbohydrate fluxes in ob/ob mice and the effects of acute leptin administration were studied in vivo by use of a dual-isotope tracer infusion. Metabolic sources of plasma glucose (gluconeogenesis (GNG) and glycogenolysis) and hepatic glycogen (GNG, direct synthesis and pre-existing) were determined in 20-h-fasted mice infused with [2-13C1]glycerol and [U13C6]glucose for 3 h. Total glucose output (TGO) and the rate of appearance (Ra) of plasma glycerol were measured by isotope dilution. GNG, the direct pathway of hepatic glycogen synthesis and hepatic triose-phosphate flux were determined by mass isotopomer distribution analysis (MIDA). Serum glucose, insulin, leptin and liver glycogen concentrations were also measured. After a 24-h fast, ob/ob mice had 2-fold higher TGO, 2.5-fold elevated liver glycogen content and markedly higher glycogenolytic flux to glucose, absolute GNG and direct glycogen synthesis rates (10-fold increased) compared to the control group. Ob/ob mice also had elevated triose-phosphate flux compared to controls (40 vs. 22 mg/kg lean body mass/min). A model of intrahepatic flux distributions in control and ob/ob mice is presented. In summary, elevated fasting plasma glucose concentrations are due to increased TGO in ob/ob mice, which is maintained by both increased GNG and increased glycogenolysis. Furthermore, the ob/ob mice have major alterations in fasting hepatic carbohydrate fluxes into triose-phosphate pools and glycogen. We support the model that actions of leptin on hepatic glucose metabolism require insulin or other factors.
Turner
S M
SM
KineMed Inc., Emeryville, CA 94608, USA. sturner@kinemed.com
Linfoot
P A
PA
Neese
R A
RA
Hellerstein
M K
MK
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D005215:Fasting; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008112:Liver Glycogen / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008954:Models, Biological
D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D008112:Liver Glycogen; D005947:Glucose