Clofibrate improves glucose tolerance in fat-fed rats but decreases hepatic glucose consumption capacity.
OBJECTIVE
High-fat (HF) diets cause glucose intolerance. Fibrates improve glucose tolerance. We have tried to obtain information on possible hepatic mechanisms contributing to this effect.


METHODS
Rats were fed a HF diet, isocaloric with the control diet, for 3 weeks without or with clofibrate. Several parameters related to liver glucose and glycogen metabolism were measured.


RESULTS
Clofibrate prevented the induction of glucose intolerance by 3 weeks HF feeding. Improved glucose tolerance by clofibrate was not due to increases in glucose phosphorylation or glycolysis in the liver, since both the HF diet and clofibrate suppressed glucokinase and pyruvate kinase activities with no effect on glucose 6-phosphatase. Clofibrate decreased glycogen storage in both control and HF rats. Clofibrate, with and without HF feeding, inhibited weight gain during the experimental period. Body temperature was significantly elevated by clofibrate, indicative of an increased basal metabolic rate. The capacity of liver mitochondria to oxidize long-chain fatty acids increased by clofibrate treatment. Mitochondria did not show uncoupling.


CONCLUSIONS
Clofibrate does not improve glucose tolerance by improving hepatic glucose or glycogen metabolism. Peripheral glucose oxidation may be facilitated by increased energy dissipation.
Gustafson
Lori A
LA
Department of Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Kuipers
Folkert
F
Wiegman
Coen
C
Sauerwein
Hans P
HP
Romijn
Johannes A
JA
Meijer
Alfred J
AJ
D000821:Animal Feed; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001831:Body Temperature / Q000187:drug effects; D002994:Clofibrate / Q000494:pharmacology*; D004041:Dietary Fats / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005934:Glucagon / Q000097:blood; D005941:Glucokinase / Q000378:metabolism; D018149:Glucose Intolerance / Q000188:drug therapy*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D000960:Hypolipidemic Agents; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D006003:Glycogen; D005934:Glucagon; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; D002994:Clofibrate