THE INDIRECT PATHWAY OF HEPATIC GLYCOGEN-SYNTHESIS AND REDUCTION OF FOOD-INTAKE BY METABOLIC-INHIBITORS

The increasingly recognized role of the indirect pathway (glycolysis followed by hepatic gluconeogenesis) for glucose utilization and glycogen synthesis by the liver led us to administer 3-mercaptopicolinate (3MP), an inhibitor of phosphoenolpyruvate-carboxykinase, in an attempt to assess the role of liver glycogen or hexose-phosphates in the food-intake reducing effects of (-)hydroxy-citrate. Administration of (-)hydroxy-citrate increased hepatic glycogen content in i.v. glucose refed rats. Using the glucuronide probe technique, the mechanism of increased glycogen deposition was shown to be prolongation of indirect pathway (recycled) input. Daily (-)hydroxy-citrate significantly reduced food intake (from 12.0 +/- 2.3 to 6.4 +/- 3.6 g/day, p < 0.05) and had no chronic effect on hepatic glycogen content in rats trained to a single daily meal (meal-fed). Administration of 3MP completely suppressed hepatic glycogen synthesis (< 0.5 mg/g) when given alone or with (-)hydroxy-citrate. Isotopic studies confirmed inhibition of the indirect pathway of UDP-glucose synthesis. 3MP accentuated rather than prevented the (-)hydroxy-citrate reduction in food intake in meal-fed rats (intake 2.7 +/- 2.4 g/day). When given alone, 3MP also reduced intake (6.1 +/- 3.6 g/day). Severe hypoglycemia was observed (glucose < 20 mg/dl) in several meal-fed rats given repeated daily doses of 3MP, yet food intake did not occur despite food availability. Neither 3MP nor (-)hydroxy-citrate had any effects when given after the daily meal. We conclude that the role of the indirect glycogen synthesis pathway must be considered in any theory of regulation of food intake by hepatic metabolites and that, if the effects of these metabolic inhibitors can be shown not to be toxic or non-specific, neither hepatic glycogen nor hexose-phosphates are involved in the food-intake suppressive effects of (-)hydroxycitrate.