Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and food intake

Abstract

The American diet, especially that of adolescents, contains highly palatable foods of high-energy content and large amounts of high-fructose sweeteners. These factors are believed to contribute to the obesity epidemic and insulin resistance. Previous investigations revealed that the central metabolism of glucose suppresses food intake mediated by the hypothalamic AMP-kinase/malonyl-CoA signaling system. Unlike glucose, centrally administered fructose increases food intake. Evidence presented herein indicates that the more rapid initial steps of central fructose metabolism deplete hypothalamic ATP level, whereas the slower regulated steps of glucose metabolism elevate hypothalamic ATP level. Consistent with effects on the [ATP]/[AMP] ratio, fructose increases phosphorylation/activation of hypothalamic AMP kinase causing phosphorylation/inactivation of acetyl-CoA carboxylase, whereas glucose has the inverse effects. The changes provoked by central fructose administration reduce hypothalamic malonyl-CoA level and thereby increase food intake. These findings explain the paradoxical fructose effect on food intake and lend credence to the malonyl-CoA hypothesis.

Fig. 1.

Effects of i.p. fructose injection on blood sugar and hypothalamic malonyl–CoA levels. (A) Food-deprived mice were given i.p. injections of fructose (4 g/kg of body weight) after which blood fructose and glucose were quantified (n = 4 per group). (B) Mice treated as in A were given an i.c.v. injection of 2-DG (2 μl of 5 mM 2-DG) or vehicle and 10 min later hypothalami were extirpated for malonyl–Co A analysis (n = 4 per group). **, P < 0.001; *, P < 0.01 versus i.p. glucose only; #, P < 0.05 versus i.c.v. 2DG/i.p. glucose.

Fig. 2.

Metabolic pathways of entry of (A) glucose and (B) fructose into the glycolytic pathway of the CNS. GK, glucokinase; KHK, ketohexokinase; DHAP, dihypoxyacetone; Gald, glyceraldehyde.

Fig. 3.

Effect of i.c.v. injection of fructose on hypothalamic ATP level. Food-deprived mice were given i.c.v. injections (400 μg/2 μl) of fructose or glucose and hypothalamic ATP concentration determined at 0, 10, and 20 min after injection (n = 4 per group). **, P < 0.001; *, P < 0.01 versus glucose.

Fig. 4.

Effect i.c.v. injection of fructose on the phosphorylation state of AMPK. Food-deprived mice were given i.c.v. injections (400 μg/2 μl) of fructose or glucose, and 10 min later hypothalami were lysed and subjected to SDS/PAGE and immunoblotting with antibodies to P-AMPK and AMPK (n = 4 mice per group). **, P < 0.001 versus control; #, P < 0.001 versus fructose.

Fig. 5.

Effect i.c.v. injection of fructose on the phosphorylation state of ACC. Food-deprived mice were given i.c.v. injections (400 μg/2 μl) of fructose or glucose, and 10 min later hypothalami were lysed and subjected to SDS/PAGE and immunoblotting with antibodies to ACC and P-ACC (n = 4 mice per group). *, P < 0.01 versus control; #, P < 0.01 versus fructose.

Fig. 6.

Effect i.c.v. injection of fructose and glucose on the level of hypothalamic malonyl–CoA. Food-deprived mice were given i.c.v. injections (400 μg/2 μl) of fructose or glucose at the indicated times the malonyl–CoA levels in hypothalami were quantified (n = 4 mice per group). **, P < 0.001.

Fig. 7.

Effect of i.c.v. injection of fructose and glucose on neuropeptide mRNA expression and food intake. Food-deprived mice were given i.c.v. injections (400 μg/2 μl) of fructose or glucose (n = 4 mice per group). (A) After 10 min hypothalami were removed, RNA was isolated, and mRNA content was determined as described (9, 16). **, P < 0.01; *, P < 0.05 versus fructose; ##, P < 0.01; #, P < 0.05 versus glucose. (B) Mice were given access to food and food intake measured over the next 30 min (n = 4 mice per group). *, P < 0.01 versus control.