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/malonylCoA 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.acetyl-CoA carboxylase ͉ AMP kinase ͉ high-fructose corn syrup ͉ hypothalamic ATP ͉ obesity O ver the past three decades there has been an alarming increase in the incidence of obesity and type 2 diabetes in the United States (1). Particularly troubling is the rise of these conditions in youth (2). Paralleling this rise has been the extensive use of high-fructose sweeteners in the diet and increasing evidence that fructose may be a contributing factor to the obesity epidemic (3). These correlations are consistent with the finding that high-fructose diets promote insulin resistance, glucose intolerance, and increased rates of hepatic lipogenesis in laboratory animals (4).Although both glucose and fructose enter metabolism via the glycolytic pathway, the initial steps of hepatic fructose metabolism differ from those of glucose. Likewise, recent evidence suggests that sugar metabolism in regions of the central nervous system (CNS) that control food intake and energy expenditure, fructose metabolism also differs from that of glucose. It is known that the initial steps of hepatic fructose metabolism use a different set of enzymes that allow this sugar to bypass the rate-limiting step [catalyzed by phosphofructokinase (PFK)] in the glycolytic pathway. Similar enzymes of fructose metabolism are found in regions of the CNS that play an important role in monitoring energy balance and satiety control (5-7). These findings are consistent with a recent report (ref. 8 and findings reported herein) that centrally-administered fructose provokes feeding. In contrast, the central administration of glucose causes satiety (8,9). In this article, we provide a molecular basis for these differences. It should be noted, however, that uncertainty remains regarding the extent to which fructose in systemic circulation can cross the blood-brain barrier to enter these regions of the brain ...

Obesity and energy balance: is the tail wagging the dog?

“…The paradoxical state of cellular energy depletion may be interpreted by the brain as a state of energy deprivation, increasing appetite and energy intake via an activation of AMP kinase (Cha et al, 2008). In rats, for example, central administration of fructose increases appe-tite and energy intake (Cha et al, 2008). The rapid decrease in ATP levels associated with fructose metabolism is assumed to activate AMP kinase and inhibit the down-stream production of malonyl-co-A, a known appetite suppressant (Wolfgang et al, 2007).…”

“…The elevation of lactate concentration, which follows fructose ingestion increases the rate of hepatic gluconeogenesis, and contributes to the cellular depletion of ATP (Johnson et al, 1989;Caton et al, 2011). As a consequence, high levels of insulin in response to the raised plasma glucose impact indirectly on the brain to generate feelings of hunger and tiredness through a rapid decline in fuel availability for motor activities in the peripheral tissues, while at the same time the fructose generates systemic effects on ATP levels, depleting cellular energy availability (Johnson et al, 1989;Cha et al, 2008).…”

“…The rapid decrease in ATP levels associated with fructose metabolism is assumed to activate AMP kinase and inhibit the down-stream production of malonyl-co-A, a known appetite suppressant (Wolfgang et al, 2007). This in turn leads to stimulation of the anorexigenic neurocircuitry (decreased levels of cocaine and amphetamine-regulated transcript and proopiomelanocortin) in the hippocampus, and increased activity of the orexigenic pathway (reduced levels of neuropeptide Y and agouti-related peptide) (Cha et al, 2008).…”

“…In addition, the rapid metabolism of fructose and the activation of energy-demanding processes increase the adenosine monophosphate (AMP):ATP ratio (Leclerc et al, 1998;Muoio et al, 1999;Cha et al, 2008). This paradoxical state of cellular starvation activates the catabolic enzyme AMP-kinase which, in trying to replenish the cellular ATP levels, orchestrates a series of different oxidative mechanisms including glucose and lipid oxidation and the activation of glycogenlysis (Dzamko and Steinberg, 2009).…”

“…The sustained hyperinsulinaemia elicits a systemic anabolic drive, which stimulates fat accumulation in adipose tissue and skeletal muscle. The paradoxical state of cellular energy depletion may be interpreted by the brain as a state of energy deprivation, increasing appetite and energy intake via an activation of AMP kinase (Cha et al, 2008). In rats, for example, central administration of fructose increases appe-tite and energy intake (Cha et al, 2008).…”