Citrate diminishes hypothalamic acetyl-CoA carboxylase phosphorylation and modulates satiety signals and hepatic mechanisms involved in glucose homeostasis in rats

Jun 7, 2008Life sciences

Citrate reduces a key enzyme modification in the brain’s hunger control area and influences fullness signals and liver processes related to blood sugar balance in rats

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Abstract

ICV citrate injection resulted in significant reductions in food intake and weight gain compared to control groups.

ICV citrate injection decreased food intake and weight gain, showing a possible role in energy mobilization.
Citrate injection led to an 80% reduction in hypothalamic ACC phosphorylation, a key component of the energy regulation pathway.
During fasting, citrate treatment reduced hypothalamic AMPK phosphorylation by 75%, indicating a potential impact on energy expenditure.
ICV citrate resulted in lower blood glucose levels during glucose tolerance tests and enhanced glucose uptake during clamp studies.
Liver glycogen content was significantly higher in citrate-treated animals compared to controls (23.3 vs. 2.7 microg mL(-1) mg(-1)).
Citrate treatment reduced liver AMPK phosphorylation by 80%, and blocking beta3-adrenergic receptors negated its effects on AMPK.

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The hypothalamic AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) pathway is known to play an important role in the control of food intake and energy expenditure. Here, we hypothesize that citrate, an intermediate metabolite, activates hypothalamic ACC and is involved in the control of energy mobilization. Initially, we showed that ICV citrate injection decreased food intake and diminished weight gain significantly when compared to control and pair-fed group results. In addition, we showed that intracerebroventricular (ICV) injection of citrate diminished (80% of control) the phosphorylation of ACC, an important AMPK substrate. Furthermore, citrate treatment inhibited (75% of control) hypothalamic AMPK phosphorylation during fasting. In addition to its central effect, ICV citrate injection led to low blood glucose levels during glucose tolerance test (GTT) and high glucose uptake during hyperglycemic-euglycemic clamp. Accordingly, liver glycogen content was higher in animals given citrate (ICV) than in the control group (23.3+/-2.5 vs. 2.7+/-0.5 microg mL(-1) mg(-1), respectively). Interestingly, liver AMPK phosphorylation was reduced (80%) by the citrate treatment. The pharmacological blockade of beta3-adrenergic receptor (SR 59230A) blocked the effect of ICV citrate and citrate plus insulin on liver AMPK phosphorylation. Consistently with these results, rats treated with citrate (ICV) presented improved insulin signal transduction in liver, skeletal muscle, and epididymal fat pad. Similar results were obtained by hypothalamic administration of ARA-A, a competitive inhibitor of AMPK. Our results suggest that the citrate produced by mitochondria may modulate ACC phosphorylation in the hypothalamus, controlling food intake and coordinating a multiorgan network that controls glucose homeostasis and energy uptake through the adrenergic system.

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Citrate diminishes hypothalamic acetyl-CoA carboxylase phosphorylation and modulates satiety signals and hepatic mechanisms involved in glucose homeostasis in rats

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