Abstract
Leucine has been shown to acutely inhibit hepatic glucose production in rodents by a mechanism requiring its metabolism to acetyl-CoA in the mediobasal hypothalamus (MBH). In the early stages, all branched-chain amino acids (BCAA) are metabolized by a shared set of enzymes to produce a ketoacid, which is later metabolized to acetyl-CoA. Consequently, isoleucine and valine may also modulate glucose metabolism. To examine this possibility we performed intrahypothalamic infusions of isoleucine or valine in rats and assessed whole body glucose kinetics under basal conditions and during euglycemic pancreatic clamps. Furthermore, because high fat diet (HFD) consumption is known to interfere with central glucoregulation, we also asked whether the action of BCAAs was affected by HFD. We fed rats a lard-rich diet for a short interval and examined their response to central leucine. The results showed that both isoleucine and valine individually lowered blood glucose by decreasing liver glucose production. Furthermore, the action of the BCAA leucine was markedly attenuated by HFD feeding. We conclude that all three BCAAs centrally modulate glucose metabolism in the liver and that their action is disrupted by HFD-induced insulin resistance.
Highlights
Excessive calorie intake resulting from the consumption of fat-rich diets is the most important environmental factor contributing to the emergence and worsening of the current world pandemic of diabetes and obesity [1,2]
We have shown that the metabolism of leucine to acetyl-CoA in the mediobasal hypothalamus (MBH) is coupled to the inhibition of endogenous glucose production (EGP) and a consequent decrease of circulating glucose levels [16]
During the clamps, when glucose and insulin levels in circulation are kept constant, both isoleucine and valine individually produced a marked increase in the glucose infusion rate (GIR) required to maintain euglycemia compared to vehicle (Figure 3A)
Summary
Excessive calorie intake resulting from the consumption of fat-rich diets is the most important environmental factor contributing to the emergence and worsening of the current world pandemic of diabetes and obesity [1,2]. Mammals have developed complex mechanisms for detecting changes in the availability of nutrients and responding to them with metabolic adaptations to maintain homeostasis. Dietary protein and amino acids (AA) exert a powerful influence on insulin action and glucose metabolism. The mechanisms underlying this effect are generally attributed to the metabolic actions of AAs in the liver and skeletal muscle [7,8,9,10,11,12,13]. A number of metabolic actions of AAs have been localized to the MBH of rodents [14,15,16,17]. Leucine is transaminated to α-KIC by the Nutrients 2016, 8, 79; doi:10.3390/nu8020079 www.mdpi.com/journal/nutrients
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