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  • In the present study we observed a decrease in


    In the present study, we observed a decrease in body weight gain in Tg rats. It is uncertain whether this effect is due to Denr, Gpr81, or Gpr109a. In this regard, Gpr81 mice have been reported to have reduced body weight gain [28]. Moreover, a small clinical study has reported that obese patients taking nicotinic calmodulin dependent protein kinase had decreased body weight [42]. Thus, although further studies are required to investigate this mechanism, the body weight-lowering effect of nicotinic acid might be partially the result of inducing GPR109A signaling. In recent large clinical studies, AIM-HIGH and HPS2-THRIVE, the additional treatment of nicotinic acid to statin-based LDL-C lowering therapy did not decrease the major vascular events on the patients who had atherosclerotic vascular diseases [43,44]. In the AIM-HIGH study, the secondary analysis showed a trend of decreased cardiovascular events in patients who have both high TG (≥198 mg/dL) and low HDL-C (<33 mg/dL) [45]. Therefore, nicotinic acid has a potential to treat such type of patients. To date, however, there are no reported GPR109A agonists that can induce clinically meaningful changes in LDL-C and HDL-C. Hence, whether GPR109A agonist could decrease the cardiovascular events is unclear. Meanwhile, considering our data and the result of GSK256073 in clinical study where about 36% plasma TG reduction was shown, GPR109A agonist could induce plasma TG lowering. Based on the preferable involvement of GPR109A on the glucose metabolism, GPR109A agonist may be a therapy for metabolic syndrome. The question has been raised as to why most GPR109A agonists failed to induce the plasma lipid changes seen with nicotinic acid in clinical studies. Potential reasons are that a rebound in baseline NEFA levels or tachyphylaxis were observed in those studies. Another possible reason is that nicotinic acid may have another molecular target. In this regard, in addition to Dgat2 reduction, nicotinic acid has also been reported to directly inhibit Dgat2 [38], and this might be a contributor to nicotinic acid efficacy. There is also the possibility that GPR109A is the main mediator of nicotinic acid TG-lowering, and it may simply be that the pharmacologic profile of the compound and its dosing regimen might be key factors for TG-lowering efficacy. There is a limitation in our study. The BAC clone used for creating Tg rats contains other genes such as Denr and Gpr81. Although we refered to the possible effects of these genes on the phenotype shown in Tg rats, we could not exclude the possibility that these genes affected the phenotype of Tg rats.
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    Introduction The brain requires large amounts of energy to carry out its functions. Although it only represents 2% of the total human body mass, it consumes up to 20% of the oxygen and 25% of the glucose supply [1]. Cognitive functions, establishment of new memories or motor coordination, to cite some examples, are encoded in form of electrical signals that are propagated within specific neuronal circuits. To ensure that such neuronal circuits operate appropriately, neuronal excitability needs to be exquisitely regulated, and a high supply of energy in form of ATP is needed to support ion pumps and channels that set the threshold for neuronal firing rates. Importantly, deregulation of electrical activity in the brain can lead to neurological disorders, such as epilepsy. Therefore, metabolic flow has to be tightly regulated. Brain cells rely on mitochondria for energy metabolism. In addition to supplying ATP, mitochondria play a central role in brain metabolism by buffering calcium or providing intermediate metabolites as biosynthetic precursors of neurotransmitters. Mitochondria also harbor the machinery in charge of executing programmed cell death or apoptosis. In summary, mitochondria are essential organelles that play a central role in neuronal physiology [2]. Nutrients are channeled into mitochondria to be processed. Glucose is the main fuel of the brain. However, brain cells can utilize alternative substrates as "energy fuels" to yield ATP and meet the high energy demand posed by neuronal electrical activity [3]. Compelling evidence has shown that the choice of select fuels also has an impact on neuronal firing rates [4]. In this review, we will provide a brief overview of some of the mechanisms by which select nutrients and metabolic flow have been proposed to modulate neuronal excitability.