Abstract
Brain pathways, including those in hypothalamus and nucleus of the solitary tract, influence food intake, nutrient preferences, metabolism and development of obesity in ways that often differ between males and females. Branched chain amino acids, including leucine, can suppress food intake, alter metabolism and change vulnerability to obesity. The SLC6A15 (v7-3) gene encodes a sodium-dependent transporter of leucine and other branched chain amino acids that is expressed by neurons in hypothalamus and nucleus of the solitary tract. We now report that SLC6A15 knockout attenuates leucine's abilities to reduce both: a) intake of normal chow and b) weight gain produced by access to a high fat diet in gender-selective fashions. We identify SNPs in the human SLC6A15 that are associated with body mass index and insulin resistance in males. These observations in mice and humans support a novel, gender-selective role for brain amino acid compartmentalization mediated by SLC6A15 in diet and obesity-associated phenotypes.
Highlights
Amino acids can influence weight control by mechanisms that include enhanced postprandial and post absorptive satiety [1,2], energy expenditure [3,4] and insulin action [5,6]
We report use of these knockout mice to assess roles for SLC6A15 in regulation of food intake and body weight by dietary leucine in male and female mice fed a high fat diet
WT and KO females displayed similar effects of leucine on calorie consumption (Figure 1B; analysis of variance (ANOVA) effect of leucine p = 0.063; leucine * genotype p = 0.354). We noted that both KO males and females consumed significantly more fluids; this difference was further exacerbated by leucine supplementation (Figure S1)
Summary
Amino acids can influence weight control by mechanisms that include enhanced postprandial and post absorptive satiety [1,2], energy expenditure [3,4] and insulin action [5,6]. Interest in the ways in which amino acids influence nutrition and body weight is boosted by increasing rates of obesity [9,10] and elucidation of some of the genetic influences on these processes [11,12,13,14,15]. Essential branched-chain amino acids (BCAA), including leucine, constitute up to 20% of dietary protein and make significant contributions to the influences of protein on body weight [16]. Hypothalamic concentrations of BCAA rise rapidly after protein ingestion [17,18]. Dietary administration of leucine or mixtures of BCAA increase thermogenesis, augment protein synthesis and alter insulin actions [6,19,20]. Leucine administered into the brain decreases food intake and body weight while increasing hypothalamic signaling through mTOR pathways [21,22]. Firing rates of key arcuate/mediobasal hypothalamic neurons increase promptly upon application of leucine in ways that correspond to increased cFos expression in these hypothalamic neurons and interconnected neurons of the nucleus of the solitary tract [22]
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