Suppression of circadian secretion of glucagon-like peptide-1 by the saturated fatty acid, palmitate

被引:39
作者
Martchenko, A. [1 ]
Oh, R. H. [1 ]
Wheeler, S. E. [1 ]
Gurges, P. [1 ]
Chalmers, J. A. [1 ]
Brubaker, P. L. [1 ,2 ]
机构
[1] Univ Toronto, Dept Physiol, Toronto, ON, Canada
[2] Univ Toronto, Dept Med, Toronto, ON, Canada
基金
加拿大健康研究院;
关键词
Bmal1; exocytosis; GLP-1; mitochondrial metabolism; Nampt; DIET-INDUCED OBESITY; INSULIN-SECRETION; GENE-EXPRESSION; CLOCK GENES; METABOLISM; RHYTHMS; STRESS; CYCLE; BMAL1; GLP-1;
D O I
10.1111/apha.13007
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
AimGlucagon-like peptide-1 is an incretin hormone secreted by the intestinal L-cell with a circadian rhythm that parallels expression of the core clock gene, Bmal1. Although feeding rats a high-fat/high-sucrose Western diet impairs rhythmic glucagon-like peptide-1 release, the mechanisms underlying this effect remain unclear. Therefore, the aim of this study was to determine the pathway(s) by which the saturated fat, palmitate, a major component of the Western diet, impairs circadian glucagon-like peptide-1 secretion. MethodsMurine mGLUTag L-cells were synchronized, and the effects of palmitate pre-treatment on gene expression and glucagon-like peptide-1 secretion were determined, in addition to metabolite quantification, mitochondrial function analysis and enzyme inhibition and activation assays. Glucagon-like peptide-1 secretion was also analysed in ileal crypt cultures from control and Bmal1 knockout mice. ResultsPre-treatment with palmitate dampened Bmal1 mRNA and protein expression and glucagon-like peptide-1 secretion at 8 but not 20 hours after cell synchronization (P < .05-.001). Glucagon-like peptide-1 release was also impaired in Bmal1 knockout cultures as compared to wild-type controls (P < .001). Palmitate pre-treatment reduced expression of the Bmal1 downstream target, nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in the synthesis of NAD(+). This was paralleled by dampening of total NAD(+) levels, as well as impaired mitochondrial function and ATP production (P < .05-.001). Whereas direct inhibition of nicotinamide phosphoribosyltransferase also decreased glucagon-like peptide-1 release, activation of this enzyme restored glucagon-like peptide-1 secretion in the presence of palmitate. ConclusionPalmitate impairs L-cell clock function at the peak of Bmal1 gene expression, thereby impairing mitochondrial function and ultimately rhythmic glucagon-like peptide-1 secretion.
引用
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页数:12
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