Journal
ACTA PHYSIOLOGICA
Volume 222, Issue 4, Pages -Publisher
WILEY
DOI: 10.1111/apha.13007
Keywords
Bmal1; exocytosis; GLP-1; mitochondrial metabolism; Nampt
Categories
Funding
- Canadian Institutes of Health Research (CIHR) [PJT-15308]
- Ontario Graduate Scholarship (OGS) programme
- Banting and Best Diabetes Centre, University of Toronto (BBDC)
- Banting Research Foundation
- Canada Research Chairs Program
- Canadian Diabetes Association [OG-3-13-4024]
- Canadian Foundation for Innovation [19442]
- Ontario Research Fund [30961]
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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.
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