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

Dec 2, 2017Acta physiologica (Oxford, England)

Palmitate, a saturated fat, reduces daily release of the hormone glucagon-like peptide-1

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Abstract

Pre-treatment with palmitate reduced glucagon-like peptide-1 secretion by dampening Bmal1 expression and impairing mitochondrial function.

Palmitate pre-treatment decreased Bmal1 mRNA and protein expression at 8 hours after synchronization.
Glucagon-like peptide-1 release was significantly lower in Bmal1 knockout cultures compared to wild-type controls.
Palmitate reduced the expression of nicotinamide phosphoribosyltransferase, affecting NAD synthesis.
Total NAD levels were diminished, along with impaired mitochondrial function and ATP production.
Inhibition of nicotinamide phosphoribosyltransferase decreased glucagon-like peptide-1 release, while its activation restored secretion in the presence of palmitate.

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AIM: Glucagon-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.

METHODS: Murine 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.

RESULTS: Pre-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 NADlevels, 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. + +

CONCLUSION: Palmitate 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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Suppression of circadian secretion of glucagon‐like peptide‐1 by the saturated fatty acid, palmitate

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