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

Martchenko, Alexandre; Oh, Robin H.; Wheeler, Sarah E.; Gurges, Patrick; Chalmers, J. P.; Brubaker, Patricia L.

doi:10.1111/apha.13007

Cited by 35 publications

(61 citation statements)

References 56 publications

(112 reference statements)

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“…Moreover, the genetic variant is localized near the regulatory region for Acyl-CoA Synthetase Long Chain 5 (ACSL5) which activates fatty acids to generate long chain fatty acyl CoA [45]. Consistent with our model, Martchenko and colleagues [46] have recently reported fatty acid-induced lowering of circadian release of GLP-1 from L-cells as a result of decreased Bmal1 expression. Similarly, Filipello et al [47] reported decreased insulin-dependent GLP-1 secretion from L-cell-derived GLUTag cells, and increased glucagon release, upon fatty acid treatment.…”

Section: Discussionsupporting

confidence: 84%

Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

Nguyen-Tu

Martínez-Sánchez

Leclerc

et al. 2020

Preprint

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Transcription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/beta-catenin signalling pathway and its expression is critical for adipocyte development. The precise role of TCF7L2 in glucose and lipid metabolism in adult adipocytes remains to be defined. Here, we aim to investigate how changes in TCF7L2 expression in mature adipocytes affect glucose homeostasis. Tcf7l2 was selectively ablated from mature adipocytes in C57BL/6J mice using an adiponectin promoter-driven Cre recombinase to recombine alleles floxed at exon 1 of the Tcf7l2 gene. Mice lacking Tcf7l2 in mature adipocytes displayed normal body weight. Male mice exhibited normal glucose homeostasis at eight weeks of age. Male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance (AUC increased 1.14 ± 0.04 -fold, p=0.03), as assessed by intraperitoneal glucose tolerance test, and changes in fat mass at 16 weeks (increased by 1.4 ± 0.09-fold, p=0.007). Homozygote knockout mice exhibited impaired oral glucose tolerance at 16 weeks of age (AUC increased 2.15 ± 0.15-fold, p=0.0001). Islets of Langerhans exhibited impaired glucose-stimulated insulin secretion in vitro (decreased 0.54 ± 0.13-fold aTCF7L2KO vs control, p=0.02), but no changes in in vivo glucosestimulated insulin secretion. Female mice in which one or two alleles of the Tcf7l2 gene was knocked out in adipocytes displayed no changes in glucose tolerance, insulin sensitivity or insulin secretion.Plasma levels of glucagon-like peptide-1 and gastric inhibitory polypeptide were lowered in knockout mice (decreased 0.57 ± 0.03-fold and 0.41 ± 0.12-fold, p=0.04 and p=0.002, respectively), whilst plasma free fatty acids and Fatty Acid Binding Protein 4 circulating levels were increased by 1.27 ± 0.07 and 1.78 ± 0.32-fold, respectively (p=0.05 and p=0.03). Mice with biallelic Tcf7l2 deletion exposed to high fat diet for 9 weeks exhibited impaired glucose tolerance (p=0.003 at 15 min after glucose injection) which was associated with reduced in vivo glucose-stimulated insulin secretion (decreased 0.51 ± 0.03-fold, p=0.02). Thus, our data indicate that loss of Tcf7l2 gene expression in adipocytes leads to impairments on metabolic responses which are dependent on gender, age and nutritional status. Our findings further illuminate the role of TCF7L2 in the maintenance of glucose homeostasis.

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Section: Discussionsupporting

confidence: 84%

Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

Nguyen-Tu

Martínez-Sánchez

Leclerc

et al. 2020

Preprint

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“…However, the in vivo situation, where different neural and endocrine signals, central and local, are simultaneously reaching the islet cells, is highly complex to dissect (Figure B). Rhythmic blood levels reported for most of the hormones including insulin, glucagon, GLP1, adrenalin and corticosteroids, in combination with feeding rhythms, add additional complexity levels to this puzzle.…”

Section: Zooming Into the Pancreatic Islet Clock: Molecular Oscillatomentioning

confidence: 99%

Time zones of pancreatic islet metabolism

Petrenko

Philippe

Dibner

2018

Diabetes Obesity Metabolism

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Most living beings possess an intrinsic system of circadian oscillators, allowing anticipation of the Earth's rotation around its own axis. The mammalian circadian timing system orchestrates nearly all aspects of physiology and behaviour. Together with systemic signals originating from the central clock that resides in the hypothalamic suprachiasmatic nucleus, peripheral oscillators orchestrate tissue-specific fluctuations in gene transcription and translation, and posttranslational modifications, driving overt rhythms in physiology and behaviour. There is accumulating evidence of a reciprocal connection between the circadian oscillator and most aspects of physiology and metabolism, in particular as the circadian system plays a critical role in orchestrating body glucose homeostasis. Recent reports imply that circadian clocks operative in the endocrine pancreas regulate insulin secretion, and that islet clock perturbation in rodents leads to the development of overt type 2 diabetes. While whole islet clocks have been extensively studied during the last years, the heterogeneity of islet cell oscillators and the interplay between α- and β-cellular clocks for orchestrating glucagon and insulin secretion have only recently gained attention. Here, we review recent findings on the molecular makeup of the circadian clocks operative in pancreatic islet cells in rodents and in humans, and focus on the physiologically relevant synchronizers that are resetting these time-keepers. Moreover, the implication of islet clock functional outputs in the temporal coordination of metabolism in health and disease will be highlighted.

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“…[40][41][42][43][44] The ability of kinetic models to take into account time dependent input in plasma nutrient and hormone composition as well as protein abundances, enables the time-dependent computational assessment of organ functions even in such highly dynamic situations, something that cannot be achieved with other modelling methods like statistical modelling or flux balance models. These are subjected to considerable diurnal variation and constitute a network, where individual habit, gene expression, hormone release and metabolite levels are interdependent.…”

mentioning

confidence: 99%

“…These are subjected to considerable diurnal variation and constitute a network, where individual habit, gene expression, hormone release and metabolite levels are interdependent. [40][41][42][43][44] The ability of kinetic models to take into account time dependent input in plasma nutrient and hormone composition as well as protein abundances, enables the time-dependent computational assessment of organ functions even in such highly dynamic situations, something that cannot be achieved with other modelling methods like statistical modelling or flux balance models. 45…”

mentioning

confidence: 99%

Metabolic modelling of kidney diseases: Lessons learned from the liver

2019

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

Abstract: 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.

Cited by 35 publications

References 56 publications

Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

Time zones of pancreatic islet metabolism

Metabolic modelling of kidney diseases: Lessons learned from the liver

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