d-Alanine Affects the Circadian Clock to Regulate Glucose Metabolism in Kidney.
Journal
Kidney360
ISSN: 2641-7650
Titre abrégé: Kidney360
Pays: United States
ID NLM: 101766381
Informations de publication
Date de publication:
15 Dec 2023
15 Dec 2023
Historique:
received:
22
09
2023
accepted:
07
12
2023
medline:
15
12
2023
pubmed:
15
12
2023
entrez:
15
12
2023
Statut:
aheadofprint
Résumé
The aberrant glucose circadian rhythm is associated with the pathogenesis of diabetes. Similar to glucose metabolism in kidney and liver, d-alanine, a rare enantiomer of alanine, shows circadian alteration, although the effect of d-alanine on glucose metabolism has not been explored. Here we show that d-alanine acts on the circadian clock and affects glucose metabolism in the kidney. The blood and urinary levels of d-alanine in mice were measured using two-dimensional high performance liquid chromatography system. Metabolic effects of d-alanine were analysed in mice and in primary culture of kidney proximal tubular cells from mice. Behavioural and gene expression analyses of circadian rhythm were performed using mice bred under constant darkness. d-Alanine levels in blood exhibited a clear intrinsic circadian rhythm. Since this rhythm was regulated by the kidney through urinary excretion, we examined the effect of d-alanine on kidney. In kidney, d-alanine induced expressions of genes involved in gluconeogenesis and circadian rhythm. Treatment of d-alanine mediated glucose production in mice. Ex vivo glucose production assay demonstrated that treatment of d-alanine induced glucose production in primary culture of kidney proximal tubular cells, where d-amino acids are known to be reabsorbed, but not in that of liver cells. Gluconeogenetic effect of d-alanine has an intraday variation, and this effect was in part mediated through circadian transcriptional network. Under constant darkness, treatment of d-alanine normalized the circadian cycle of behaviour and kidney gene expressions. d-Alanine induces gluconeogenesis in the kidney and adjusts the period of the circadian clock. Normalization of circadian cycle by d-alanine may provide the therapeutic options for life style-related diseases and shift workers.
Sections du résumé
BACKGROUND
BACKGROUND
The aberrant glucose circadian rhythm is associated with the pathogenesis of diabetes. Similar to glucose metabolism in kidney and liver, d-alanine, a rare enantiomer of alanine, shows circadian alteration, although the effect of d-alanine on glucose metabolism has not been explored. Here we show that d-alanine acts on the circadian clock and affects glucose metabolism in the kidney.
METHODS
METHODS
The blood and urinary levels of d-alanine in mice were measured using two-dimensional high performance liquid chromatography system. Metabolic effects of d-alanine were analysed in mice and in primary culture of kidney proximal tubular cells from mice. Behavioural and gene expression analyses of circadian rhythm were performed using mice bred under constant darkness.
RESULTS
RESULTS
d-Alanine levels in blood exhibited a clear intrinsic circadian rhythm. Since this rhythm was regulated by the kidney through urinary excretion, we examined the effect of d-alanine on kidney. In kidney, d-alanine induced expressions of genes involved in gluconeogenesis and circadian rhythm. Treatment of d-alanine mediated glucose production in mice. Ex vivo glucose production assay demonstrated that treatment of d-alanine induced glucose production in primary culture of kidney proximal tubular cells, where d-amino acids are known to be reabsorbed, but not in that of liver cells. Gluconeogenetic effect of d-alanine has an intraday variation, and this effect was in part mediated through circadian transcriptional network. Under constant darkness, treatment of d-alanine normalized the circadian cycle of behaviour and kidney gene expressions.
CONCLUSIONS
CONCLUSIONS
d-Alanine induces gluconeogenesis in the kidney and adjusts the period of the circadian clock. Normalization of circadian cycle by d-alanine may provide the therapeutic options for life style-related diseases and shift workers.
Identifiants
pubmed: 38098136
doi: 10.34067/KID.0000000000000345
pii: 02200512-990000000-00306
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.