Diurnal variation in PDK4 expression is associated with plasma free fatty acid availability in people.

Diurnal variation in PDK4 expression is associated with plasma free fatty acid availability in people.

J Clin Endocrinol Metab. 2017 Dec 26;:

Authors: Yamaguchi S, Moseley AC, Almeda-Valdes P, Stromsdorfer KL, Franczyk MP, Okunade AL, Patterson BW, Klein S, Yoshino J

Abstract
Context: Many biological pathways involved in regulating substrate metabolism display rhythmic oscillation patterns over a 24-hour period. In rodents, clock genes regulate circadian rhythms of metabolic genes and substrate metabolism. However, the inter-relationships among substrate metabolism, metabolic genes, and clock genes have not been fully explored in people.
Objective: We tested the hypothesis that diurnal expression pattern of pyruvate dehydrogenase kinase 4 (PDK4), a key metabolic enzyme involved in fuel switching between glucose and free fatty acids (FFA), is associated with plasma FFA concentration and clock genes.
Design and Methods: We analyzed peripheral blood mononuclear cells (PBMC), subcutaneous adipose tissue, and plasma samples obtained serially over 24 h from metabolically-healthy women (n=10, BMI=28.0 ± 1.1) and evaluated the inter-relationships among PDK4, plasma FFA, and clock genes. We also determined the potential mechanisms responsible for PDK4 transcriptional regulation by using primary human PBMC and adipocytes.
Results: We found PDK4 diurnal expression patterns were similar in PBMC and adipose tissue (ρ=0.84, P<0.001). The diurnal variation in PBMC PDK4 expression correlated more strongly with plasma FFA (ρ=0.86, P<0.001) and insulin (ρ=0.63, P<0.001) concentrations than clock genes. Data obtained from primary human PBMC and adipocyte culture experiments demonstrated that FFA directly induced PDK4 gene expression (P<0.001), at least in part, through activation of peroxisome proliferator-activated receptor alpha (PPAR-α).
Conclusions: Our results suggest that plasma FFA availability is an important regulator of diurnal expression patterns of PDK4, and identify a novel interaction between plasma FFA and cellular diurnal rhythms in regulating substrate metabolism.

PMID: 29294006 [PubMed - as supplied by publisher]

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