Expression profile of mRNAs encoding core circadian regulatory proteins in human subcutaneous adipose tissue: correlation with age and body mass index

Abstract

Objective Circadian mechanisms underlie the physiology of mammals as an adaptation to the earth’s rotation on its axis. Highly conserved core circadian regulatory proteins (CCRP) maintain an oscillatory expression profile in the central and peripheral tissues. The CCRP include both a positive and negative arm as well as downstream transcriptional regulators. Recent studies in murine models have determined that the mRNAs encoding the CCRP are present in multiple adipose tissue depots and exhibit a robust oscillatory expression profile. The current study set out to examine the expression of CCRP mRNAs in human subcutaneous adipose tissues. Design Retrospective analysis of total RNA isolated from subcutaneous adipose tissue. Subjects 150 healthy female and male lean (BMI < 25), overweight (BMI between 25 and 29.99) or obese (BMI >30) subjects of varied ethnic backgrounds undergoing elective liposuction or surgical procedures. Results The expression of the CCRP mRNAs displayed a significant correlation between each other and mRNAs representative of adipogenic biomarkers. Hierarchical cluster analyses of mRNAs isolated from the cohort of female Caucasian subjects (n = 116) identified three major clusters based on expression of downstream CCRP mRNAs. The mRNAs encoding D site of albumin promoter binding protein (DBP), E4 promoter binding protein 4 (E4BP4), PPARγ Co-Activator 1β (PGC-1β), and Rev-erb α were negatively correlated with BMI in a lean cluster (n = 66), positively correlated with BMI in a younger overweight/obese cluster (n = 19), and not significantly correlated with BMI in an older, overweight/obese cluster (n = 31). Conclusions These data confirm and extend findings that link the CCRP and circadian mechanisms to the risk of obesity.

Transcriptional Repressor E4-binding Protein 4 (E4BP4) Regulates Metabolic Hormone Fibroblast Growth Factor 21 (FGF21) during Circadian Cycles and Feeding

“…Several studies have presented data showing that the levels of E4BP4 and its circadian counterpart DBP are correlated to body mass index in humans, and their levels change in high fat diet-fed animals (77,78). Interestingly, Fgf21 also shows dysregulation in those conditions.…”

Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals

“…Finally, genome-wide association studies indicate that polymorphisms in the melatonin receptors MTNR1A and MTNR1B, which are expressed not only in the SCN but also in many peripheral tissues, are linked to increased plasma glucose levels and risk of type 2 diabetes (Bouatia-Naji et al, 2009;Lyssenko et al, 2009;Prokopenko et al, 2009). Altered oscillations of mRNAs encoding circadian regulatory proteins within human subcutaneous adipose tissue are correlated with increased risk of obesity (Wu et al, 2009). Specifically, CLOCK gene polymorphisms are associated with metabolic syndrome, whereas REV-ERBa polymorphisms seem to modulate adiposity in both adult and young people (Garaulet and Madrid, 2009;Goumidi et al, 2013).…”

Clock Genes and Clock-Controlled Genes in the Regulation of Metabolic Rhythms

“…Moreover, the oscillation of clock gene expression within human adipocytes and the correlation between altered clock gene expression and obesity in humans (Wu et al, 2009) impinge on the links between chronotype, clock genotype, and metabolic pathways and on the mechanisms of metabolic derangement in animal models and humans. (i) Obesity induced by high-fat/high-calorie diet alters the clock gene machinery in mouse adipose tissue and liver, suggesting that obesity and metabolic syndrome are highly correlated with the expression of circadian clock genes (Hsieh et al, 2010;Kohsaka et al, 2007).…”