Circadian Rhythm of Clock Genes in Human Adipose Explants

Abstract

To analyze in severely obese women the circadian expression of the clock genes hPer2, hBmal1, and hCry1 in explants from subcutaneous (SAT) and visceral (VAT) adipose tissue (AT), in order to elucidate whether this circadian clockwork can oscillate accurately and independently of the suprachiasmatic nucleus (SCN) and if glucocorticoid metabolism-related genes such as glucocorticoid receptor (hGr) and 11β-hydroxysteroid dehydrogenase 1 (h11β5Hsd1) and the transcription factor peroxisome proliferator activated receptor γ (hPPARγ) are part of the clock controlled genes. AT biopsies were obtained from morbid obese patients (BMI >40 kg/m2) (n = 7). Anthropometric variables were measured and fasting plasma lipids and lipoprotein concentrations were analyzed. In order to carry out rhythmic expression analysis, AT explants were cultured during 24 h and gene expression was performed at the following times (T): 0, 6, 12, and 18 h, with quantitative real-time PCR. Clock genes oscillated accurately and independently of the SCN in AT explants. Their intrinsic oscillatory mechanism regulated the timing of other genes such as hPPARγ and glucocorticoid-related genes. Circadian patterns differed between VAT and SAT. Correlation analyses between the genetic circadian oscillation and components of the metabolic syndrome (MetS) revealed that subjects with a higher sagittal diameter showed an increased circadian variability in hPer2 expression (r = 0.91; P = 0.031) and hBmal1 (r = 0.90; P = 0.040). Data demonstrate the presence of peripheral circadian oscillators in human AT independently of the central circadian control mechanism. This knowledge paves the way for a better understanding of the circadian contribution to medical conditions such as obesity and MetS.

Activity/inactivity circadian rhythm shows high similarities between young obesity-induced rats and old rats

“…In recent years, it has been reported that some functions of adipose tissue follow a rhythmic pattern which give to this tissue the role of peripheral oscillator (29,32). Leptin hormone is produced by adipose tissue as a function of fat stores, i.e., after release by the adipose tissue, leptin provides signals to the brain giving information about the status of the body's energy stores (43).…”

Endocrine, Lifestyle, and Genetic Factors in the Development of Metabolic Syndrome

“…GomezAbellan et al (60) demonstrated Clock genes in human adipose tissue and their association with MetS. In the next study (61), the same authors confi rmed that peripheral Clock genes (hPer2, hBmal1, and hCry1) in explants of adipose tissue in morbidly obese women oscillated accurately and independently of the SCN. They also observed that peripheral Clock genes controlled the timing of GR and 11β-HSD1 genes, and that this intracellular circadian clock could independently regulate peripheral cell functions.…”

Circadian rhythms and clocks in adipose tissues: current insights

“…[19][20][21][22][23][24] In line with this, several hundreds of genes display a diurnal expression rhythm in the adipose tissue of rodent 4,17,25,26 and human, 21 some of which are involved in core adipose functions such as lipolysis, adipogenesis, and metabolic inflammation (detailed genes are specified in Figure 2). 18,21,25 The role of the circadian clock machinery in adipocyte physiology has been described in both in vitro and in animal studies.…”