Chronobiology and Obesity: The Orchestra Out of Tune

Marta Garaulet; Purificación Gómez-Abellán; Juan Antonio Madrid

Disclosures

Clin Lipidology. 2010;5(2):181-188. 

In This Article

Adipose Tissue Changes during the Day

The core clock mechanism has been shown to be linked with lipogenic and adipogenic pathways; key metabolic enzymes in adipose tissue and transcription activators related to lipid metabolism interact with and affect the core clock mechanism; moreover, the circadian clock is influenced by hormones, nutrients and timed meals.[38] In this sense, one of the most important questions related to the circadian system and obesity was to elucidate whether adipose tissue displayed circadian rhythmicity or whether it had an internal peripheral clock. Analysis of murine adipose tissue revealed robust 24-h rhythms of clock gene expression. The relative phasing of genes in adipose tissue is consistent with SCN rhythms and the molecular model of the circadian clock.[33,39] Moreover, the use of microarrays suggests that up of 20% of the murine and the human adipose transcriptome is expressed according to a diurnal rhythm.[10,39,40] Different studies have already demonstrated the circadian rhythm of adipocyte-secreted proteins in adipose tissue from experimental models[41] and in human serum.[8]

In vitro, we have recently investigated rhythmic gene expression in explants of human white adipose tissue. Visceral and subcutaneous adipose tissue was removed from obese subjects, kept in tissue culture conditions overnight and then analyzed every 6 h over a 24-h period.[6] Clock genes oscillated accurately and independently of the suprachiasmatic nucleus in adipose tissue explants (Figure 2). Their intrinsic oscillatory mechanism appeared to coordinate the timing of other genes such as hPpar and glucocorticoid-related genes. Circadian patterns differed between visceral adipose tissue and subcutaneous adipose tissue.

Figure 2.

Rhythmic expression of clock genes (hPer2, hBmal1 and hCry1) in human subcutaneous and visceral adipose tissue. (A)hPer2, (B)hBmal1 and (C)hCry1. Adipose depots were isolated at 6-h intervals over the course of the day from adipose tissue cultures (time at 0, 6, 12 and 18 h). Results are presented relative to the lowest basal relative expression for each gene.
Data are reported as means ± standard error of the mean (SEM). SEM of differences in cycle threshold are represented in parenthesis.
AU: Arbitrary unit.
Adapted from [5].

With respect to the circadian rhythmicity of adipocytokines, it has been demonstrated that adiponectin, resistin, visfatin and leptin rhythms are attenuated with obesity in experimental models.[33] Recently, our own group has demonstrated that the mRNA expression profiles of adiponectin and its receptors (ADIPOR1 and ADIPOR2) clearly showed 24-h rhythms in human subcutaneous and visceral adipose tissue explants from morbidly obese patients. In this same study, adiposity was associated with CD. Indeed, correlation analyses between the genetic circadian oscillation and components of the metabolic syndrome revealed that adiposity and abdominal obesity correlated with a decrease in adiponectin and adiponectin-receptor amplitude.[42] Another example of the possible association between CD and obesity is related to the circadian rhythmicity of the enzyme lipoprotein lipase (LPL). This enzyme has been related to the accumulation of fatty acids in adipocytes. In normal conditions, LPL displays a circadian rhythmicity, in which the maximal expression coincides with meal times; this situation facilitates the accumulation of fat in adipose tissue. However, if meals occur out of phase with LPL expression levels, the individual may be prone to storing circulating FFA in ectopic tissues, producing lipotoxicity and, as a consequence hepatic, muscular or pancreatic comorbidities and the metabolic syndrome (MetS).[43] Overall, these data indicate the importance of the time of day in adipose tissue function and the functional relationship between metabolic state and the phasing and robustness of adipose rhythms.

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