The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal clock system, and sleep, constitute risk factors for disorders including obesity, diabetes mellitus, cardiovascular disease, thrombosis and even inflammation. An exciting aspect of the field has been the integration of behavioral and physiological approaches, and the emerging insight into both neural and peripheral tissues in disease pathogenesis. Consideration of the cell and molecular links between disorders of circadian rhythms and sleep with metabolic syndrome has begun to open new opportunities for mechanism-based therapeutics.

Central-omental obesity plays a causative role in the pathogenesis of the metabolic syndrome. Adipokines are involved in the pathogenesis of this syndrome. However, adipokines secreted by omental adipose tissue (OAT) are still poorly characterized in human obesity. Therefore, we searched for novel adipokines abnormally secreted by OAT in obesity and examined their relationships with some features of metabolic syndrome and the respective contribution of adipocytes vs. stromal-vascular cells. OAT from obese and nonobese men was fractionated into adipocytes and SV cells, which were then cultured. Medium was screened by medium-scale protein arrays and ELISAs. Adipokine mRNA levels were measured by real-time RT-qPCR. We detected 16 cytokines secreted by each cellular fraction of lean and obese subjects. Of the 16 cytokines, six adipokines were newly identified as secretory products of OAT, which were dysregulated in obesity: three chemokines (growth-related oncogen factor, RANTES, macrophage inflammatory protein-1β), one interleukin (IL-7), one tissue inhibitor of metalloproteinases (TIMP-1), and one growth factor (thrombopoietin). Their secretion and expression were enhanced in obesity, with a relatively similar contribution of the two fractions. The higher proportion of macrophages and endothelial cells in obesity may contribute to this enhanced production as well as changes in intrinsic properties of hypertrophied adipocytes. Accordingly, mRNA concentrations of most of these adipokines increased during adipocyte differentiation. Eventually, expression of the investigated adipokines did correlate with several features of the metabolic syndrome. In conclusion, six adipokines were newly identified as oversecreted by OAT in obesity. These adipokines may link obesity to its cardiovascular or metabolic comorbidities.

Circadian timekeeping allows appropriate temporal regulation of an organism’s internal metabolism to anticipate and respond to recurrent daily changes in the environment. Evidence from animal genetic models and from humans under circadian misalignment (such as shift work or jet lag) shows that disruption of circadian rhythms contributes to the development of obesity and metabolic disease. Inappropriate timing of food intake and high-fat feeding also lead to disruptions of the temporal coordination of metabolism and physiology and subsequently promote its pathogenesis. This review illustrates the impact of genetically or environmentally induced molecular clock disruption (at the level of the brain and peripheral tissues) and the interplay between the circadian system and metabolic processes. Here, we discuss some mechanisms responsible for diet-induced circadian desynchrony and consider the impact of nutritional cues in inter-organ communication, with a particular focus on the communication between peripheral organs and brain. Finally, we discuss the relay of environmental information by signal-dependent transcription factors to adjust the timing of gene oscillations. Collectively, a better knowledge of the mechanisms by which the circadian clock function can be compromised will lead to novel preventive and therapeutic strategies for obesity and other metabolic disorders arising from circadian desynchrony.