gsk4112 and Obesity

Disruption of the circadian rhythm is a contributory factor to clinical and pathophysiological conditions, including cancer, the metabolic syndrome, and inflammation. Chronic and systemic inflammation are a potential trigger of type 2 diabetes and cardiovascular disease and are caused by the infiltration of large numbers of inflammatory macrophages into tissue. Although recent studies identified the circadian clock gene Rev-erbα, a member of the orphan nuclear receptors, as a key mediator between clockwork and inflammation, the molecular mechanism remains unknown. In this study, we demonstrate that Rev-erbα modulates the inflammatory function of macrophages through the direct regulation of Ccl2 expression. Clinical conditions associated with chronic and systemic inflammation, such as aging or obesity, dampened Rev-erbα gene expression in peritoneal macrophages from C57BL/6J mice. Rev-erbα agonists or overexpression of Rev-erbα in the murine macrophage cell line RAW264 suppressed the induction of Ccl2 following an LPS endotoxin challenge. We discovered that Rev-erbα represses Ccl2 expression directly through a Rev-erbα-binding motif in the Ccl2 promoter region. Rev-erbα also suppressed CCL2-activated signals, ERK and p38, which was recovered by the addition of exogenous CCL2. Further, Rev-erbα impaired cell adhesion and migration, which are inflammatory responses activated through the ERK- and p38-signaling pathways, respectively. Peritoneal macrophages from mice lacking Rev-erbα display increases in Ccl2 expression. These data suggest that Rev-erbα regulates the inflammatory infiltration of macrophages through the suppression of Ccl2 expression. Therefore, Rev-erbα may be a key link between aging- or obesity-associated impairment of clockwork and inflammation.

Topics: Age Factors; Animals; Cell Adhesion; Cell Line; Cell Movement; Chemokine CCL2; Circadian Clocks; Gene Expression; Gene Expression Regulation; Glycine; Inflammation; Integrin beta1; Lipopolysaccharides; Macrophages; Macrophages, Peritoneal; Male; Mice; Mice, Knockout; Nuclear Receptor Subfamily 1, Group D, Member 1; Nuclear Receptor Subfamily 1, Group F, Member 1; Obesity; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Response Elements; Thiophenes; Transcriptional Activation; Vascular Cell Adhesion Molecule-1

Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.

Topics: Adipose Tissue; Animals; Biological Clocks; Circadian Rhythm; Disease Models, Animal; Energy Metabolism; HEK293 Cells; Humans; Hypothalamus; Liver; Metabolome; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muscle, Skeletal; Nuclear Receptor Subfamily 1, Group D, Member 1; Obesity; Pyrrolidines; Receptors, Cytoplasmic and Nuclear; Repressor Proteins; Thiophenes