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Role of the nuclear receptor Rev-erbalpha in lipid and glucose homeostasis and the transduction of circadian signals into metabolic responses

Final Report Summary - GLUCOCLOCK (Role of the nuclear receptor Rev-erbalpha in lipid and glucose homeostasis and the transduction of circadian signals into metabolic responses.)

The increasing incidence of obesity and type 2 diabetes and their medical consequences is becoming a major health problem in the European Community and has a considerable economic and social cost. Importantly, there is an increased incidence of obesity, metabolic syndrome and cardiovascular disease among workers subjected to shifted or fragmented working hours. These observations and many others demonstrate the existence of a causal relationship between rhythm disturbances and metabolic disorders and cardiovascular events. There is therefore an urgent need to understand the basics of these diseases.
At the molecular level, the clock consists in several interlocked feedback loops in which the nuclear receptor Rev-erba plays key roles. Emerging evidence demonstrates that genes of the clock machinery directly influence energy homeostasis and that mutations in clock genes lead to metabolic disorders. In mice, mutations or deletion in clock genes lead to features of the metabolic syndrome. In addition, coordination of circadian and metabolic cycles is suggested by studies showing that cellular redox status, body temperature and abundance of NAD+ and the AMP/ATP ratio drive the clock to gate metabolic reactions to the appropriate time window.
Interestingly, we and others have shown that Rev-erba is involved in lipid metabolism, bile acid synthesis and adipogenesis. In addition, Rev-erba regulates the gluconeogenesis pathway, thereby suggesting a role for Rev-erba in glucose metabolism and in the fasting/refeeding transition. We have also shown that Rev-erba controls NAD+ cellular levels, mitochondrial activity and ATP production in skeletal muscle in gain- and loss-of function studies. Rev-erb-a-deficiency in skeletal muscle leads to reduced mitochondrial content and oxidative function, resulting in compromised exercise capacity. Fatty acid oxidation was reduced in Rev-erba-deficient skeletal muscle. This phenotype was recapitulated in isolated fibers and in muscle cells upon Rev-erbα knock-down, while Rev-erb-a over-expression increased the number of mitochondria with improved respiratory capacity. Rev-erb-a-deficiency resulted in deactivation of the Lkb1–Ampk–Sirt1–Ppargc1-a signaling pathway, whereas autophagy was up-regulated, resulting in both impaired mitochondrial biogenesis and increased clearance. Muscle over-expression or pharmacological activation of Rev-erb-a increased respiration and exercise capacity. These results identify Rev-erb-a as a pharmacological target which improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function and suggest that Rev-erba, as part of the clock machinery, adapt mitochondrial activity to the circadian time. These results have been published in Nature Medicine (Woldt et al., 2013).
Therefore Rev-erba is a clock component and a clock-regulated gene which plays a crucial role in the coordination of metabolic processes and peripheral circadian outputs. Our results provide molecular evidence for the development of new therapeutic approaches to treat mitochondrial-related metabolic disorders that take circadian rhythms into account. Several chemical hits and leads have been produced that, for some of them, were tested in our study with promising results.