Endocrine Abstracts

Nuclear hormone receptors (NHRs) are a large family of ligand-activated transcription factors that regulate programs of cellular growth, differentiation and homeostasis. The structurally conserved ligand binding domains (LBDs) of NHRs bind to hydrophobic small molecules including steroid hormones, fat soluble vitamins and bile acids, thereby interpreting small molecule cues to affect transcriptional readouts.

The temporal correspondence between metabolic and circadian rhythms suggests the inherent coupling of these two key physiologic processes. Sleep, inactivity and fasting are opposed by wakefulness, motivated behavior and the fed state. Thus we are interested whether there may be common mechanism for ‘entraining’ both the clock and key metabolic pathways. We provide evidence that the energy sensor AMPK, via actions as an atypical transcriptional regulator, may function as one such dual entrainment trigger.

In regards to the clock, we provide genetic, mechanistic and pharmacologic evidence that AMPK-dependent phosphorylation enables cryptochrome (e.g. Cry1) to act as energy sensor for metabolic entrainment of the circadian clock. We show that Cry1 acts as a glucocorticoid receptor (GR) repressor and thus controls cyclic glucose production from the liver. In addition, we find that in muscle, usually active PPARd agonists (such as GW1516) are able to promote increased running endurance, suggesting the potential of drugs that can promote the benefits of exercise even in sedentary mice. Finally, we show that the AMPK agonist AICAR is a prototypic “exercise mimetic,’ enhancing endurance by stimulating mitochondrial function in muscle. Pharmacologic exercise from AMPK has important therapeutic implications in metabolic disease, atherosclerosis and frailty, as well as an already realized potential for athletic abuse.

Declaration of funding

This work was supported by the National Institute of Health (grant DK057978-32), the Glenn Foundation, the Ellison Medical Foundation and the Helmsley Charitable Trust. Dr Evans is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute.