Hypothalamic NAD+-Sirtuin Axis: Function and Regulation.

The rapidly expanding elderly population and obesity endemic have become part of continuing global health care problems. The hypothalamus is a critical center for the homeostatic regulation of energy and glucose metabolism, circadian rhythm, and aging-related physiology. Nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuins are referred to as master metabolic regulators that link the cellular energy status to adaptive transcriptional responses. Mounting evidence now indicates that hypothalamic sirtuins are essential for adequate hypothalamic neuronal functions. Owing to the NAD+-dependence of sirtuin activity, adequate hypothalamic NAD+ contents are pivotal for maintaining energy homeostasis and circadian physiology. Here, we comprehensively review the regulatory roles of the hypothalamic neuronal NAD+-sirtuin axis in a normal physiological context and their changes in obesity and the aging process. We also discuss the therapeutic potential of NAD+ biology-targeting drugs in aging/obesity-related metabolic and circadian disorders.

Clock desynchronisation: why and how?

The internal clock located in the suprachiasmatic nuclei of the anterior hypothalamus is controlled by external (environment and social life) and genetic factors. Desynchronisation of the organism occurs when the clock does no longer work in harmony with the environ- mentalfactors. Rhythm desynchronization can be related to a conflict between the clock and environmentalfactors (shift work, night shift, transmeridianflight), to inefficient synchro- nizers (aging, psychiatric diseases..), to badly received synchronizers (circadian rhythm sleep disorders with e.g delayed or advanced sleep phase syndromes), or to the use of some drugs (lithium, propofol, alcohol...). In the long term rhythm desynchronisation can result in serious illnesses and the use of resynchronizing agents like melatonin or bright light are useful to the clock resynchronization.

Autochronometric abnormalities in patients with cerebral pathology in various locations.

Dysfunction of the limbic structures of the temporal lobe of the brain (predominantly the hippocampus), chiasma, hypothalamus, and epiphysis is accompanied by impairment of internal estimation of time periods. In patients with lesions of the temporal lobes and base of the skull, changes in measures of autochronometry were uniform, were the most marked, and were not directly associated with locomotor parameters or with changes in the general functional state of the CNS. In patients with spinal cord or vertebral lesions, including tumors, and in those with extensive lesions of the frontoparietal areas of the neocortex, there were no profound defects in endogenous time estimation, regardless of impairments of the functional state of the synaptic and motor system. These data identify the cerebral oscillatory formations--the hippocampus, the hypothalamic area, and the epiphysis--as structures directly involved in the physiological mechanisms controlling autochronometry.