Circadian peak dopaminergic activity response at the biological clock pacemaker (suprachiasmatic nucleus) area mediates the metabolic responsiveness to a high fat diet

Abstract

Among vertebrate species of the major vertebrate classes in the wild, a seasonal rhythm of whole body fuel metabolism, oscillating from lean to obese condition, is a common biological phenomenon. This annual cycle is driven in part by annual changes in the circadian dopaminergic signaling at the suprachiasmatic nuclei (SCN), with diminution of circadian peak dopaminergic activity at the SCN facilitating development of the seasonal obese insulin resistant condition. The present study investigated whether such an ancient circadian dopamine-SCN activity system for expression of the seasonal obese, insulin resistant phenotype may be operative in animals made obese, insulin resistant by high fat feeding and if so whether reinstatement of the circadian dopaminergic peak at the SCN would be sufficient to reverse the adverse metabolic impact of the high fat diet without alteration of caloric intake. First, we identified the supramammillary nucleus as a novel site providing the majority of dopaminergic neuronal input to the SCN. We further identified dopamine D2 receptors within the peri-SCN region as functional in mediating SCN responsiveness to local dopamine. In lean, insulin sensitive rats the peak in the circadian rhythm of dopamine release at the peri-SCN coincided with the daily peak in SCN electrophysiological responsiveness to local dopamine administration. However, in rats made obese, insulin resistant by high fat diet feeding, these coincident circadian peak activities were both markedly attenuated or abolished. Reinstatement of the circadian peak in dopamine level at the peri-SCN by its appropriate circadian-timed daily microinjection to this area, but not outside this circadian time-interval, abrogated the obese, insulin resistant condition without altering consumption of the high fat diet. These findings suggest that the circadian peak of dopaminergic activity at the peri-SCN/SCN is a key modulator of metabolism and of responsiveness to adverse metabolic consequences of high fat diet consumption.

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