Hypomorphic Expression of Pitx3 Disrupts Circadian Clocks and Prevents Metabolic Entrainment of Energy Expenditure

Abstract

Daily adaptation of metabolic activity to light-dark cycles to maintain homeostasis is controlled by hypothalamic nuclei receiving information from the retina and from nutritional inputs that vary according to feeding cycles. We show that selective hypomorphic expression of the transcription factor gene Pitx3 prevents light-dependent entrainment of the central pacemaker in the suprachiasmatic nucleus. This translates into altered behavioral and metabolic outputs affecting locomotor activity, feeding patterns, energy expenditure, and corticosterone secretion that correlate with dysfunctional expression of clock genes in the ventromedial hypothalamus, liver, and brown adipose tissue. Metabolic entrainment bytime-restricted feeding restores clock function in the liver and brown adipose tissue but not in the ventromedial hypothalamus and, remarkably, fails to synchronize energy expenditure and locomotor and hormonal outputs. Thus, our study reveals a central role of the priming of the suprachiasmatic nucleus with retinal innervation in the hypothalamic regulation of cyclic metabolic homeostasis.