Hypomorphic Expression of Pitx3 Disrupts Circadian Clocks and Prevents Metabolic Entrainment of Energy Expenditure.
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 by time-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.
['Del Río-Martín|Almudena|A|', 'Pérez-Taboada|Iara|I|', 'Fernández-Pérez|Antonio|A|', 'Moratalla|Rosario|R|', 'de la Villa|Pedro|P|', 'Vallejo|Mario|M|']
D000273:Adipose Tissue D000818:Animals D057906:Circadian Clocks D003345:Corticosterone D004734:Energy Metabolism D005247:Feeding Behavior D018398:Homeodomain Proteins D007031:Hypothalamus D008099:Liver D008124:Locomotion D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D013493:Suprachiasmatic Nucleus D014157:Transcription Factors
circadian clock suprachiasmatic nucleus ventromedial hypothalamus brown adipose tissue arcuate nucleus energy metabolism food intake intrinsically photosensitive retinal ganglion cells retinohypothalamic tract time restricted feeding