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

• Main Authors: Almudena del Río-Martín, Iara Pérez-Taboada, Antonio Fernández-Pérez, Rosario Moratalla, Pedro de la Villa, Mario Vallejo
• Format: Article
• Language: English
• Published: Elsevier 2019-12-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719314986

Summary: 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 et al. show that lack of innervation of the suprachiasmatic nucleus by retinal axons prevents light-dependent entrainment of central and peripheral circadian clocks. Consequently, cyclic behavioral, metabolic, and endocrine outputs are permanently altered and resistant to rescue by metabolic entrainment via food-restricted feeding. Keywords: suprachiasmatic nucleus, ventromedial hypothalamus, retinohypothalamic tract, intrinsically photosensitive retinal ganglion cells, circadian clock, energy metabolism, food intake, arcuate nucleus, time restricted feeding, brown adipose tissue