SUN-LB125 Violet Sensitive Preoptic Area Neurons That Express Opsin 5 Regulate Thermogenesis and Energy Metabolism

Abstract

The thermogenic potential of brown adipose tissue (BAT) is a promising therapeutic target in the treatment of obesity and metabolic disorders. The preoptic area (POA) is a region in the anterior hypothalamus responsible for autonomic thermoregulation by means of modulating BAT activity through sympathetic nerve activity (SNA). Neurons in the POA express opsin-5 (OPN5), an atypical opsin found in various extraretinal tissues and known to respond to violet wavelengths with a lambda-max of 380 nm. OPN5 has previously been shown to regulate seasonal breeding behavior in birds. Loss of OPN5 in mice have been demonstrated to impair circadian photoentrainment. We have also shown OPN5 to be required in retinal ganglion cells for in vivo entrainment of a retina circadian clock independent of the suprachiasmatic nucleus. To date, no other physiological role for mammalian OPN5 has been proposed. The same POA neurons that express OPN5 also engage the central thermoregulatory circuit that modulates BAT activity. We show that POA OPN5 neurons polysynaptically project to the BAT using a retrograde PRV-mRFP1 pseudorabies virus. Also via a genetically targeted glycoprotein-deleted rabies virus injected into the POA, we identified labeled neurons in the rostral raphe pallidus (rRPa), the lateral parabrachial nucleus (LPB), and the dorsomedial hypothalamus (DMH), all nuclei known to participate in central BAT thermoregulation. Opn5-/- mice better defend their core body temperature during acute 4°C challenge. Our results indicate this effect to be due to increased BAT thermogenesis and not heat retention or pyrexia. Furthermore, BAT thermogenesis target gene transcripts (Ucp-1, Prdm16, Pgc-1a) were elevated in these cold stressed Opn5-/- animals. To demonstrate the importance of OPN5’s violet light sensing function in cold defense, C57BL/6J mice reared from E16.5 without 380 nm light largely phenocopy Opn5-/- animals when acutely cold challenged. Furthermore, chemogenetic inhibition of POA OPN5 neurons further augments cold exposure defense and BAT activation. Indirect calorimetry studies reveal Opn5-/- mice to be hypermetabolic, consuming more food and having a higher energy expenditure than controls. Paradoxically, this increased turnover does not translate to weight-gain resistance under high fat challenge. Our results suggest a mechanism where near-UV sensitive hypothalamic OPN5 neurons regulate BAT thermogenesis directly, proposing that the mammalian autonomic thermoregulatory apparatus is light responsive.