The opsin family of G-protein coupled receptors are employed as light detectors in animals. Opsin 5 (neuropsin, OPN5) is a highly conserved, violet light (380 nm λ max ) sensitive opsin 1 , 2 . In mice, OPN5 is a known photoreceptor in retina 3 and skin 4 but is also expressed in the hypothalamic preoptic area (POA) 5 . Here we describe a light-sensing pathway in which Opn5 expressing POA neurons regulate brown adipose tissue (BAT) thermogenesis. We show Opn5 expression in glutamatergic warm-sensing POA neurons that receive synaptic input from multiple thermoregulatory nuclei. We further show that Opn5 POA neurons project to BAT and decrease its activity under chemogenetic stimulation. Opn5 null mice show overactive BAT, elevated body temperature, and exaggerated thermogenesis when cold challenged. Moreover, violet photostimulation during cold exposure acutely suppresses BAT temperature in wild-type, but not in Opn5 null mice. Direct measurements of intracellular cAMP ex vivo reveal that Opn5 POA neurons increase cAMP when stimulated with violet light. This analysis thus identifies a violet light sensitive deep brain photoreceptor that normally suppresses BAT thermogenesis.

BAU, NA, SR and UT performed experimental analysis. MB designed and built the required lighting systems. MD and ZK provided essential tools. M-TN, SV, GN, YO, EB, SR, RSH, PMI and RNVG designed experiments and provided coordinating leadership within the collaborative group. M-TN, SV, GN EB, PMI, RNVG and RAL wrote the paper. RAL designed experimental analysis and provided overall project leadership.

Highlights d Adipocytes express encephalopsin (OPN3), a 480 nm bluelight-sensitive opsin d Mice lacking OPN3 or blue light have diminished thermogenesis during cold exposure d Loss of OPN3 reduces oxygen consumption and energy expenditure d White adipocyte OPN3 promotes lipolysis during cold exposure

We confirm previous findings of sevoflurane-induced neuronal injury. Dexmedetomidine, even in the highest dose, did not cause similar injury, but provided lesser degrees of anaesthesia and pain control. No mitigation of sevoflurane-induced injury was observed with dexmedetomidine supplementation, suggesting that future studies should focus on anaesthetic-sparing effects of dexmedetomidine, rather than injury-preventing effects.

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The preoptic area of the hypothalamus is a homeostatic control center. The heterogeneous neurons in this nucleus function to regulate the sleep/wake cycle, reproduction, thirst and hydration, as well as thermogenesis and other metabolic responses. Several recent studies have analyzed preoptic neuronal populations and demonstrated neuronal subtype-specific roles in suppression of thermogenesis. These studies showed similar thermogenesis responses to chemogenetic modulation, and similar synaptic tracing patterns for neurons that were responsive to cold, to inflammatory stimuli, and to violet light. A reanalysis of single-cell/nucleus RNA-sequencing datasets of the preoptic nucleus indicate that these studies have converged on a common neuronal population that when activated, are sufficient to suppress thermogenesis. Expanding on a previous name for these neurons (Q neurons, which reflect their ability to promote quiescence and expression of Qrfp), we propose a new name: QPLOT neurons, to reflect numerous molecular markers of this population and to capture its broader roles in metabolic regulation. Here, we summarize previous findings on this population and present a unified description of QPLOT neurons, the excitatory preoptic neuronal population that integrate a variety of thermal, metabolic, hormonal and environmental stimuli in order to regulate metabolism and thermogenesis.

Animals have evolved light-sensitive G protein–coupled receptors, known as opsins, to detect coherent and ambient light for visual and nonvisual functions. These opsins have evolved to satisfy the particular lighting niches of the organisms that express them. While many unique patterns of evolution have been identified in mammals for rod and cone opsins, far less is known about the atypical mammalian opsins. Using genomic data from over 400 mammalian species from 22 orders, unique patterns of evolution for each mammalian opsins were identified, including photoisomerases, RGR-opsin (RGR) and peropsin (RRH), as well as atypical opsins, encephalopsin (OPN3), melanopsin (OPN4), and neuropsin (OPN5). The results demonstrate that OPN5 and rhodopsin show extreme conservation across all mammalian lineages. The cone opsins, SWS1 and LWS, and the nonvisual opsins, OPN3 and RRH, demonstrate a moderate degree of sequence conservation relative to other opsins, with some instances of lineage-specific gene loss. Finally, the photoisomerase, RGR, and the best-studied atypical opsin, OPN4, have high sequence diversity within mammals. These conservation patterns are maintained in human populations. Importantly, all mammalian opsins retain key amino acid residues important for conjugation to retinal-based chromophores, permitting light sensitivity. These patterns of evolution are discussed along with known functions of each atypical opsin, such as in circadian or metabolic physiology, to provide insight into the observed patterns of evolutionary constraint.

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