Violet-light suppression of thermogenesis by opsin 5 hypothalamic neurons
Authors: Amanda L Holt
Rajib Mukherjee
April N Smith
Courtney D Linne
Durgesh Tiwari
Richard A Lang
Joan Sanchez-Gurmaches
Gowri Nayak
Shruti Vemaraju
Christina Gross
Shane D&#x27;Souza
Randy J Seeley
Alison Sweeney
Kevin X Zhang
Nathan T Petts
Kevin D Gaitonde
Stace Kernodle
Matthew Batie
Brian A Upton
Ethan D Buhr
Russell N Van Gelder
Journal: Nature (2020)
Discipline: Multidisciplinary
Keywords: Opsin 5; light detectors; violet light; photoreceptor; thermogenesis
Affiliations: The Visual Systems Group, Abrahamson Pediatric Eye Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Center for Chronobiology, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Molecular and Developmental Biology Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, OH, USA., Medical Scientist Training Program, University of Cincinnati, College of Medicine, Cincinnati, OH, USA., Department of Surgery, University of Michigan, School of Public Health, Ann Arbor, MI, USA., Department of Physics, Yale University, New Haven, CT, USA., Division of Clinical Engineering, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Department of Ophthalmology, University of Washington Medical School, Seattle, WA, USA., Department of Biological Structure, University of Washington Medical School, Seattle, WA, USA., Department of Pathology, University of Washington Medical School, Seattle, WA, USA., Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, USA., Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Department of Internal Medicine, University of Michigan, School of Public Health, Ann Arbor, MI, USA., The Visual Systems Group, Abrahamson Pediatric Eye Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. ., Center for Chronobiology, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. ., Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. ., Department of Ophthalmology, University of Cincinnati, College of Medicine, Cincinnati, OH, USA. .

Abstract:  The opsin family of G-protein-coupled receptors are used as light detectors in animals. Opsin 5 (also known as neuropsin or OPN5) is a highly conserved opsin that is sensitive to visible violet light1,2. In mice, OPN5 is a known photoreceptor in the retina3 and skin4 but is also expressed in the hypothalamic preoptic area (POA)5. Here we describe a light-sensing pathway in which POA neurons that express Opn5 regulate thermogenesis in brown adipose tissue (BAT). We show that Opn5 is expressed in glutamatergic warm-sensing POA neurons that receive synaptic input from several 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, increased body temperature, and exaggerated thermogenesis when cold-challenged. Moreover, violet photostimulation during cold exposure acutely suppresses BAT temperature in wild-type mice but not in Opn5-null mice. Direct measurements of intracellular cAMP ex vivo show 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. 

Retracted: No

PubPeer comments:
 Concerns about u201cExtended Data Fig. 10u201d by comparing with raw data available here: https: www.nature.com articles s41586-020-2683-0#Sec39 Trying to reproduce figures presented in the article, relative light is calculated, as described in the figure caption, by normalization to surface measurements (Flux Flux_surface). The resulting spectrum is quite different (see red square below). ![file] Could the authors explain the difference between the two graphs or the method of normalization used? Other concerns: What strain of mice has been used for the measurement of light penetrance in the brain? You shaved the mice before the measurement. Do you think the hair could have significantly decreased the penetrance of light, especially if pigmented? I am also relatively sceptical about the relevance of data about light induce phase shift of the circadian clock of the skin (Buhr et al. 2019) in this analysis of light penetrance in the brain. , 
 Related to the previous comment. Using raw data of Extended Data Fig. 10 (available here: https: www.nature.com articles s41586-020-2683-0#Sec39), the full spectrum show some sort of u201cjumpu201d in the measures around 750 nm for the position -1mm and deeper. This is not explicitly presented in the manuscript (only 350 nm to 700 nm are shown in Extended Data Fig.10) but as this u201cjumpu201d does not appear for the surface and -0.5mm measurement and show an important increase of light penetrance (around half a log unit), it seems to be important to be explained. Could the authors clarify what happened? ![file] , 
 Related to the two previous comments. By looking at individual values in raw data of Extended Data Fig. 10 (available here: https: www.nature.com articles s41586-020-2683-0#Sec39 , below averaged data in the Excel sheet), I noticed that the individual values show frequently a plateau between 600 nm and 800 nm. Only one animal shows this plateau for the surface measure. For -1mm and deeper, all three animals show this plateau. ![file] In the context of light measurement, it is probably a sign of saturation of the spectrophotometer. Could the authors explain how they obtained the spectrum shown in Extended Data Fig. 10 from saturating raw data? ,