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Violet-light suppression of thermogenesis by opsin 5 hypothalamic neurons

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.

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Fig. 1: Opn5 is expressed in excitatory, warm-sensitive hypothalamic POA neurons.
Fig. 2: Opn5 POA neurons regulate BAT thermogenesis.
Fig. 3: Violet light acutely suppresses BAT thermogenesis.
Fig. 4: Opn5 POA neurons respond to violet light ex vivo.

Data availability

Source data are provided with this paper. All other relevant data are available from the corresponding authors upon request. Source data are provided with this paper.

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Acknowledgements

We thank P. Speeg for mouse colony management; Y. Chen and Y.-C. Hu of the CCHMC Transgenic Animal and Genome Editing Core Facility for mouse line development; M. Kofron of the CCHMC Confocal Imaging Core Facility for assistance; M. Talley for consultation on M-FISH; T. Nakamura, V. Borra and A. Vonberg for assistance with metabolic experimentation; A. Ahmed for technical assistance; J. Lighton and B. Joos of Sable Systems International for assistance with indirect calorimetry; and T. Delehanty of TSE Systems for assistance with temperature telemetry. This work was supported by NIGMS 5T32GM063483 (University of Cincinnati MSTP), NEI R01 s EY027711 and EY027077 (to R.A.L.); NIGMS R01 GM124246 (to E.D.B.), NEI R01 EY026921 (to R.N.V.G.), NEI P30 EY001730 (to the Vision Research Core at the University of Washington); NIDDK P30 DK089503 (to R.J.S. and the Michigan Nutrition Obesity Research Center); the Mark J. Daily, MD Research Fund (to the University of Washington); and unrestricted grants to the University of Washington Department of Ophthalmology from Research to Prevent Blindness. This work was also supported by a Packard Foundation fellowship (to A.S.); American Heart Association grant 18CDA34080527 (to J.S.G.); and funds from the Goldman Chair of the Abrahamson Pediatric Eye Institute at CCHMC.

Author information

Authors and Affiliations

Authors

Contributions

S.V., K.X.Z. and R.A.L. conceived and directed the study. K.X.Z. and S.D. performed imaging experiments and quantitative analysis. S.D. performed M-FISH experiments. K.X.Z. performed stereotaxic and telemetry surgeries, and chemogenetic experiments. K.X.Z., S.D., B.A.U., S.V. and G.N. performed cold exposure experiments. C.D.L. and R.M. performed western blotting. K.X.Z. performed viral tracing studies. K.X.Z. and K.D.G. performed CAMPER experiments. K.X.Z. and B.A.U. performed locomotion experiments. S.K. and R.J.S. performed indirect calorimetry experiments. A.H.J. and A.S. provided expertise in radiometry and performed radiometric experiments with K.X.Z. and B.A.U. N.T.P. and M.B. designed and constructed custom electronic equipment. A.N.S. performed Xgal labelling. D.T. assisted with neuroanatomical studies. E.D.B., R.N.V.G., C.G., J.S.G. and R.J.S. consulted on experimental design and reviewed the manuscript. K.X.Z. and S.D. analysed data. K.X.Z., S.D. and R.A.L. wrote the manuscript. R.A.L. provided coordinating project leadership.

Corresponding author

Correspondence to Richard A. Lang.

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Competing interests

R.J.S. receives research support from Novo Nordisk, Zafgen, Kallyope, Pfizer, and Ironwood Pharmaceuticals.

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Extended data figures and tables

Extended Data Fig. 1 Opn5 lineage survey across the CNS and thermogenic organs.

ac, Brain atlas representation (a) and coronal brain sections (b, c) of P21 Opn5cre/+;Ai14 mouse highlighting tdTomato expression (red) in the raphe pallidus (RPa). d, Coronal brain section from P10 Opn5lacZ/+ mouse showing that the RPa is negative for Xgal labelling. ek, Representative confocal images from IB4 labelled (green) P35 Opn5cre/+;Ai14 (expressing tdTomato, red) tissues across the organism. iBAT (e), perigonadal white adipose tissue (pgWAT) (f), thyroid gland (g), liver (h), cardiac muscle (i), adrenal glands (j), and pancreas (k). Scale bars, 100 μm (ek), 150 μm (c, d), 500 μm (b).

Extended Data Fig. 2 M-FISH and presynaptic tracing of Opn5 POA neurons.

a, b, Representative images of Opn5cre/+;Ai14 POA neurons probed for Ptgds (green), tdTomato (red), Trpm2 (blue) and labelled with DAPI for nuclei (greyscale) (a) with corresponding quantification of overlap (n = 3 mice; 92 cells) (b). c, Representative images of Opn5cre/+;Ai14 cells (red) also positive for Trpm2 (blue) but with Ptgds labelling (green) that is below the background labelling threshold. Scale bars, 5 μm (c), 25 μm (a). d, Schematic of the mouse genetics used for rabies viral tracing. e, Experimental timeline for POA-tracing, and primary infected neurons (yellow). fo, Traced neurons (red) located in the paraventricular nucleus (PVN) (fh), supraoptic nucleus (SON) (f, g, i), dorsomedial hypothalamus (DMH) (j, k), lateral parabrachial (LBP) (l, m), and raphe pallidus (RPa) (n, o). Green regions in g and i are optic tracts with axons from Opn5 retinal ganglion cells. p, Schematic representation of nuclei presynaptic to Opn5 POA neurons. Data in b are mean ± s.e.m. Scale bars, 5 μm (c), 25 μm (a), 75 μm (e), 100 μm (h, i, k, o) or 200 μm (g, m). 2Cb, lobule 2 of cerebellar vermis.

Source data

Extended Data Fig. 3 Thermoregulation by Opn5 POA neurons is not context-dependent.

a, b, qPCR of thermogenesis genes in iBAT 6 h after CNO induction in mice with viral-mediated expression of stimulatory hM3D(Gq) DREADD (a) or inhibitory hM4D(Gi) DREADD (b) in the POA. (a) Opn5+/+ (n = 5), Opn5cre/+ (n = 5), and Opn5cre/− (n = 8). (b) Opn5+/+ (n = 6), Opn5cre/+ (n = 5), and Opn5cre/− (n = 4). P values are indicated above the bars. cf, Similar to Fig. 2, Opn5cre/− POA was injected with AAV5-hM3D(Gq) DREADD (c, e; n = 8 mice per condition) or AAV5-hM4D(Gi) DREADD (d, f; n = 6 mice per condition). Telemetric BAT and core recordings after intraperitoneal administration of CNO or vehicle (open arrowheads) at the 2 h mark. gl, Opn5+/+, Opn5cre/+, Opn5cre/− (n = 6 per genotype and condition) mice were injected with AAV5-hM4D(Gi) DREADD, and followed by chemogenetic manipulations as previously described, but at 4 °C ambient temperature. All data are mean ± s.e.m. P values are from (a, b) ANOVA with Tukey post hoc analysis (a, b), or one-way repeated measures ANOVA (c, l).

Source data

Extended Data Fig. 4 Opn5 loss-of-function exaggerates BAT thermogenesis.

a, Immunohistochemistry for UCP1 protein in iBAT from Opn5+/+ and Opn5−/− mice. b, UCP1 immunoblots for iBAT comparing ambient temperature (22 °C) and 72 h 4 °C exposure for Opn5+/+ (n = 3) and Opn5−/− (n = 3) mice. ce, Representative immunofluorescence of TH+ innervation of iBAT (c) used for quantification in d and e. f, Core temperature assessment (rectal) of Opn5+/+ and Opn5−/− mice during 3 h cold exposure. g, qPCR of thermogenesis genes (Ucp1, Pgc1a, Prdm16 and Cidea) in iBAT from mice in f. h, i, Forty-eight hour assessment of body temperature rhythms in Opn5+/+ (n = 3 mice) and Opn5−/− (n = 3 mice) mice using telemetry sensors in iBAT (h) and core (i) under 12 h/12 h light/dark lighting conditions. j, k, Infrared thermography of P8 (j) and P90 (k) Opn5+/+ and Opn5−/− mice following 30 min cold challenge. l, m, Quantification of thermographic images focused on interscapular region (l), and tail (m). n, Representative POA images from Opn5cre/+; Ai14 and Leprcre/+; Ai14 mice, plus Leprcre/+; Ai14 colocalization with Opn5lacZ/+ expression (Xgal). o, Quantification of overlap in n. p, Core temperature assessment (rectal) of control (Opn5fl/fl) and Leprcre; Opn5fl/fl mice during 3 h cold challenge. q, qPCR of thermogenesis genes in iBAT from mice in p. r, Immunohistochemistry for UCP1 protein in iBAT from Opn5fl/fl and Leprcre; Opn5fl/fl mice. s, UCP1 immunoblots for iBAT comparing ambient temperature (22 °C) and 72 h 4 °C exposure for Opn5fl/fl (n = 3) and Leprcre;Opn5fl/fl (n = 3) mice. tv, Representative immunofluorescence of TH+ innervation of iBAT (t) used for quantification in u and v. Scale bars, 50 μm (a, c, r, t), 100 μm (n). Data are mean ± s.e.m. P values are from one-way repeated measures ANOVA (d, f, h, i, l, m, p, u), ANOVA with Tukey post hoc analysis (g, q) or two-tailed Student’s t-test (e, v).

Source data

Extended Data Fig. 5 Opn5 null mice have altered energy homeostasis.

a, Body mass, body composition (lean mass/fat mass), and fat mass as a percentage of body mass (fat mass percentage) comparison between Opn5+/+ (n = 10) and Opn5−/− (n = 12) mice. b, Schematic describing ambient temperature changes throughout experiment and the duration of measurement intervals. c, Indirect calorimetry (TSE Systems, PhenoMaster Cages) measurements of energy expenditure in adult Opn5+/+ (grey trace, n = 15) and Opn5−/− (blue trace, n = 9) mice at ambient temperatures of 22 °C, 16 °C, 10 °C and 28 °C. d, Mass–energy relationships of data in c represented as generalized linear models. e, Respiratory exchange ratio (RER = VCO2/VO2) obtained from the same mice. f, Spontaneous locomotor activity (XY) monitoring was performed via infrared beam breaks. g, Twenty-four-hour average food consumption from Opn5+/+ (grey bars, n = 11) and Opn5−/− (blue bars, n = 7) mice at each ambient temperature. Mice exhibiting ‘food grinding’ behaviour were excluded from the analysis. h, Twenty-four-hour average water consumption from Opn5+/+ (grey bars, n = 14) and Opn5−/− (blue bars, n = 9) mice at each temperature. P values are from two-tailed Student’s t-tests (a), one-way repeated measures ANOVA across 6-h time interval (c, e, f), two-way ANCOVA with body mass as covariate (d), or ANOVA with Holm–Sîdak corrected multiple comparisons (g, h). Data in c, e, f show a 24h period of mean ± s.e.m. data for both genotypes during lights on (06:00–18:00, yellow shaded region) followed by lights off (18:00–06:00, grey shaded region). Data in a, g and h are represented as mean ± s.e.m.

Source data

Extended Data Fig. 6 OPN5 regulates thermogenesis and lipid metabolism, but not thyroid and cardiovascular activity.

ad, Serum lipid quantifications from male (n = 13 Opn5+/+, n = 12 Opn5−/−) and female (n = 8 Opn5+/+, n = 5 Opn5−/−) mice for triglycerides (a), phospholipids (b), cholesterol (c), and non-esterified fatty acids (NEFA) (d). e, Serum thyroxine (T4) from male Opn5+/+ (n = 11) and Opn5−/− (n = 9) mice. f, Serum thyrotropin-releasing hormone (TRH) from male Opn5+/+ (n = 12) and Opn5−/− (n = 11) mice. g, Adipose depot weight (mg) comparison between male Opn5+/+ (n = 14) and Opn5−/− (n = 8) mice. inWAT, inguinal white adipose tissue. h, Representative images highlighting inWAT cell size (H&E) and iWAT UCP1 (IHC) from Opn5+/+ and Opn5−/− mice. Scale bars, 50 μm. i, Quantification of inWAT cell size for Opn5+/+ (n = 4) and Opn5−/− (n = 5) mice. j, Schematic representation of mouse blood pressure recording system. Animals are movement-restricted in a mouse restraint and the tail is fitted proximally with an occlusion cuff and distally with a volume pressure recording (VPR) cuff. k, Example trial from tail blood pressure recording. Data are represented as line graphs for occlusion cuff pressure (mmHg; left y-axis) and VPR cuff pressure (mmHg; right y-axis). l, Quantification of blood pressure (SBP, systolic blood pressure; DBP, diastolic blood pressure), mean arterial pressure (MAP), and pulse rate (bpm) from Opn5+/+ (n = 10-11) and Opn5−/− (n = 12-13) mice. m, Indirect calorimetry and locomotion from Opn5+/+ (n = 6, grey trace) and Opn5−/− (n = 6, blue trace) mice treated with 1.0 mg/kg β3 adrenergic receptor agonist CL-316,243 (solid line) or vehicle control (saline, dotted line). Intraperitoneal injection of agonist or saline was performed at the 1 h time point (indicated by arrow). All data are mean ± s.e.m. p values are from (ag, l) two-tailed Student’s t-test, (i, m) 1-way repeated measures ANOVA.

Source data

Extended Data Fig. 7 Overlap of Lepr and Opn5 expression is limited to the POA.

ag, Lepr-lineage and Opn5 expression survey across multiple tissues (n = 3 mice). Representative images of tdTomato (Leprcre; Ai14) and Xgal (Opn5lacZ/+) domains from the dorsomedial hypothalamus (a), arcuate nucleus (ARC) (b), choroid plexus (c), cerebellum (d), raphe pallidus (e), retina (f), and ear skin (g). Scale bars, 100 μm (ae), 50 μm (f, g).

Extended Data Fig. 8 Violet light does not change locomotor behaviour in cold exposed mice.

a, Photograph of experimental setup in 4 °C. b, Average speed in cm/s of 2-month-old male Opn5+/+ (grey trace; n = 6) and Opn5−/− (blue trace; n = 6) mice binned in 5 min intervals. Violet 380 nm LEDs were switched on after 80 min (1:20 mark). c, Cumulative distance in meters travelled by Opn5+/+ (n = 6) and Opn5−/− (n = 6) mice before and after violet supplementation, along with total cumulative distance. d, Total cumulative distance plotted across time. e, Absolute speed in cm/s of a representative pair (n = 1 Opn5+/+ and n = 1 Opn5−/−) of mice. fg, Representative mouse locomotion trace (centroid-based motion tracking) of the Opn5+/+ (f) and Opn5−/− (g) mouse from (e). hi, Selective locomotion traces in 30 min bins ranging from 0:50 – 1:20, 1:20 – 1:50, and 1:50 – 2:20, for the Opn5+/+ (h) and Opn5−/− (i) experimental pair of mice from (e). P values are from (b, d) 1-way repeated measures ANOVA, and (log p value graphs from b and d), (c) two-tailed Student’s t-test. Data in (bd) are represented as mean ± s.e.m.

Source data

Extended Data Fig. 9 Violet light deprivation alters BAT innervation and sensitivity to sympathetic nervous system input.

a, Lighting protocol used to generate ‘full spectrum’ and ‘minus violet’ mice. b, Spectral quality of lighting used in ‘full spectrum’ (top) and ‘minus violet’ (bottom) housing. Colored boxes indicate wavelength bounds used to estimate flux (photons cm-2s-1). c, UCP1 IHC of ‘full spectrum’ (top) and ‘minus violet’ (bottom) mice. d, Immunoblots of UCP1 at baseline (22 °C) and following 72 h cold adaptation (72h 4 °C) between ‘full spectrum’ (n = 3) and ‘minus violet’ (n = 3) mice. eg, Representative images (e) of TH+ (tyrosine hydroxylase) innervation of BAT used for quantification represented in (f) and (g). h, Core temperature assessment (rectal) of ‘full spectrum’ and ‘minus violet’ mice during a 3h cold challenge. i, QPCR of thermogenesis genes (Ucp1, Pgc1α, Prdm16, Cidea) in iBAT from the mice used in (h). j, Adipose depot weight (mg) comparison between ‘full spectrum’ (n = 5) and ‘minus violet’ (n = 5) mice. k, Representative images highlighting inWAT cell size (haematoxylin and eosin) and iWAT UCP1 (IHC). l, Quantification of inWAT cell size H&E images for ‘full spectrum’ (n = 4) and ‘minus violet’ (n = 4) groups. m, Indirect calorimetry from ‘full spectrum’ (n = 6, grey trace) and ‘minus violet’ (n = 6, purple trace) mice treated with 1.0 mg kg−1 β3 adrenergic receptor agonist CL-316,243 (solid line) or vehicle (saline, dotted line). Administration of agonist or saline was performed at the 1 h time point (indicated by arrow). Data are mean ± s.e.m. P values are from one-way repeated measures ANOVA (f, h, l, m), ANOVA with Tukey post hoc analysis (i), or two-tailed Student’s t-test (g, j). Scale bars, 50 μm.

Source data

Extended Data Fig. 10 Measurement of photon flux within the POA.

a, Schematic of experimental setup for measuring intra-cranial photon flux as described in Methods. b, Holt–Sweeney microprobe consisting of a pulled optic fibre with an attached transparent spherical diffusing tip. Scale bar, 100 μm. c, Measurement depths and probe path within cranium. d, Absolute photon flux within mouse cranium with OPN5 action spectrum superimposed (adapted from2 with data points from4). Top blue trace represents surface flux and, at the λmax of OPN5, is about 3.4 × 1013 photons cm−2 s−1. At the maximum 4.0 mm depth (grey trace), the flux at the λmax of OPN5 is approximately 9.5 × 1010 photons cm−2 s−1. e, Relative photon flux normalized to surface measurements. Each trace is expressed as mean ± s.e.m. from n = 3 mice.

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Zhang, K.X., D’Souza, S., Upton, B.A. et al. Violet-light suppression of thermogenesis by opsin 5 hypothalamic neurons. Nature 585, 420–425 (2020). https://doi.org/10.1038/s41586-020-2683-0

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