Adaptive Thermogenesis in Mice Is Enhanced by Opsin 3-Dependent Adipocyte Light Sensing

Nayak, Gowri; Zhang, Kevin X.; Vemaraju, Shruti; Odaka, Yoshinobu; Buhr, Ethan D.; Holt-Jones, Amanda; Kernodle, Stace; Smith, April N.; Upton, Brian A.; D'Souza, Shane P; Zhan, Jesse; Díaz, Nicolás M.; Nguyen, My-Linh Thi; Mukherjee, Rajib; Gordon, Shannon A.; Wu, Gang; Schmidt, Robert E.; Xue, Mei; Petts, Nathan T.; Batie, Matthew; Rao, Sujata; Hogenesch, John B.; Nakamura, Takahisa; Sweeney, Alison; Seeley, Randy J.; Gelder, Russell N. Van; Sanchez-Gurmaches, Joan; Lang, Richard A.

doi:10.1016/j.celrep.2019.12.043

Cited by 65 publications

(80 citation statements)

References 96 publications

(119 reference statements)

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“…OPN3 homologs in mosquito, pufferfish, zebrafish, and chicken absorb blue light (Koyanagi et al, 2013;Sugihara et al, 2016). Human OPN3, however, does not absorb visible light by UV-visible spectroscopy (Ozdeslik et al, 2019), despite several studies indicating OPN3-meditated blue light responses in mammals (Kato et al, 2016;Buscone et al, 2017;Barreto Ortiz et al, 2018;Regazzetti et al, 2018;Yoshimoto et al, 2018;Castellano-Pellicena et al, 2019;Nayak et al, 2020;Sato et al, 2020). In lower vertebrates, photosensitive areas in the diencephalon contain many light-responsive pigments and opsins that directly mediate physiological reactions like color change and motor responses independent of the eyes or pineal glands (Van Veen et al, 1976;Tabata, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…It is likely that the OPN3 knock-out mouse has a yet unidentified neurologic phenotype that does not manifest in the conditions or life span to which we house our mice. Indeed, the knock-out mouse was first generated years ago (Buhr et al, 2015), but it has just recently been discovered that only when perturbing normal living and physiological conditions does the OPN3 knock-out mouse exhibit diet-induced obesity and insulin resistance because of dysregulation of metabolic processes in brown adipocytes (Sato et al, 2020) and deficiency in thermogenesis under cold shock because of dysregulation of lipolysis in adipose tissue (Nayak et al, 2020). Interestingly, none of these phenotypes have demonstrated correlations to OPN3 expression in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its discovery more than two decades ago, OPN3 remains one of the least characterized opsins and its expression profile and function are unknown in many of the tissues where it is expressed. The studies published thus far have focused primarily on OPN3 expression or function in the skin (for review, see Olinski et al, 2020), lungs (White et al, 2008;Barreto Ortiz et al, 2018;Yim et al, 2019), colon (Yoshimoto et al, 2018), liver (Jiao et al, 2012), and adipocytes (Nayak et al, 2020;Sato et al, 2020), but OPN3 has yet to gain attention in the brain, where it was first discovered.…”

Section: Introductionmentioning

confidence: 99%

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Endogenous Opsin 3 (OPN3) Protein Expression in the Adult Brain Using a Novel OPN3-mCherry Knock-In Mouse Model

Olinski

Tsuda

Kauer

et al. 2020

eNeuro

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The opsins have been studied extensively for their functions in visual phototransduction; however, the mechanisms underlying extraocular opsin signaling remain poorly understood. The first mammalian extraocular opsin to be discovered, opsin 3 (OPN3), was found in the brain more than two decades ago, yet its function remains unknown. A significant hindrance to studying OPN3 has been a lack of specific antibodies against mammalian OPN3, resulting in an incomplete understanding of its expression in the brain. Although Opn3 promoter-driven reporter mice have been generated to examine general OPN3 localization, they lack the regulated expression of the endogenous protein and the ability to study its subcellular localization. To circumvent these issues, we have created a knock-in OPN3-mCherry mouse model in which the fusion protein OPN3-mCherry is expressed Significance Statement Before the current report, there had been a significant lack of encephalic opsin 3 (OPN3) protein characterization, likely driven by the absence of murine OPN3 antibodies. This study describes a novel OPN3-mCherry knock-in mouse that we used to analyze endogenous OPN3 protein expression across the brain. We have uncovered new aspects of OPN3: localization to previously undocumented brain subregions, expression in GABAergic neurons and non-neuronal cells, and punctate subcellular localization in the soma. Our OPN3 expression map is an invaluable step toward discovering its elusive encephalic functions. The OPN3-mCherry mouse will facilitate investigation of OPN3 not only in the brain, but also across the entire organism, a useful feature as OPN3 is emerging as a possible mediator of phototransduction outside the brain.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endogenous Opsin 3 (OPN3) Protein Expression in the Adult Brain Using a Novel OPN3-mCherry Knock-In Mouse Model

Olinski

Tsuda

Kauer

et al. 2020

eNeuro

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“…55 Mice have been shown to express opsins in their skin, 15,56 as well as in their brain (Opn3 and Opn5), 57,58 testis (Opn5), 57 adipose tissue (Opn3), 59 vascular smooth muscle, 60,61 iris (Opn4), 62 and ciliary body (Opn5). 63 Recent work has suggested a photosensitive role for Opn3 in regulating metabolism in murine adipose tissue 59,64 and has demonstrated that Opn5 functions as a photopigment synchronizing circadian entrainment in skin in vivo. 12 Pulmonary arterial diameter has also recently been shown to be light sensitive and use an Opn4-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

Wounding Induces Facultative Opn5-Dependent Circadian Photoreception in the Murine Cornea

Díaz

Lang

Gelder

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Autonomous molecular circadian clocks are present in the majority of mammalian tissues. These clocks are synchronized to phases appropriate for their physiologic role by internal systemic cues, external environmental cues, or both. The circadian clocks of the in vivo mouse cornea synchronize to the phase of the brain's master clock primarily through systemic cues, but ex vivo corneal clocks entrain to environmental light cycles. We evaluated the underlying mechanisms of this difference. METHODS. Molecular circadian clocks of mouse corneas were evaluated in vivo and ex vivo for response to environmental light. The presence of opsins and effect of genetic deletion of opsins were evaluated for influence on circadian photoresponses. Opn5-expressing cells were identified using Opn5 Cre ;Ai14 mice and RT-PCR, and they were characterized using immunocytochemistry. RESULTS. Molecular circadian clocks of the cornea remain in phase with behavioral circadian locomotor rhythms in vivo but are photoentrainable in tissue culture. After fullthickness incision or epithelial debridement, expression of the opsin photopigment Opn5 is induced in the cornea in a subset of preexisting epithelial cells adjacent to the wound site. This induction coincides with conferral of direct, short-wavelength light sensitivity to the circadian clocks throughout the cornea. CONCLUSIONS. Corneal circadian rhythms become photosensitive after wounding. Opn5 gene function (but not Opn3 or Opn4 function) is necessary for induced photosensitivity. These results demonstrate that opsin-dependent direct light sensitivity can be facultatively induced in the murine cornea.

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“…Briefly, we observed that higher levels of PA consistently corresponded to decreased adiposity. Interestingly, sunlight exposure was related to less subcutaneous fat but more visceral fat, which may be due to compensatory behaviors, such as feeling more hunger after a workout; present weight status (39); or the differential impact of sunlight on the mass of different adipose tissue types (5,15). PA levels may independently increase serum vitamin D levels.…”

Section: Original Articlementioning

confidence: 99%

Walking in the Light: How History of Physical Activity, Sunlight, and Vitamin D Account for Body Fat—A UK Biobank Study

Klinedinst

Meier

Larsen

et al. 2020

Obesity

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Objective: The high prevalence of vitamin D deficiency and obesity drives the need for successful strategies that elevate vitamin D levels, prevent adipogenesis, and stimulate lipolysis. This study provides a theoretical model to evaluate how physical activity (PA) and sunlight exposure influence serum vitamin D levels and regional adiposity. This study hypothesized a posteriori that sunlight is associated with undifferentiated visceral adiposity by increasing the ratio of brown to white adipose tissue. Methods: Using 10-year longitudinal data, accelerometry, a sun-exposure questionnaire, and regional adiposity quantified by dual-energy x-ray absorptiometry imaging, a structural-equation mediation model of growth curves was constructed with a data-driven methodology. Results: Sunlight and PA conjointly increased serum vitamin D. Changes in vitamin D levels partially mediated how sunlight and PA impacted adiposity in visceral and subcutaneous regions within a subjective PA model. In an objective PA model, vitamin D was a mediator for subcutaneous regions only. Interestingly, sunlight was associated with less adiposity in subcutaneous regions but greater adiposity in visceral regions. Conclusions: Sunlight and PA may increase vitamin D levels. For the first time, this study characterizes a positive association between sunlight and visceral adiposity. Further investigation and experimentation are necessary to clarify the physiological role of sunlight exposure on adipose tissue.

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Adaptive Thermogenesis in Mice Is Enhanced by Opsin 3-Dependent Adipocyte Light Sensing

Cited by 65 publications

References 96 publications

Endogenous Opsin 3 (OPN3) Protein Expression in the Adult Brain Using a Novel OPN3-mCherry Knock-In Mouse Model

Endogenous Opsin 3 (OPN3) Protein Expression in the Adult Brain Using a Novel OPN3-mCherry Knock-In Mouse Model

Wounding Induces Facultative Opn5-Dependent Circadian Photoreception in the Murine Cornea

Walking in the Light: How History of Physical Activity, Sunlight, and Vitamin D Account for Body Fat—A UK Biobank Study

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