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Nonvisual opsins 3 and 5 in the Regulation of Mammalian Thermogenesis and Energy Homeostasis

Zhang, Kevin X
http://orcid.org/0000-0002-6028-6536
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595847143989177

Abstract Details

2020, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
The notion that light response pathways regulate mammalian physiology is well established (for example, metabolic regulation mediated by the circadian clock). In the current circadian regulation model, light stimulation received by our eyes entrains a circadian clock in the suprachiasmatic nucleus (SCN). In turn, this clock regulates a series of downstream responses that match our physiology to our activity cycle. Disruption of circadian photoentrainment as a consequence of arrhythmic light stimulation (for example, in shift workers) can have serious consequences including metabolic abnormalities and increased susceptibility to certain types of cancer. It is also well established that non-ocular tissues can respond to light and regulate physiological responses. Insects and vertebrates alike express the light-detecting “atypical” opsins in the brain and peripheral tissues and employ these opsins in various ways. For example, in zebrafish, light can entrain the circadian clock in organs directly, without the need for input from eyes. Furthermore, in birds, seasonal breeding is regulated by a brain photoreceptor that requires neuropsin (OPN5). Currently, it is not understood whether mammals also use non-ocular light sensing to regulate physiology. This thesis addresses this question by examining the function of two atypical opsins, OPN3 (encephalopsin) and OPN5 (neuropsin). Preliminary data show that Opn3 is expressed in adipocytes and is required for a light-dependent thermoregulatory response to ambient cold temperatures. In mice, conditional deletion of Opn3 from adipocytes or the acute withdrawal of 480 nm blue light (?max of OPN3) results in a diminished ability to defend core body temperature against 4°C cold exposure. Additionally, 480 nm blue light elevates intracellular cAMP and phosphorylated HSL in differentiated primary white adipocytes in vitro, suggesting that the light-sensing activity of OPN3 in adipocytes promotes lipolysis, thus providing metabolic fuel for thermogenesis in the brown adipose tissue (BAT). Radiometric measurements of photon flux in the interscapular adipose of anesthetized mice further demonstrate that 480 nm light of sufficient intensity reaches subcutaneous adipose to stimulate OPN3 in vivo. Opn5 expression was detected in neurons within the preoptic area (POA) of the hypothalamus, and shown to project to BAT. Interestingly, Opn5 mutant mice show the opposite phenotype to the Opn3 null and have elevated thermogenesis and cold defense abilities. Correspondingly, wild-type mice raised in the absence of violet 380 nm light (?max of OPN5) possess phenotypes that mimic the Opn5 null, directly implicating the violet light-detecting activity of OPN5 in this POA-BAT neuraxis. Further analysis of the Opn5 null reveals elevated metabolism, supported by augmented food intake and energy expenditure. Increased tyrosine hydroxylase (TH) positive nerve fibers in the BAT of Opn5 mutant mice suggests globally elevated sympathetic nervous activity, corroborated by decreased serum lipids, insulin, and changes seen in multiple other organ systems. Ultimately, this thesis describes a previously unknown light-sensitive energy management pathway in mammals, incorporating both blue-sensitive OPN3 in adipocytes, and violet-sensitive OPN5 in the POA. This work identifies light as a key substrate of mammalian thermoregulation and energy homeostasis, and carries broad implications for human biology and human health.
Richard Lang, Ph.D. (Committee Chair)
Kenneth Campbell, Ph.D. (Committee Member)
John Hogenesch, Ph.D. (Committee Member)
Louis Muglia, M.D., Ph.D. (Committee Member)
Juan Sanchez-Gurmaches, Ph.D. (Committee Member)
299 p.
Neurology
Thermogenesis; Metabolism; Opsin; Hypothalamus; Preoptic; Neuropsin

Recommended Citations

Citations

  • Zhang, K. X. (2020). Nonvisual opsins 3 and 5 in the Regulation of Mammalian Thermogenesis and Energy Homeostasis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595847143989177

    APA Style (7th edition)

  • Zhang, Kevin. Nonvisual opsins 3 and 5 in the Regulation of Mammalian Thermogenesis and Energy Homeostasis. 2020. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595847143989177.

    MLA Style (8th edition)

  • Zhang, Kevin. "Nonvisual opsins 3 and 5 in the Regulation of Mammalian Thermogenesis and Energy Homeostasis." Doctoral dissertation, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595847143989177

    Chicago Manual of Style (17th edition)

ucin1595847143989177
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This open access ETD is published by University of Cincinnati and OhioLINK.