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RDH1 suppresses adiposity by promoting brown adipose adaptation to fasting and re-feeding

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Abstract

RDH1 is one of the several enzymes that catalyze the first of the two reactions to convert retinol into all-trans-retinoic acid (atRA). Here, we show that Rdh1-null mice fed a low-fat diet gain more weight as adiposity (17% males, 13% females) than wild-type mice by 20 weeks old, despite neither consuming more calories nor decreasing activity. Glucose intolerance and insulin resistance develop following increased adiposity. Despite the increase in white fat pads, epididymal white adipose does not express Rdh1, nor does muscle. Brown adipose tissue (BAT) and liver express Rdh1 at relatively high levels compared to other tissues. Rdh1 ablation lowered body temperatures during ambient conditions. Given the decreased body temperature, we focused on BAT. A lack of differences in BAT adipogenic gene expression between Rdh1-null mice and wild-type mice, including Pparg, Prdm16, Zfp516 and Zfp521, indicated that the phenotype was not driven by brown adipose hyperplasia. Rather, Rdh1 ablation eliminated the increase in BAT atRA that occurs after re-feeding. This disruption of atRA homeostasis increased fatty acid uptake, but attenuated lipolysis in primary brown adipocytes, resulting in increased lipid content and larger lipid droplets. Rdh1 ablation also decreased mitochondrial proteins, including CYCS and UCP1, the mitochondria oxygen consumption rate, and disrupted the mitochondria membrane potential, further reflecting impaired BAT function, resulting in both BAT and white adipose hypertrophy. RNAseq revealed dysregulation of 424 BAT genes in null mice, which segregated predominantly into differences after fasting vs after re-feeding. Exceptions were Rbp4 and Gbp2b, which increased during both dietary conditions. Rbp4 encodes the serum retinol-binding protein—an insulin desensitizer. Gbp2b encodes a GTPase. Because Gbp2b increased several hundred-fold, we overexpressed it in brown adipocytes. This caused a shift to larger lipid droplets, suggesting that GBP2b affects signaling downstream of the β-adrenergic receptor during basal thermogenesis. Thus, Rdh1-generated atRA in BAT regulates multiple genes that promote BAT adaptation to whole-body energy status, such as fasting and re-feeding. These gene expression changes promote optimum mitochondria function and thermogenesis, limiting adiposity. Attenuation of adiposity and insulin resistance suggests that RDH1 mitigates metabolic syndrome.

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Acknowledgements

This work was supported by grants from the National Institutes of Health DK102014 and DK112754 (JLN), UC Berkeley College of Natural Resources Sponsored Projects for Undergraduate Research (MW), and a UC Berkeley NIH Bridges to Baccalaureate Grant R25GM095401 (CEG). CRK and KMO were supported by NIH Predoctoral Training Grant DK061918. The authors would like to thank Milena Tintcheva for KO mouse colony management and technical help with cell culture studies. Di Yang preformed immunolabeling for F4/80 in BAT. We thank Valerie Hynh, Jared Williams, and AgroSUP Dijon interns Julie Contini, Jeremy Rolland, Fabrice Orellana and Paul Snocks for assisting with microscopy, data collection and LD morphology analysis, and Julie Brayer for assistance with western blot experiments. Special thanks to Steve Ruzin and Denise Schichnes from the UC Berkeley CNR Biological Imaging Facility (BIF) for support of this project. Research reported in this publication was supported in part by the National Institutes of Health S10 program under award number 1S10RR026866-01 to UC Berkeley BIF. Maureen Kane and Jinshan Wang contributed to preliminary retinoid measurements. Matthew Bruss and Simply FlorCruz performed preliminary MIDA experiments. Mariarita Perri assisted with serum lipid measurements. Lilyana Chandra, Audrey Kim, Jane Kim, William Whang, Nicholas Bonniot, and Delphine Foucault assisted with animal studies.

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Author notes

  1. Sean P. Gordon

    Present address: DOE Joint Genome Institute, 2800 Mitchell Dr # 100, Walnut Creek, CA, 94598, USA

  2. Charles R. Krois

    Present address: Department of Chemistry and Geology, Minnesota State University, 241 Ford Hall, Mankato, MN, 56001, USA

  3. Priscilla Huang

    Present address: Arizona College of Osteopathic Medicine, Midwestern University, 19555 North 59th Avenue, Glendale, AZ, 85308, USA

  4. Claire Zaversnik

    Present address: AgroSup Dijon, 26 Bd Petitjean, 21000, Dijon, France

  5. Conan S. Liu

    Present address: Sidney Kimmel Medical College, 1025 Walnut Street, Philadelphia, PA, 19104, USA

  6. Madelyn R. Wheeler

    Present address: UC Davis School of Medicine, 4102 Sherman Way, Sacramento, CA, 95817, USA

  7. Kristin M. Obrochta

    Present address: Biomarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA, 94949, USA

  8. Jin H. Min

    Present address: Nova Southeastern University, 3301 College Avenue, Fort Lauderdale, FL, 33314, USA

  9. Candice B. Herber

    Present address: University of California, San Francisco, Rock Hall 281, 1550 4th Street, San Francisco, CA, 94158, USA

  10. Airlia C. Thompson

    Present address: Stanford University, Lorry Lokey Building Room 164, 337 Campus Drive, Stanford, CA, 94305-5020, USA

  11. Ishan D. Shah

    Present address: Keck School of Medicine, University of Southern California, 1975 Zonal Avenue, Keith Administration (KAM) 100, Los Angeles, CA, 90089-9020, USA

Authors and Affiliations

  1. Graduate Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 119 Morgan Hall, Berkeley, CA, 94720-3104, USA

    Charles R. Krois, Marta G. Vuckovic, Priscilla Huang, Claire Zaversnik, Conan S. Liu, Candice E. Gibson, Madelyn R. Wheeler, Kristin M. Obrochta, Jin H. Min, Candice B. Herber, Airlia C. Thompson, Ishan D. Shah, Marc K. Hellerstein & Joseph L. Napoli

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  1. Charles R. Krois
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Contributions

CRK, MGV, and JLN contributed to designing the study, analyzing the data and writing the manuscript. CRK, MGV, PH, CG, CZ, CSL, KMO, JHM, CBH, MRW and ACT performed experimental work and reviewed the manuscript. SPG analyzed RNAseq data. IDS analyzed RARE data. MKH reviewed mass isotopic dilution analysis studies.

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Correspondence to Joseph L. Napoli.

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Krois, C.R., Vuckovic, M.G., Huang, P. et al. RDH1 suppresses adiposity by promoting brown adipose adaptation to fasting and re-feeding. Cell. Mol. Life Sci. 76, 2425–2447 (2019). https://doi.org/10.1007/s00018-019-03046-z

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