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

• Published in: Cellular and molecular life sciences : CMLS 2019-06, Vol.76 (12), p.2425-2447
• Main Authors: Krois, Charles R., Vuckovic, Marta G., Huang, Priscilla, Zaversnik, Claire, Liu, Conan S., Gibson, Candice E., Wheeler, Madelyn R., Obrochta, Kristin M., Min, Jin H., Herber, Candice B., Thompson, Airlia C., Shah, Ishan D., Gordon, Sean P., Hellerstein, Marc K., Napoli, Joseph L.
• Format: Article
• Language: English
• Subjects: Ablation; Adaptation; Adipocytes; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - physiology; Adiposity; Adrenergic receptors; Animals; Attenuation; Biochemistry; Biomedical and Life Sciences; Biomedicine; Body temperature; Calories; Cell Biology; Chemical reactions; Diet, Fat-Restricted; Droplets; Eating; Energy balance; Energy Metabolism; Fasting; Feeding; Female; Gene Deletion; Gene expression; Genes; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; Glucose tolerance; Guanosine triphosphatases; Homeostasis; Hydroxysteroid Dehydrogenases - genetics; Hydroxysteroid Dehydrogenases - metabolism; Hyperplasia; Hypertrophy; Insulin; Insulin Resistance; Intolerance; Life Sciences; Lipid Metabolism; Lipids; Lipolysis; Liver; Low fat diet; Male; Membrane potential; Metabolic disorders; Metabolic syndrome; Mice; Mice, Inbred C57BL; Mitochondria; Muscles; Nutrient deficiency; Original Article; Oxygen consumption; Phenotypes; Proteins; Retinoic acid; Thermogenesis; Tretinoin - metabolism; Vitamin A - metabolism; Weight
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-019-03046-z

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.