Decreased YB-1 expression denervates brown adipose tissue and contributes to age-related metabolic dysfunction

Abstract

Thermogenesis in brown adipose tissue (BAT) declines with aging, however, the underlying mechanism remains unclear. Here, we show that the expression of Y-box binding protein 1 (YB-1), a critical DNA/RNA binding protein, decreased in the BAT of aged mice due to the reduction of microbial metabolite butyrate. Genetic ablation of YB-1 in the BAT accelerated diet-induced obesity and BAT thermogenic dysfunction. In contrast, overexpression of YB-1 in the BAT of aged mice was sufficient to promote BAT thermogenesis, thus alleviating diet-induced obesity and insulin resistance. Interestingly, YB-1 had no direct effect on adipose UCP1 expression. Instead, YB-1 promoted axon guidance of BAT via regulating the expression of Slit2, thus potentiating sympathetic innervation and thermogenesis. Moreover, we have identified that a natural compound Sciadopitysin, which promotes YB-1 protein stability and nuclear translocation, alleviated BAT aging and metabolic disorders. Together, we reveal a novel fat-sympathetic nerve unit in regulating BAT senescence and provide a promising strategy against age-related metabolic disorders.

References

[1] Zoico E, Rubele S, De Caro A, et al. Brown and Beige adipose tissue and aging. Front Endocrinol (Lausanne). 2019;10:368.

[2] Fu X, Liu Z, Zhu C, Mou H, Kong Q. Nondigestible carbohydrates, butyrate, and butyrate-producing bacteria. Crit Rev Food Sci Nutr. 2019;59(1):S130-S152.

[3] Wang RX, Lee JS, Campbell EL, Colgan SP. Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of Actin-associated protein synaptopodin. Proc Natl Acad Sci USA. 2020;117(21):11648-11657.

[4] Li G, Lin J, Zhang C, et al. Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease. Gut Microbes. 2021;13(1):1968257.

[5] Wu H, Tremaroli V, Schmidt C, et al. The gut microbiota in prediabetes and diabetes: a population-based cross-sectional study. Cell Metab. 2020;32(3):379-390.e373.

[6] Hong YH, Nishimura Y, Hishikawa D, et al. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology. 2005;146(12):5092-5099.

[7] Lu Y, Fan C, Li P, Lu Y, Chang X, Qi K. Short chain fatty acids prevent high-fat-diet-induced obesity in mice by regulating G protein-coupled receptors and gut microbiota. Sci Rep. 2016;6:37589.

[8] Lyabin DN, Eliseeva IA, Ovchinnikov LP. YB-1 protein: functions and regulation. Wiley Interdiscip Rev RNA. 2014;5(1):95-110.

[9] Mordovkina D, Lyabin DN, Smolin EA, Sogorina EM, Ovchinnikov LP, Eliseeva I. Y-box binding proteins in mRNP assembly, translation and stability control. Biomolecules. 2020;10(4):591.

[10] Ma S, Sun S, Geng L, et al. Caloric restriction reprograms the single-cell transcriptional landscape of Rattus norvegicus aging. Cell. 2020;180(5):984-1001.e1022.

[11] Xiao YZ, Yang M, Xiao Y, et al. Reducing hypothalamic stem cell senescence protects against aging-associated physiological decline. Cell Metab. 2020;31(3):534-548.e535.

[12] Rabiee A, Plucinska K, Isidor MS, et al. White adipose remodeling during browning in mice involves YBX1 to drive thermogenic commitment. Mol Metab. 2021;44:101137.

[13] Park JH, Kang HJ, Kang SI, et al. A multifunctional protein, EWS, is essential for early brown fat lineage determination. Dev Cell. 2013;26(4):393-404.

[14] Wang D, Liu CD, Li HF, et al. LSD1 mediates microbial metabolite butyrate-induced thermogenesis in brown and white adipose tissue. Metabolism. 2020;102:154011.

[15] Martin-Gallausiaux C, Marinelli L, Blottière HM, Larraufie P, Lapaque N. SCFA: mechanisms and functional importance in the gut. Proc Nutr Soc. 2021;80(1):37-49.

[16] Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol. 2015;11(10):577-591.

[17] Coll M, Arino S, Martinez-Sanchez C, et al. Ductular reaction promotes intrahepatic angiogenesis through Slit2-roundabout 1 signaling. Hepatology. 2022;75(2):353-368.

[18] Ieda M, Fukuda K, Hisaka Y, et al. Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression. J Clin Invest. 2004;113(6):876-884.

[19] Greene LA, Tischler AS. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci USA. 1976;73(7):2424-2428.

[20] Cui X, Jing J, Wu R, et al. Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue. Nat Commun. 2021;12(1):5362.

[21] Wang YN, Tang Y, He Z, et al. Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue. Nat Metab. 2021;3(11):1536-1551.

[22] Cariboni A, Andrews WD, Memi F, et al. Slit2 and Robo3 modulate the migration of GnRH-secreting neurons. Development. 2012;139(18):3326-3331.

[23] Lu ZH, Books JT, Ley TJ. YB-1 is important for late-stage embryonic development, optimal cellular stress responses, and the prevention of premature senescence. Mol Cell Biol. 2005;25(11):4625-4637.

[24] Wu R, Cao S, Li F, et al. RNA-binding protein YBX1 promotes brown adipogenesis and thermogenesis via PINK1/PRKN-mediated mitophagy. FASEB J. 2022;36(3):e22219.

RIGHTS & PERMISSIONS

2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.