title: Glucoraphanin Ameliorates Obesity and Insulin Resistance Through Adipose Tissue Browning and Reduction of Metabolic Endotoxemia in Mice.
abstract: Low-grade sustained inflammation links obesity to insulin resistance and nonalcoholic fatty liver disease (NAFLD). However, therapeutic approaches to improve systemic energy balance and chronic inflammation in obesity are limited. Pharmacological activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) alleviates obesity and insulin resistance in mice; however, Nrf2 inducers are not clinically available owing to safety concerns. Thus, we examined whether dietary glucoraphanin, a stable precursor of the Nrf2 inducer sulforaphane, ameliorates systemic energy balance, chronic inflammation, insulin resistance, and NAFLD in high-fat diet (HFD)-fed mice. Glucoraphanin supplementation attenuated weight gain, decreased hepatic steatosis, and improved glucose tolerance and insulin sensitivity in HFD-fed wild-type mice but not in HFD-fed Nrf2 knockout mice. Compared with vehicle-treated controls, glucoraphanin-treated HFD-fed mice had lower plasma lipopolysaccharide levels and decreased relative abundance of the gram-negative bacteria family Desulfovibrionaceae in their gut microbiomes. In HFD-fed mice, glucoraphanin increased energy expenditure and the protein expression of uncoupling protein 1 (Ucp1) in inguinal and epididymal adipose depots. Additionally, in this group, glucoraphanin attenuated hepatic lipogenic gene expression, lipid peroxidation, classically activated M1-like macrophage accumulation, and inflammatory signaling pathways. By promoting fat browning, limiting metabolic endotoxemia-related chronic inflammation, and modulating redox stress, glucoraphanin may mitigate obesity, insulin resistance, and NAFLD.
authors.affiliation: Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Naoto
authors.identifier: 0000-0002-2389-2334
authors.initials: N
authors.lastname: Nagata
authors.affiliation: Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kohno
authors.affiliation: Research and Development Division, Kagome Co., Ltd., Nasushiobara, Tochigi, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ushida
authors.affiliation: Research and Development Division, Kagome Co., Ltd., Nasushiobara, Tochigi, Japan.
authors.forename: Yudai
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Research and Development Division, Kagome Co., Ltd., Nasushiobara, Tochigi, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Umeda
authors.affiliation: Research and Development Division, Kagome Co., Ltd., Nasushiobara, Tochigi, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Fuke
authors.affiliation: Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhuge
authors.affiliation: Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nagashimada
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Takahashi
authors.affiliation: Research and Development Division, Kagome Co., Ltd., Nasushiobara, Tochigi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suganuma
authors.affiliation: Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan tota@staff.kanazawa-u.ac.jp.|Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors.forename: Tsuguhito
authors.initials: T
authors.lastname: Ota
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D003901:Desulfovibrio; D059305:Diet, High-Fat; D019446:Endotoxemia; D004734:Energy Metabolism / Q000187:drug effects; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D005961:Glucosinolates / Q000494:pharmacology*; D007096:Imidoesters / Q000494:pharmacology*; D007249:Inflammation; D007333:Insulin Resistance; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D010091:Oximes; D013454:Sulfoxides; D000071256:Uncoupling Protein 1 / Q000187:drug effects / Q000378:metabolism
chemical_list: D005961:Glucosinolates; D007096:Imidoesters; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010091:Oximes; D013454:Sulfoxides; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C119494:glucoraphanin