title: High-fat diet-induced obesity and insulin resistance were ameliorated via enhanced fecal bile acid excretion in tumor necrosis factor-alpha receptor knockout mice.
abstract: Tumor necrosis factor-α (TNF-α) is one of the main mediators of inflammatory response activated by fatty acids in obesity, and this signaling through TNF-α receptor (TNFR) is responsible for obesity-associated insulin resistance. Recently, TNF-α has shown to affect lipid metabolism including the regulation of lipase activity and bile acid synthesis. However, there is scanty in vivo evidence for the involvement of TNF-α in this process, and the mechanistic role of TNFR remains unclear. In this study, TNFR2 knockout mice (R2KO) and wild-type (WT) mice were fed commercial normal diet (ND) or high-fat diet (HFD) for 8 weeks. In R2KO/HFD mice, the increase in body weight and the accumulation of fat were significantly ameliorated compared with WT/HFD mice in association with the decrease in plasma total cholesterol (137.7±3.1 vs. 98.6±3.1 mg/dL, P<0.005), glucose (221.9±14.7 vs. 167.3±8.1 mg/dL, P<0.01), and insulin (5.1±0.3 vs. 3.4±0.3 ng/mL, P<0.05). Fecal excretion of lipid contents was significantly increased in R2KO mice. In R2KO/HFD mice, the decrease in hepatic cholesterol-7a-hydroxylase activity, the rate-limiting enzyme in bile acid synthesis, was inhibited (1.7±0.2 vs. 8.1±1.0 pmol/min/mg protein, P<0.01). These results suggested that HFD-induced obesity with metabolic derangements could be ameliorated in mice lacking TNF-α receptor 2 via increasing fecal bile acid and lipid content excretion. Therefore, TNF-α signaling through TNFR2 is essentially involved in the bile acid synthesis and excretion of lipids, resulting in its beneficial effects.
authors.affiliation: Department REDOX Medicinal Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. yamato68@redoxnavi.med.kyushu-u.ac.jp
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamato
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shiba
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.forename: Naoko
authors.initials: N
authors.lastname: Seri
authors.forename: Wataru
authors.initials: W
authors.lastname: Kudo
authors.forename: Makoto
authors.initials: M
authors.lastname: Ando
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamada
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kinugawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism / Q000502:physiology*; D059305:Diet, High-Fat; D005243:Feces / Q000737:chemistry; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008055:Lipids / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D001647:Bile Acids and Salts; D008055:Lipids; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha