Dietary steamed wheat bran increases postprandial fat oxidation in association with a reduced blood glucose-dependent insulinotropic polypeptide response in mice.

Obesity is a global epidemic associated with a higher risk of cardiovascular disease and metabolic disorders, such as type 2 diabetes. Previous studies demonstrated that chronic feeding of steamed wheat bran (WB) decreases obesity. To clarify the underlying mechanism and the responsible component for the anti-obesity effects of steamed WB, we investigated the effects of dietary steamed WB and arabinoxylan on postprandial energy metabolism and blood variables. Overnight-fasted male C57BL/6J mice were fed an isocaloric diet with or without steamed WB (30%). Energy metabolism was evaluated using an indirect calorimeter, and plasma glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) levels were measured for 120 min after feeding. We similarly investigated the effect of arabinoxylan, a major component of steamed WB. Mice fed the WB diet had higher postprandial fat oxidation and a lower blood GIP response compared with mice fed the control diet. Mice fed the arabinoxylan diet exhibited a dose-dependent postprandial blood GIP response; increasing the arabinoxylan content in the diet led to a lower postprandial blood GIP response. The arabinoxylan-fed mice also had higher fat oxidation and energy expenditure compared with the control mice. In conclusion, the findings of the present study revealed that dietary steamed WB increases fat oxidation in mice. Increased fat oxidation may have a significant role in the anti-obesity effects of steamed WB. The postprandial effects of steamed WB are due to arabinoxylan, a major component of WB. The reduction of the postprandial blood GIP response may be responsible for the increase in postprandial fat utilization after feeding on a diet containing steamed WB and arabinoxylan.

Identifying quantitative trait loci affecting resistance to congenital hypothyroidism in 129/SvJcl strain mice.

Tyrosylprotein sulfotransferase 2 (TPST2) is one of the enzymes responsible for tyrosine O-sulfation and catalyzes the sulfation of the specific tyrosine residue of thyroid stimulating hormone receptor (TSHR). Since this modification is indispensable for the activation of TSH signaling, a non-functional TPST2 mutation (Tpst2(grt)) in DW/J-grt mice leads to congenital hypothyroidism (CH) characterized by severe thyroid hypoplasia and dwarfism related to TSH hyporesponsiveness. Previous studies indicated that the genetic background of the 129(+Ter)/SvJcl (129) mouse strain ameliorates Tpst2(grt)-induced CH. To identify loci responsible for CH resistance in 129 mice, we performed quantitative trait locus (QTL) analysis using backcross progenies from susceptible DW/J and resistant 129 mice. We used the first principal component calculated from body weights at 5, 8 and 10 weeks as an indicator of CH, and QTL analysis mapped a major QTL showing a highly significant linkage to the distal portion of chromosome (Chr) 2; between D2Mit62 and D2Mit304, particularly close to D2Mit255. In addition, two male-specific QTLs showing statistically suggestive linkage were also detected on Chrs 4 and 18, respectively. All QTL alleles derived from the 129 strain increased resistance to growth retardation. There was also a positive correlation between recovery from thyroid hypoplasia and the presence of the 129 allele at D2Mit255 in male progenies. These results suggested that the major QTL on Chr 2 is involved in thyroid development. Moreover, since DW/J congenic strain mice carrying both a Tpst2(grt) mutation and 129 alleles in the major QTL show resistance to dwarfism and thyroid hypoplasia, we confirmed the presence of the resistant gene in this region, and that it is involved in thyroid development. Further genetical analysis should lead to identification of genes for CH tolerance and, from a better understanding of thyroid organogenesis and function, the subsequent development of new treatments for thyroid disorders.

Hypothyroid phenotype of the Tpst2 mutant mouse is dependent upon genetic background.

DW/J-grt is a congenital hypothyroid mouse model that is characterized by growth retardation, significantly lowered T3 and T4 levels, and severe thyroid hypoplasia related to TSH hyporesponsiveness. Previously, we identified the point mutation of the Tpst2 gene in DW/J-grt mice that causes a decrease in the enzymatic activity, and demonstrated that the Tpst2 transgene rescues the mutant phenotypes both in vitro and in vivo. The severity of hypothyroidism is highly variable indicating the influence of modifier genes in humans. In this study, to identify the modifier/resistant gene(s) to hypothyroidism, we produced congenic strains carrying this Tpst2(grt) mutation on the C57BL/6J and 129/SvJcl (129) genetic backgrounds and analyzed growth rate and thyroid function. Interestingly, the 129 congenic mice exhibited normal growth and thyroid function. The result suggests that 129 strain has the modifier(s) of attenuation of hypothyroidism. Therefore, the identification of the modifier loci of 129 mice will provide important new information about the gene(s) related to congenital hypothyroidism.

Female infertility in grt mice is caused by thyroid hormone deficiency, not by insufficient TPST2 activity in the reproductive organs.

The growth-retarded (grt) mouse has an autosomal recessive hypothyroidism and the female shows lifelong infertility. We previously reported that these mutant phenotypes are caused by a deficiency in the enzymatic activity of tyrosylprotein sulfotransferase-2 (TPST2), and severe thyroid hypogenesis and consequent dwarfism are mainly due to the impairment of the tyrosine sulfation of thyroid-stimulating hormone receptor (TSHR) by TPST2. Although TPST2 is ubiquitously expressed and many proteins are predicted to be tyrosine sulfated and involved in many biological processes, the functional roles of tyrosine sulfation in the reproductive organs remain unclear. These findings tempted us to hypothesize two possible mechanisms underlying the infertility; a deficiency in TPST2 activity in the reproductive organs might cause the infertility in grt mice, or a significant decrease in serum thyroid hormones might impair the normal development of reproductive organs. When mutant female mice were fed a diet supplemented with sufficient thyroid powder to correct their growth retardation, the rate of copulation, pregnancy, and parturition was completely restored. Therefore, we concluded that the infertility in grt female is due to a thyroid hormone deficiency.

A mutation in Tpst2 encoding tyrosylprotein sulfotransferase causes dwarfism associated with hypothyroidism.

The growth-retarded (grt) mouse has an autosomal recessive, fetal-onset, severe thyroid hypoplasia related to TSH hyporesponsiveness. Through genetic mapping and complementation experiments, we show that grt is a missense mutation of a highly conserved region of the tyrosylprotein sulfotransferase 2 (Tpst2) gene, encoding one of the two Tpst genes implicated in posttranslational tyrosine O-sulfation. We present evidence that the grt mutation leads to a loss of TPST2 activity, and TPST2 isoform has a high degree of substrate preference for TSH receptor (TSHR). The expression of TPST2 can restore TSH-TSHR-mediated cAMP production in fibroblasts derived from grt mice. Therefore, we propose that the tyrosine sulfation of TSHR by TPST2 is crucial for TSH signaling and resultant thyroid gland function.