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Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, Australia
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Department of Molecular and Translational Research, Monash University, Melbourne, Victoria, Australia
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MR developed relatively normally to birth but during the first week postnatally developed symptoms of pseudohypoaldosteronism, losing weight with a failure to survive and eventually died by day 10. MR-null mice displayed hyperkalaemia, hyponatraemia
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gonadectomy in pttg −/− males with and without added estradiol therapy, compared with pttg −/− control male mice (data not shown). Discussion In pttg -null mice, sexually dimorphic diabetes is associated with β
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The latent transforming growth factor (TGF)-beta binding proteins (LTBP)-1, -3 and -4 bind the latent form of the multipotent cytokine TGF-beta. To examine the function of the LTBPs, we made a null mutation of Ltbp-3 by gene targeting. The homozygous mutant animals developed cranio-facial malformations by 12 days. By three months, there was a pronounced rounding of the cranial vault, extension of the mandible beyond the maxilla, and kyphosis. The mutant animals developed osteosclerosis of the long bones and vertebrae as well as osteoarthritis between 6 and 9 months of age. These latter phenotypic changes were similar to those described for mice that have impaired TGF-beta signaling. Thus, we suggest that Ltbp-3 plays an important role in regulating TGF-beta bioavailability as the phenotype of the Ltbp-3 null mouse appears to result from decreased TGF-beta signaling. Histological examination of the skulls from null animals revealed no effects on calvarial suture closure. However, the synchondroses in the skull base were obliterated within 2 weeks of birth. This is in contrast to the wild-type synchondroses, which remain unossified throughout the life of the animal and enable growth of the skull base through endochondral ossification. Histological changes in mutant basooccipital-basosphenoid synchondrosis were observed 1.5 days after birth. Compared with wild-type or heterozygous littermates, the basooccipital-basosphenoid synchondrosis of Ltbp-3 null mice contained increased numbers of hypertrophic chondrocytes. The expression of bone sialoprotein-1 (a marker for osteoblasts) was observed in cells surrounding the synchondrosis at postnatal day 1.5 indicating ectopic ossification. The expression of Indian hedgehog (Ihh) (a marker for chondrocytes committed to hypertrophic differentiation) was found through the basooccipital-basosphenoid synchondrosis, whereas the expression of parathyroid hormone related protein (PTHrP), which inhibits chondrocyte differentiation, appeared to be diminished in Ltbp-3 null mice. This suggests that Ltbp-3 may control chondrocyte differentiation by regulating TGF-beta availability. TGF-beta may regulate PTHrP expression either downstream of Ihh or independently of Ihh signaling.
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expression of these hormones in somatotrope LEPR-null mice ( Odle et al. 2016 ). These data pointed to the possibility that leptin may also regulate multi-hormonal expression by a subset of somatotropes. We also reported that Pou1f1 was reduced in the
Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
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Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
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Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
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Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
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Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
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Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
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Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
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Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11β-hydroxysteroid dehydrogenase type 1 null mice. Journal of Biological Chemistry 276 41293 –41300. Morton NM , Paterson JM
Department of Molecular and Cellular Biology,
Department of Medicine, The Breast Center, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, 1100 Bates Street, Houston, Texas 77030, USA
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Department of Molecular and Cellular Biology,
Department of Medicine, The Breast Center, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, 1100 Bates Street, Houston, Texas 77030, USA
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Department of Molecular and Cellular Biology,
Department of Medicine, The Breast Center, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, 1100 Bates Street, Houston, Texas 77030, USA
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Department of Molecular and Cellular Biology,
Department of Medicine, The Breast Center, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, 1100 Bates Street, Houston, Texas 77030, USA
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Department of Molecular and Cellular Biology,
Department of Medicine, The Breast Center, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, 1100 Bates Street, Houston, Texas 77030, USA
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Department of Molecular and Cellular Biology,
Department of Medicine, The Breast Center, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, 1100 Bates Street, Houston, Texas 77030, USA
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Department of Molecular and Cellular Biology,
Department of Medicine, The Breast Center, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, 1100 Bates Street, Houston, Texas 77030, USA
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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+/+ mammary tissue. Each bar represents the mean ± s.d . for two mice. The authors thank Dr C Ronald Kahn for providing the Irs1 null mice. They also thank Dr Xiaojiang Cui for help with the immunoprecipitation analysis. Funding This
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PE, but this may not have been detected by the histological methods; this illustrates the value of OPT in revealing additional aspects of mutant morphology. Indeed, this is similar to the situation reported in the asplenic phenotype of Bapx1 null
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Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
Department of Child Health, University of Missouri, Columbia, Missouri, USA
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Premenopausal females are protected against adipose tissue inflammation and insulin resistance, until loss of ovarian hormone production (e.g., menopause). There is some evidence that females have greater brown adipose tissue (BAT) thermogenic capacity. Because BAT mass correlates inversely with insulin resistance, we hypothesized that increased uncoupling protein 1 (UCP1) expression contributes to the superior metabolic health of females. Given that UCP1 transiently increases in BAT following ovariectomy (OVX), we hypothesized that UCP1 may ‘buffer’ OVX-mediated metabolic dysfunction. Accordingly, female UCP1-knockout (KO) and WT mice received OVX or sham (SHM) surgeries at 12 weeks of age creating four groups (n = 10/group), which were followed for 14 weeks and compared for body weight and adiposity, food intake, energy expenditure and spontaneous physical activity (metabolic chambers), insulin resistance (HOMA-IR, ADIPO-IR and glucose tolerance testing) and adipose tissue phenotype (histology, gene and protein expression). Two-way ANOVA was used to assess the main effects of genotype (G), OVX treatment (O) and genotype by treatment (GxO) interactions, which were considered significant when P ≤ 0.05. UCP1KO mice experienced a more adverse metabolic response to OVX than WT. Whereas OVX-induced weight gain was not synergistically greater for KO compared to WT (GxO, NS), OVX-induced insulin resistance was significantly exacerbated in KO compared to WT (GxO for HOMA-IR, P < 0.05). These results suggest UCP1 is protective against metabolic dysfunction associated with loss of ovarian hormones and support the need for more research into therapeutics to selectively target UCP1 for prevention and treatment of metabolic dysfunction following ovarian hormone loss.
Metabolic Research Laboratory, Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford Churchill Hospital, Oxford, UK
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Metabolic Research Laboratory, Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford Churchill Hospital, Oxford, UK
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Metabolic Research Laboratory, Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford Churchill Hospital, Oxford, UK
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Metabolic Research Laboratory, Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford Churchill Hospital, Oxford, UK
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), which provides an indication of total flux through the FA synthetic pathway ( Islam et al. 2005 ). Recently, it has been demonstrated that postabsorptive (6 h starved) PPARα null mice exhibit increased whole-body glucose turnover (production and
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2006 ). Scarb1 -null mice show high HDL-associated cholesterol (HDL-C) levels due to impaired selective uptake of cholesterol by the liver ( Rigotti et al . 1997 ). Also, Scarb1 -null male mice exhibit lack of SR-BI-mediated cholesterol uptake from
