Decreased body weight in young Osterix-Cre transgenic mice results in delayed cortical bone expansion and accrual

We seek to determine whether increased energy dissipation in adipose tissue can prevent obesity. Transgenic mice with C57BL6/J background and the adipocyte lipid-binding protein (aP2) gene promoter directing expression of the mitochondrial uncoupling protein (UCP) gene in white and brown fat were used. Physiologically, UCP is essential for nonshivering thermogenesis in brown fat. Mice were assigned to a chow or a high-fat (HF) diet at 3 mo of age. Over the next 25 wk, gains of body weight were similar in corresponding subgroups (n = 6-8) of female and male mice: 4-5 g in chow nontransgenic and transgenic, 20 g in HF nontransgenic, and 9-11 g in HF transgenic mice. The lower body weight gain in the HF transgenic vs. nontransgenic mice corresponded to a twofold lower feed efficiency. Gonadal fat was enlarged, but subcutaneous white fat was decreased in the transgenic vs. nontransgenic mice in both dietary conditions. The results suggest that UCP synthesized from the aP2 gene promoter is capable of reducing dietary obesity.

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Consequences of thyroid hormone deficiency induced by the specific ablation of thyroid follicle cells in adult transgenic mice

Journal of Endocrinology ◽

10.1677/joe.0.1430107 ◽

1994 ◽

Vol 143 (1) ◽

pp. 107-120 ◽

Cited By ~ 15

Author(s):

H Wallace ◽

K McLaren ◽

R Al-Shawi ◽

J O Bishop

Keyword(s):

Body Weight ◽

Thyroid Hormone ◽

Transgenic Mice ◽

Follicle Cells ◽

Hormone Deficiency ◽

Mrna Levels ◽

Thyroid Follicle ◽

Receptor Mrna ◽

The Many ◽

Tsh Levels

Abstract The herpes simplex type 1 virus thymidine kinase (HSV1-TK) reporter gene was coupled to a bovine thyroglobulin promoter (TG-tk construct). Within the thyroid glands of transgenic mice expression was confined to thyroid follicle cells. Infusion of Ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl]guanine) to 8 to 12 week transgenic females led to the complete loss of thyroid HSV1-TK activity (at 3 to 4 days) and thyroid follicles (between 7 and 14 days). During the first 5 days of treatment a single reciprocal oscillation in circulating thyroxine (T4) and TSH levels occurred. By 14 days the circulating triiodothyronine (T3) and T4 levels of all treated animals were below the detection limits of the assays, while TSH levels were elevated ten-fold and continued to increase thereafter. During 14 days of treatment the thyroids regressed, protein content fell by 80–90% and the C cells, normally dispersed within the central region of each gland, came together in aggregates. Pituitary GH levels in females rose and fell back to normal within 14 days and between 14 and 28 days fell to a level comparable with that of GH-deficient lit/lit mice. The levels of hepatic GH receptor mRNA and the predominant 6·6 kb T3 receptor mRNA were unaffected by thyrocyte ablation. Thyrocyte ablation had no effect on the level of prolactin (Prl) receptor mRNA in females, but increased Prl receptor mRNA levels in males and eliminated group 1 major urinary protein (MUP) mRNA in females. T4 replacement reversed the effects of thyrocyte ablation on MUP mRNA in females and on Prl receptor mRNA in males. Despite the many physiological changes induced by thyrocyte ablation, ablated mice have been maintained for up to 1 year without thyroid hormone supplementation. T4-deficient females were normally fertile and carried pups to term. Although transgenic males expressed HSV1-TK ectopically in spermatids and spermatozoa at levels similar to thyrocyte levels, a rate of Ganciclovir infusion which successfully ablated the thyrocytes did not affect the testis. As an alternative to infusion by minipump, thyrocyte ablation could be achieved by 6 twice-daily injections of Ganciclovir, at a level of 112 μg Ganciclovir/g body weight per day, and fetuses in utero could be thyrocyte ablated by administering 50 or 15 μg/g body weight per day to pregnant females between days 14 and 18 of gestation. These data demonstrate the potential value of transgenic thyrocyte ablation in the study of the effects of thyroid hormone deprivation. Journal of Endocrinology (1994) 143, 107–120

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Mutation of the Galectin-3 Glycan Binding Domain (Lgals3-R200S) Enhances Cortical Bone Expansion in Male and Trabecular Bone Mass in Female Mice

10.1101/2020.01.09.900787 ◽

2020 ◽

Author(s):

Kevin A. Maupin ◽

Daniel Dick ◽

VARI Vivarium ◽

Transgenics Core ◽

Bart O. Williams

Keyword(s):

Bone Mass ◽

Trabecular Bone ◽

Cortical Bone ◽

Mutant Mice ◽

Slight Variation ◽

Female Mice ◽

Bone Phenotype ◽

Bone Expansion ◽

Galectin 3 ◽

Trabecular Bone Mass

AbstractThe study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.

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Enhanced cortical bone expansion in Lgals3-deficient mice during aging

Bone Research ◽

10.1038/s41413-017-0003-6 ◽

2018 ◽

Vol 6 (1) ◽

Cited By ~ 2

Author(s):

Kevin A. Maupin ◽

Kevin Weaver ◽

Alexis Bergsma ◽

Cheryl Christie ◽

Zhendong A. Zhong ◽

...

Keyword(s):

Cortical Bone ◽

Bone Expansion ◽

Deficient Mice

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Loss of perlecan heparan sulfate glycosaminoglycans lowers body weight and decreases islet amyloid deposition in human islet amyloid polypeptide transgenic mice

Protein Engineering Design and Selection ◽

10.1093/protein/gzz041 ◽

2019 ◽

Vol 32 (2) ◽

pp. 95-102

Author(s):

Andrew T Templin ◽

Mahnaz Mellati ◽

Raija Soininen ◽

Meghan F Hogan ◽

Nathalie Esser ◽

...

Keyword(s):

Body Weight ◽

Transgenic Mice ◽

Heparan Sulfate ◽

Islet Amyloid Polypeptide ◽

Amyloid Deposition ◽

Secretory Product ◽

Cell Area ◽

Β Cell ◽

Islet Amyloid

Abstract Islet amyloid is a pathologic feature of type 2 diabetes (T2D) that is associated with β-cell loss and dysfunction. These amyloid deposits form via aggregation of the β-cell secretory product islet amyloid polypeptide (IAPP) and contain other molecules including the heparan sulfate proteoglycan perlecan. Perlecan has been shown to bind amyloidogenic human IAPP (hIAPP) via its heparan sulfate glycosaminoglycan (HS GAG) chains and to enhance hIAPP aggregation in vitro. We postulated that reducing the HS GAG content of perlecan would also decrease islet amyloid deposition in vivo. hIAPP transgenic mice were crossed with Hspg2Δ3/Δ3 mice harboring a perlecan mutation that prevents HS GAG attachment (hIAPP;Hspg2Δ3/Δ3), and male offspring from this cross were fed a high fat diet for 12 months to induce islet amyloid deposition. At the end of the study body weight, islet amyloid area, β-cell area, glucose tolerance and insulin secretion were analyzed. hIAPP;Hspg2Δ3/Δ3 mice exhibited significantly less islet amyloid deposition and greater β-cell area compared to hIAPP mice expressing wild type perlecan. hIAPP;Hspg2Δ3/Δ3 mice also gained significantly less weight than other genotypes. When adjusted for differences in body weight using multiple linear regression modeling, we found no differences in islet amyloid deposition or β-cell area between hIAPP transgenic and hIAPP;Hspg2Δ3/Δ3 mice. We conclude that loss of perlecan exon 3 reduces islet amyloid deposition in vivo through indirect effects on body weight and possibly also through direct effects on hIAPP aggregation. Both of these mechanisms may promote maintenance of glucose homeostasis in the setting of T2D.

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Correlated responses to selection for large body size in oMt1a-oGH transgenic mice: reproductive traits

Genetics Research ◽

10.1017/s001667239900436x ◽

2000 ◽

Vol 75 (2) ◽

pp. 199-208 ◽

Cited By ~ 4

Author(s):

K. R. PARKS ◽

E. J. EISEN ◽

I. J. PARKER ◽

L. G. HESTER ◽

J. D. MURRAY

Keyword(s):

Body Weight ◽

Transgenic Mice ◽

Reproductive Performance ◽

Large Body ◽

Low Frequency ◽

High Growth ◽

Reproductive Traits ◽

Correlated Responses ◽

Term Selection ◽

Transgenic Lines

Correlated responses in female reproductive performance were evaluated following short-term selection within full-sib families for increased 8-week body weight in two replicates of four lines of mice: two ovine metallothionein–ovine growth hormone (oMt1a-oGH) transgene-carrier lines, one from a high-growth background (TM) and one from a control background (TC), and two non-transgenic lines, one from each of these genetic backgrounds (NM and NC, respectively). A fifth line (CC), not containing the transgene, served as a randomly selected control. The initial frequency of the oMt1a-oGH transgene construct in the TM and TC lines was 0·5. The frequency of transgenic females sampled at generations 7 and 8 of selection was 84·0% and 6·1% in the TC and TM lines, respectively. No significant female infertility differences were detected between transgene-carrier and non-transgenic lines or between transgenic and non-transgenic mice within carrier lines, whereas high-growth background lines had a higher infertility than control background lines (P < 0·05). Correlated responses in the TC transgene-carrier line were suggestive of reduced reproductive performance as indicated by increased post-implantation mortality (P < 0·05), number of dead fetuses plus implants (P < 0·05), and loss of fetuses from day 16 to parturition (P < 0·001). For the first two traits, the negative correlated responses were accounted for by the reduced performance of transgenic compared with non-transgenic females. Embryos carrying the transgene may also have a lower viability. In contrast, the NC non-transgenic line did not exhibit reduced reproductive performance for these traits. The low frequency of the transgene in the high-growth background TM line was associated with reduced fitness and a lower additive effect for 8-week body weight compared with the control background TC line.

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Dose-dependent bone-sparing effects of dietary isoflavones in the ovariectomised rat

British Journal Of Nutrition ◽

10.1079/bjn2000252 ◽

2001 ◽

Vol 85 (3) ◽

pp. 307-316 ◽

Cited By ~ 71

Author(s):

Christel Picherit ◽

Brigitte Chanteranne ◽

Catherine Bennetau-Pelissero ◽

Marie-Jeanne Davicco ◽

Patrice Lebecque ◽

...

Keyword(s):

Body Weight ◽

Bone Resorption ◽

Bone Loss ◽

Cortical Bone ◽

Bone Mineral ◽

Wistar Rats ◽

Failure Load ◽

Osteoblast Activity ◽

Metaphyseal Bone ◽

Dose Dependent

The dose-dependent bone-sparing effects of dietary isoflavones (IF) were investigated in adult (7-month-old) Wistar rats. Forty animals were ovariectomised, allocated into four groups of ten rats each, and immediately treated orally with IF at 0 (OVX), 20 (IF20), 40 (IF40) or 80 (IF80) μg/g body weight per d for 91 d; ten sham-operated (SH) controls received the same diet without added IF. Animals were killed on day 91. Both femoral failure load and total femoral, diaphyseal or metaphyseal bone mineral densities (BMD) were lower in OVX animals than in SH animals. Urinary deoxypyridinoline (DPD) excretion, a marker of bone resorption, and plasma osteocalcin (OC) levels, a marker of osteoblast activity, were higher in OVX animals than in SH animals. Total femoral and diaphyseal BMD and femoral failure load were similar in IF-treated rats and SH rats. Although metaphyseal BMD in IF40 or IF80 rats was similar to that in SH rats, its value was lower in IF20 rats than in controls. The day 91 urinary DPD excretion in IF40 and IF80 rats, but not in IF20 rats, was similar to that in SH rats. Day 91 plasma OC concentrations in IF-treated rats were similar to day 45 values, but were decreased in OVX and SH rats. Thus, daily IF consumption prevented ovariectomy-induced bone loss, both by depressing bone resorption and stimulating osteoblast activity. Moreover, as only the highest IF level induced a weak uterotrophic activity, the optimal IF dose which preserves both cancellous and cortical bone, but exhibits no oestrogen-like effects on the uterus, was 40 μg/g body weight per d.

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