Hypothalamic-Pituitary-Gonadal Axis in the Mutant Weaver Mouse

Schwartz, Neena B.; Szabó, Márta; Verina, Tatyana; Wei, Jian‐Jun; Dlouhy, Stephen R.; Won, Lisa; Heller, Alfred; Hodes, M. E.; Ghetti, Bernardino

doi:10.1159/000054387

Cited by 12 publications

(9 citation statements)

References 52 publications

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“…During the course of our study, we also found that weaver mice were growth retarded and their body weights correlated with a decrease in circulating IGF-I levels [20]. Although normal pituitary GH levels were previous reported in weaver mice [21], the circulating GH levels as well as the functional status of the GH/IGF-I axis has not been examined.…”

Section: Introductionsupporting

confidence: 53%

Role of the GH/IGF-I axis in the growth retardation of weaver mice

Yao

Bethin

Yang

et al. 2007

Endocr

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IGF-I is a well-established anabolic growth factor essential for growth and development. Although the role of the GH/IGF-I axis is established for normal postnatal growth, its functional state in neurodegenerative diseases is not fully characterized. The weaver mutant mouse is a commonly used model for studying hereditary cerebellar ataxia and provides an opportunity to investigate the function of IGF-I in postnatal growth following neurodegeneration. Previously, we reported that weaver mice are growth retarded and their body weights correlate with a decrease in circulating IGF-I levels. Because weaver mice have the same food intake/body weight ratios as their wild type littermates, our observation suggests that an impairment of the GH/IGF-I axis, rather than poor nutrition, likely contributes to their growth retardation. This study further investigated the etiology of reduced circulating IGF-I levels. We found that GH levels in weaver mice were reduced following acute insulin injection, but the hepatic GH receptor transduction pathway signaled normally as evidenced by increased STAT5b phosphorylation and IGF-I mRNA levels in response to acute GH administration. In addition, 2-week GH treatment induced a significant increase in body weight and circulating IGF-I levels in homozygous weaver mice but not in wild type littermates. In summary, a deficiency in the GH/IGF-I axis may be partially responsible for postnatal growth retardation in weaver mutant mice. This deficiency may occur at the level of the pituitary and/or hypothalamus and can be improved with GH administration.

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Section: Introductionsupporting

confidence: 53%

Role of the GH/IGF-I axis in the growth retardation of weaver mice

Yao

Bethin

Yang

et al. 2007

Endocr

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“…Both female and male weaver mice have a normal surge of sex hormones in early puberty. By D60, no genotype-dependent difference was observed in serum and pituitary FSH/ LH levels in female weaver mice or in serum and testicular testosterone levels in male weaver mice (Schwartz et al, 1998). Since the gender bias occurs after the onset of puberty (D45), the surges of circulating estrogen and androgen are likely responsible for the differences in BMD and body composition as weaver mice reach sexual maturity.…”

Section: Discussionmentioning

confidence: 94%

IGF-I improved bone mineral density and body composition of weaver mutant mice

Yao

Zhong

et al. 2008

Growth Hormone & IGF Research

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Our recent report on a parallel decrease in the body weights and serum IGF-I levels of weaver mice suggests that IGF-I's endocrine function may be impaired in neurodegenerative diseases. To further understand the overall effects of IGF-I deficiency on the postnatal growth, we measured bone mineral density (BMD), bone mineral content (BMC), lean body mass (LBM) and fat mass in male and female weaver mice and wild-type littermates on D21 (prepuberty), D45 (puberty), and D60 (postpuberty) using Dual-Energy X-ray Absorptionmetry (DEXA). In both male and female weaver mice, we found that the levels of circulating IGF-I paralleled those of BMD, BMC, and LBM, but not the fat mass. Male weaver mice have normal fat mass at all three ages studied, whereas female weaver mice showed a trend to increase their fat mass as they mature. To determine whether circulating IGF-I is a determinant of body composition, we crossbred IGF-I transgenic mice with homozygous weaver mice, which resulted in a significant increase in circulating IGF-I levels in both male and female weaver mice and normalization of their BMD, BMC and body weights. In summary, our results demonstrated that normal circulating IGF-I levels are important in maintaining BMD, BMC, and body composition in neurodegenerative diseases, such as hereditary cerebellar ataxia.

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“…4. The concentration of testosterone in the plasma of mice is notoriously variable (50,51). In these studies, for example, the range of values was very large in the npc1 1/1 mice (from 0.28 to 7.37 ng/ml).…”

Section: /Srb1mentioning

confidence: 91%

Cholesterol substrate pools and steroid hormone levels are normal in the face of mutational inactivation of NPC1 protein

Xie

Richardson

Turley

et al. 2006

Journal of Lipid Research

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Mutational inactivation of NPC1 largely blocks the movement of LDL-derived cholesterol from the lysosome to the metabolically active, cytosolic pool of sterol that is the substrate for steroid hormone production. Such a block might, in theory, lead to deficiencies in circulating levels of testosterone, progesterone, and corticosterone. However, there are at least two other sources for cellular cholesterol, de novo synthesis and scavenger receptor class B type I-mediated uptake of HDL cholesteryl ester (CE). In this study, we measured the rates of net cholesterol acquisition by these three pathways in the adrenal, ovary, and testis. In all three organs, the majority (81-98%) of cholesterol acquisition came from the selective uptake of CE from HDL and de novo synthesis. Furthermore, in the npc1 2/2 mouse, the cytosolic storage pool of CE in a tissue such as the adrenal remained constant (z25 mg/g). As a result of these alternative pathways, the plasma concentrations of testosterone (3.5 vs. 2.5 ng/ml), progesterone (8.5 vs. 6.7 ng/ml), and corticosterone (391 vs. 134 ng/ml) were either the same or elevated in the npc1 2/2 mouse, compared with the control animal.Thus, impairment of cholesterol acquisition through the NPC1-dependent, clathrin-coated pit pathway did not limit the availability of cholesterol substrate for steroid hormone synthesis in the steroidogenic cells. Essentially all cells acquire cholesterol primarily through de novo synthesis (1-3). In addition, at least three different proteins located in the plasma membrane are recognized that can also bring about the net transfer of sterol from the extracellular environment into the metabolically active pools of cholesterol within these cells. The first of these, the LDL receptor (LDLR), can take up lipoproteins that contain one of two ligands, apolipoprotein B 100 (apoB 100 ) or apoE, and these include LDL and the remnants of both VLDL and chylomicrons (4, 5). This transport process involves binding of the ligand to the receptor, clustering of the bound lipoproteins into clathrin-coated pits, and finally, internalization of these particles into the endosomal/ lysosomal compartment of the cell (6). There, acidification leads to a change in the configuration of the binding site on the LDLR, release of the lipoprotein, and ultimately, hydrolysis of the cholesteryl ester (CE) contained in these particles by an acidic cholesteryl ester esterase, i.e., acid lipase (7-9). Thus, this LDLR-dependent endocytosis results in the uptake of the cholesterol, both esterified and unesterified, carried in particles like LDL, and deposits it as unesterified sterol in the endosomal compartment of the cell.The second plasma membrane protein, scavenger receptor class B type I (SR-BI), binds lipoproteins containing apoAI such as HDL, and then processes these particles through a very different pathway (10,11). Although the details of this internalization step are not clear, in some manner cholesteryl ester from the HDL particle is selectively translocated into the cell ...

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Hypothalamic-Pituitary-Gonadal Axis in the Mutant Weaver Mouse

Cited by 12 publications

References 52 publications

Role of the GH/IGF-I axis in the growth retardation of weaver mice

Role of the GH/IGF-I axis in the growth retardation of weaver mice

IGF-I improved bone mineral density and body composition of weaver mutant mice

Cholesterol substrate pools and steroid hormone levels are normal in the face of mutational inactivation of NPC1 protein

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