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Link J.C.,Molecular Biology Institute | Chen X.,Laboratory of Neuroendocrinology of the Brain Research Institute | Prien C.,University of California at Los Angeles | Borja M.S.,Childrens Hospital Oakland Research Institute | And 5 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2015

Objective - The molecular mechanisms underlying sex differences in dyslipidemia are poorly understood. We aimed to distinguish genetic and hormonal regulators of sex differences in plasma lipid levels. Approach and Results - We assessed the role of gonadal hormones and sex chromosome complement on lipid levels using the four core genotypes mouse model (XX females, XX males, XY females, and XY males). In gonadally intact mice fed a chow diet, lipid levels were influenced by both male-female gonadal sex and XX-XY chromosome complement. Gonadectomy of adult mice revealed that the male-female differences are dependent on acute effects of gonadal hormones. In both intact and gonadectomized animals, XX mice had higher HDL cholesterol (HDL-C) levels than XY mice, regardless of male-female sex. Feeding a cholesterol-enriched diet produced distinct patterns of sex differences in lipid levels compared with a chow diet, revealing the interaction of gonadal and chromosomal sex with diet. Notably, under all dietary and gonadal conditions, HDL-C levels were higher in mice with 2 X chromosomes compared with mice with an X and Y chromosome. By generating mice with XX, XY, and XXY chromosome complements, we determined that the presence of 2 X chromosomes, and not the absence of the Y chromosome, influences HDL-C concentration. Conclusions - We demonstrate that having 2 X chromosomes versus an X and Y chromosome complement drives sex differences in HDL-C. It is conceivable that increased expression of genes escaping X-inactivation in XX mice regulates downstream processes to establish sexual dimorphism in plasma lipid levels. © 2015 American Heart Association, Inc.


Billetta R.,Kai BioEnergy | Ghahramani N.,Laboratory of Neuroendocrinology of the Brain Research Institute | Morrow O.,Sanford Burnham Institute for Medical Research | Prakken B.,EUREKA Institute for Translational Medicine | And 7 more authors.
Clinical Immunology | Year: 2012

The availability of glatiramer acetate (GA) for inducing immune tolerance is a significant advancement in the treatment of multiple sclerosis (MS). However, a sizable proportion of patients maintain active disease, regardless of treatment. Another approach to induce T-cell tolerance is therefore still an unmet medical need.We hypothesized that induction of mucosal tolerance toward a pro-inflammatory T-cell epitope derived from a heat shock protein (HSP) (RatP2) could translate into clinical benefit.We found that treatment of experimental autoimmune encephalomyelitis (EAE, a model of MS) with the peptide RatP2 determined a significant clinical improvement, which was comparable to the standard tolerization treatment (an MBP-derived peptide pool) and superior to GA. Histological analysis demonstrated a reduction of brain and spinal cord inflammatory lesions in treated animals. Moreover, with immunological analysis we identified biomarkers associated with clinical response.This work provides proof-of-concept to support the further testing of this approach as a possible complement to currently available therapies for MS. © 2012 Elsevier Inc.


Chen X.,Laboratory of Neuroendocrinology of the Brain Research Institute | McClusky R.,Laboratory of Neuroendocrinology of the Brain Research Institute | Itoh Y.,Laboratory of Neuroendocrinology of the Brain Research Institute | Reue K.,University of California at Los Angeles | Arnold A.P.,Laboratory of Neuroendocrinology of the Brain Research Institute
Endocrinology | Year: 2013

Three different models of MF1 strain mice were studied to measure the effects of gonadal secretions and sex chromosome type and number on body weight and composition, and on related metabolic variables such as glucose homeostasis, feeding, and activity. The 3 genetic models varied sex chromosome complement in different ways, as follows: 1) 'four core genotypes' mice, comprising XX and XY gonadal males, and XX and XY gonadal females; 2) the XY model comprising groups similar to XO, XX, XY, and XXY; and 3) a novel model comprising 6 groups having XO, XX, and XY chromosomes with either testes or ovaries. In gonadally intact mice, gonadal males were heavier than gonadal females, but sex chromosome complement also influenced weight. The male/female difference was abolished by adult gonadectomy, after which mice with 2 sex chromosomes (XX or XY) had greater body weight and percentage of body fat than mice with 1 X chromosome. A second sex chromosome of either type, X or Y, had similar effects, indicating that the 2 sex chromosomes each possess factors that influence body weightandcomposition in theMF1 genetic background. Sex chromosome complement also influenced metabolic variables such as food intake and glucose tolerance. The results reveal a role for the Y chromosome in metabolism independent of testes and gonadal hormones and point to a small number of X-Y gene pairs with similar coding sequences as candidates for causing these effects. Copyright © 2013 by The Endocrine Society.


PubMed | Laboratory of Neuroendocrinology of the Brain Research Institute
Type: Comparative Study | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2010

In hypothalamic astrocytes obtained from adult female rats, estradiol rapidly increased free cytoplasmic calcium concentrations ([Ca(2+)](i)) that facilitate progesterone synthesis. The present study demonstrated that estradiol (1 nm) significantly and maximally stimulated progesterone synthesis within 5 min, supporting a rapid, nongenomic mechanism. The group I metabotropic glutamate receptor (mGluR1a) antagonist LY 367385 [(S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid] attenuated both the estradiol-induced [Ca(2+)](i) release and progesterone synthesis. To investigate membrane-associated estrogen receptors (mERs), agonists for ER, ER, STX-activated protein, and GPR30 were compared. The selective ER agonist propylpyrazole triole (PPT) and STX most closely mimicked the estradiol-induced [Ca(2+)](i) responses, where PPT was more potent but less efficacious than STX. Only high doses (100 nm) of selective ER agonist diarylpropionitrile (DPN) and GPR30 agonist G-1 induced estradiol-like [Ca(2+)](i) responses. With the exception of DPN (even at 100 nm), all agonists stimulated progesterone synthesis. The PPT- and STX-induced [Ca(2+)](i) release and progesterone synthesis were blocked by LY 367385. While the G-1-stimulated [Ca(2+)](i) release was blocked by LY 367385, progesterone synthesis was not. Since GPR30 was detected intracellularly but not in the membrane, we interpreted these results to suggest that G-1 could activate mGluR1a on the membrane and GPR30 on the smooth endoplasmic reticulum to release intracellular calcium. Although STX and G-1 maximally stimulated [Ca(2+)](i) release in astrocytes from estrogen receptor- knock-out (ERKO) mice, estradiol in vivo did not stimulate progesterone synthesis in the ERKO mice. Together, these results indicate that mER is mainly responsible for the rapid, membrane-initiated estradiol-signaling that leads to progesterone synthesis in hypothalamic astrocytes.

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