Sex differences in the brain: a whole body perspective

Vries, Geert J. De; Forger, Nancy G.

doi:10.1186/s13293-015-0032-z

Cited by 117 publications

(60 citation statements)

References 174 publications

(162 reference statements)

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“…This approach allows for examination of the common obesityrelated T2D and for a wide significance of the results. The subjects were all female, and findings may therefore not automatically be applied to male subjects (48). However, we have previously compared insulin signaling in adipocytes from female and male subjects, normally and in diabetes, and found no significant differences (46).…”

Section: Methodsmentioning

confidence: 99%

Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes

Rajan¹,

Nyman

Kjølhede³

et al. 2016

Journal of Biological Chemistry

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Insulin resistance is a major aspect of type 2 diabetes (T2D), which results from impaired insulin signaling in target cells. Signaling to regulate forkhead box protein O1 (FOXO1) may be the most important mechanism for insulin to control transcription. Despite this, little is known about how insulin regulates FOXO1 and how FOXO1 may contribute to insulin resistance in adipocytes, which are the most critical cell type in the development of insulin resistance. We report a detailed mechanistic analysis of insulin control of FOXO1 in human adipocytes obtained from non-diabetic subjects and from patients with T2D. We show that FOXO1 is mainly phosphorylated through mTORC2-mediated phosphorylation of protein kinase B at Ser 473 and that this mechanism is unperturbed in T2D. We also demonstrate a cross-talk from the MAPK branch of insulin signaling to stimulate phosphorylation of FOXO1. The cellular abundance and consequently activity of FOXO1 are halved in T2D. Interestingly, inhibition of mTORC1 with rapamycin reduces the abundance of FOXO1 to the levels in T2D. This suggests that the reduction of the concentration of FOXO1 is a consequence of attenuation of mTORC1, which defines much of the diabetic state in human adipocytes. We integrate insulin control of FOXO1 in a network-wide mathematical model of insulin signaling dynamics based on compatible data from human adipocytes. The diabetic state is network-wide explained by attenuation of an mTORC1-to-insulin receptor substrate-1 (IRS1) feedback and reduced abundances of insulin receptor, GLUT4, AS160, ribosomal protein S6, and FOXO1. The model demonstrates that attenuation of the mTORC1-to-IRS1 feedback is a major mechanism of insulin resistance in the diabetic state.Insulin has a crucial function to maintain energy homeostasis at the whole-body level and at the cellular level in a variable environment of nutrient supply. Failure to sustain this function is at the center of diabetes. Type 2 diabetes (T2D) 2 is characterized by failure to properly respond to insulin in target cells (insulin resistance) and by impaired production of the hormone. Because of the central role of insulin in energy homeostasis, effects of insulin are pleiotropic, affecting almost every aspect of cellular metabolism, which is reflected in a highly branched signaling network in target cells of the hormone. T2D is also closely related to obesity (1), and the insulin resistance first develops in the adipocytes of an expanding adipose tissue. Failure to store fat in the adipose tissue then leads to ectopic fat deposition in other organs, such as liver and muscle, which is believed to spread the insulin resistance to those organs (2). Eventually the insulin-producing ␤-cells often fail to compensate for the insulin resistance, and T2D can be diagnosed. It is therefore of primary importance to understand the disease mechanisms in human adipocytes to be able to treat the disease at an early stage before other organs are affected.Forkhead box protein O1 (FOXO1) may be the most important mediator o...

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Section: Methodsmentioning

confidence: 99%

Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes

Rajan¹,

Nyman

Kjølhede³

et al. 2016

Journal of Biological Chemistry

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“…De Vries emphasized the importance of the principle of 'compensation' in considering the functionality of a variety of sex effects [59][60][61]. He and others refer to compensatory sex-dependent processes that act to reduce rather than create differences between females and males.…”

Section: Sex and Brain Functionmentioning

confidence: 99%

“…Yet, when scientists and laypeople list differences between females and males in the brain, they often implicitly assume that the more differences there are, the more different are the two sex categories, ignoring the possibility that somepossibly many-differences may compensate for others (for review and examples see [59][60][61]; see [62] for a detailed example of compensation in the dopaminergic system and [63] for similar considerations in the case of sex effects on gene networks).…”

Section: Sex and Brain Functionmentioning

confidence: 99%

Beyond sex differences: new approaches for thinking about variation in brain structure and function

Joel

Fausto‐Sterling

2016

Phil. Trans. R. Soc. B

110

106

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In the study of variation in brain structure and function that might relate to sex and gender, language matters because it frames our research questions and methods. In this article, we offer an approach to thinking about variation in brain structure and function that pulls us outside the sex differences formulation. We argue that the existence of differences between the brains of males and females does not unravel the relations between sex and the brain nor is it sufficient to characterize a population of brains. Such characterization is necessary for studying sex effects on the brain as well as for studying brain structure and function in general. Animal studies show that sex interacts with environmental, developmental and genetic factors to affect the brain. Studies of humans further suggest that human brains are better described as belonging to a single heterogeneous population rather than two distinct populations. We discuss the implications of these observations for studies of brain and behaviour in humans and in laboratory animals. We believe that studying sex effects in context and developing or adopting analytical methods that take into account the heterogeneity of the brain are crucial for the advancement of human health and well-being.

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“…The work of these authors was carried out with the same strain of mice (ICR) but they were male animals; even so, the distribution of proteins was similar to that found in females. Currently there are researchers who emphasize confirming neurohistological and neurochemical findings in both sexes because sexual dimorphism has been found in different areas of the nervous system including OB (de Vries & Forger, 2015). Other authors have confirmed the immunoreactivity of CB in the glomerular stratum (Kosaka & Kosaka, 2004) Table II.…”

Section: Discussionmentioning

confidence: 78%

Entry of Rabies Virus in the Olfactory Bulb of Mice and Effect of Infection on Cell Markers of Neurons and Astrocytes

Torres‐Fernández¹,

Daza²,

Santamaría-Romero³

et al. 2018

Int. J. Morphol.

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SUMMARY:There are few studies of infection by rabies virus in the olfactory bulb (OB). This work was carried out with the purpose of establishing the time required to detect rabies antigens in the OB of mouse, after the intramuscular inoculation of the virus and to evaluate the effect of the infection on the expression of three proteins: calbindin (CB), parvalbumin (PV) and the glial fibrillary acidic protein (GFAP). Mice were inoculated with rabies virus intramuscularly in the hind limbs. Every 8 hours, after 72 hours postinoculation (p.i.), animals were sacrificed by perfusion with paraformaldehyde and coronal sections of OB were obtained for immunohistochemical study. These cuts were used to reveal the entry and spread of viral antigens. Tissue sections obtained in the terminal phase of the disease (144 hours p.i.), and controls of the same age were also processed for immunohistochemistry of CB, PV and GFAP. Rabies virus antigens were initially detected at 80 hours p.i. in a few mitral cells. At 88 hours p.i. the antigens had spread through most of these neurons but until the terminal phase of the disease there was little dispersion of the virus towards other cellular layers of the OB. The CB protein was expressed in cells of the glomerular stratum, the PV in cells of the outer plexiform layer and the GFAP was expressed in all the layers of the OB. Viral infection generated loss of CB expression and increase of PV expression. Immunoreactivity to GFAP was increased in the outer plexiform layer of the OB as a response to infection.

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Sex differences in the brain: a whole body perspective

Cited by 117 publications

References 174 publications

Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes

Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes

Beyond sex differences: new approaches for thinking about variation in brain structure and function

Entry of Rabies Virus in the Olfactory Bulb of Mice and Effect of Infection on Cell Markers of Neurons and Astrocytes

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