Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice

Dorfman, Mauricio D.; Krull, Jordan E.; Douglass, John D.; Fasnacht, Rachael; Lara-Lince, Fernando; Meek, Thomas H.; Shi, Xiaogang; Damian, Vincent; Nguyen, Hong T.; Matsen, Miles E.; Morton, Gregory J.; Thaler, Joshua P.

doi:10.1038/ncomms14556

Cited by 134 publications

(153 citation statements)

References 70 publications

Supporting

Mentioning

140

Contrasting

Order By: Relevance

“…Interestingly, it has been recently reported that there are sex‐specific differences in hypothalamic microglial activation via the CX3CL1‐CX3CR1 pathway and that such differences are not mediated by estrogen (Dorfman et al . ). Here, we find concomitant injury to POMC neurons and microglia activation in the arcuate nucleus of male mice, but not female mice, exposed to HF diet.…”

Section: Discussionmentioning

confidence: 97%

Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Nyamugenda

Trentzsch

Russell

et al. 2019

Journal of Neurochemistry

View full text Add to dashboard Cite

The hypothalamus is essential for regulation of energy homeostasis and metabolism. Feeding hypercaloric, high‐fat (HF) diet induces hypothalamic arcuate nucleus injury and alters metabolism more severely in male than in female mice. The site(s) and extent of hypothalamic injury in male and female mice are not completely understood. In the paraventricular nucleus (PVN) of the hypothalamus, single‐minded family basic helix‐loop helix transcription factor 1 (Sim1) neurons are essential to control energy homeostasis. We tested the hypothesis that exposure to HF diet induces injury to Sim1 neurons in the PVN of male and female mice. Mice expressing membrane‐bound enhanced green fluorescent protein (mEGFP) in Sim1 neurons (Sim1‐Cre:Rosa‐mEGFP mice) were generated to visualize the effects of exposure to HF diet on these neurons. Male and female Sim1‐Cre:Rosa‐mEGFP mice exposed to HF diet had increased weight, hyperleptinemia, and developed hepatosteatosis. In male and female mice exposed to HF diet, expression of mEGFP was reduced by > 40% in Sim1 neurons of the PVN, an effect paralleled by cell apoptosis and neuronal loss, but not by microgliosis. In the arcuate nucleus of the Sim1‐Cre:Rosa‐mEGFP male mice, there was decreased alpha‐melanocyte‐stimulating hormone in proopiomelanocortin neurons projecting to the PVN, with increased cell apoptosis, neuronal loss, and microgliosis. These defects were undetectable in the arcuate nucleus of female mice exposed to the HF diet. Thus, injury to Sim1 neurons of the PVN is a shared feature of exposure to HF diet in mice of both sexes, while injury to proopiomelanocortin neurons in arcuate nucleus is specific to male mice. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

show abstract

Section: Discussionmentioning

confidence: 97%

Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Nyamugenda

Trentzsch

Russell

et al. 2019

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…Interestingly, HFD resulted in diminished CX3CL1/CX3CR1 signaling specifically in microglia of male mice, which corresponded with increased hypothalamic inflammation and glucose intolerance in these mice. Knockout of CX3CR1 in females resulted in a similar male‐like phenotype (Dorfman et al, ). The female‐specific protections were not altered by acute estradiol injection, suggesting intrinsic differences in hypothalamic male and female microglia in response to HFD that impact whole body glucose homeostasis.…”

Section: Intrinsic Immunometabolic Programming May Impart Sex Differementioning

confidence: 91%

“…HFD in males diminished CX3CR1 signaling and led to an enhanced inflammatory response, while in females CXCL1 protein was increased, but overall CXC3R1 signaling remained relatively unaffected, and no increased inflammation was observed. This figure is based on data presented in Orihuela, McPherson, and Harry (), Jaber et al (), Voloboueva, Emery, Sun, and Giffard (), L. Wang et al (), Dorfman et al ()…”

Section: Intrinsic Immunometabolic Programming May Impart Sex Differementioning

confidence: 98%

Microglia and sexual differentiation of the developing brain: A focus on ontogeny and intrinsic factors

Bordt

Ceasrine

Bilbo

2019

Glia

View full text Add to dashboard Cite

Sexual differentiation of the brain during early development likely underlies the strong sex biases prevalent in many neurological conditions. Mounting evidence indicates that microglia, the innate immune cells of the central nervous system, are intricately involved in these sex‐specific processes of differentiation. In this review, we synthesize literature demonstrating sex differences in microglial number, morphology, transcriptional state, and functionality throughout spatiotemporal development as well as highlight current literature regarding ontogeny of microglia. Along with vanRyzin et al. in this issue, we explore the idea that differences in microglia imparted by chromosomal or ontogeny‐related programming can influence microglial‐driven sexual differentiation of the brain, as well as the idea that extrinsic differences in the male and female brain microenvironment may in turn impart sex differences in microglia.

show abstract

“…Sex differences in microglial activation have been implicated in the modulation of energy homeostasis. This was shown in the hypothalamic microglial activated CX3CL1‐CXCLR1 pathway in a mouse model of obesity . Dorfman et al found that increased CXCLR1, which is associated with energy expenditure, allowed for females to be more resistant to obesity .…”

Section: Microglial Sex Differences In Homeostatic Adult Brainmentioning

confidence: 90%

Sexually dimorphic microglia and ischemic stroke

et al. 2019

View full text Add to dashboard Cite

Ischemic stroke kills more women compared with men thus emphasizing a significant sexual dimorphism in ischemic pathophysiological outcomes. However, the mechanisms behind this sexual dimorphism are yet to be fully understood. It is well established that cerebral ischemia activates a variety of inflammatory cascades and that microglia are the primary immune cells of the brain. After ischemic injury, microglia are activated and play a crucial role in progression and resolution of the neuroinflammatory response. In recent years, research has focused on the role that microglia play in this sexual dimorphism that exists in the response to central nervous system (CNS) injury. Evidence suggests that the molecular mechanisms leading to microglial activation and polarization of phenotypes may be influenced by sex, therefore causing a difference in the pro/anti‐inflammatory responses after CNS injury. Here, we review advances highlighting that sex differences in microglia are an important factor in the inflammatory responses that are seen after ischemic injury. We discuss the main differences between microglia in the healthy and diseased developing, adult, and aging brain. We also focus on the dimorphism that exists between males and females in microglial‐induced inflammation and energy metabolism after CNS injury. Finally, we describe how all of the current research and literature regarding sex differences in microglia contribute to the differences in poststroke responses between males and females.

show abstract

Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice

Cited by 134 publications

References 70 publications

Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Microglia and sexual differentiation of the developing brain: A focus on ontogeny and intrinsic factors

Sexually dimorphic microglia and ischemic stroke

Contact Info

Product

Resources

About