Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

Lainez

Nair

et al. 2021

J Neuroinflammation

Self Cite

Background Obesity is characterized by a systemic inflammation and hypothalamic neuroinflammation. Systemic inflammation is caused by macrophages that infiltrate obese adipose tissues. We previously demonstrated that high-fat diet (HFD)-fed male mice exhibited peripheral macrophage infiltration into the hypothalamus, in addition to activation of resident microglia. Since this infiltration contributes to neuroinflammation and neuronal impairment, herein we characterize the phenotype and origin of these hypothalamic macrophages in HFD mice. Methods C57BL/6J mice were fed HFD (60% kcal from fat) or control diet with matching sucrose levels, for 12–16 weeks. Males and females were analyzed separately to determine sex-specific responses to HFD. Differences in hypothalamic gene expression in HFD-fed male and female mice, compared to their lean controls, in two different areas of the hypothalamus, were determined using the NanoString neuroinflammation panel. Phenotypic changes in macrophages that infiltrated the hypothalamus in HFD-fed mice were determined by analyzing cell surface markers using flow cytometry and compared to changes in macrophages from the adipose tissue and peritoneal cavity. Adipose tissue transplantation was performed to determine the source of hypothalamic macrophages. Results We determined that hypothalamic gene expression profiles demonstrate sex-specific and region-specific diet-induced changes. Sex-specific changes included larger changes in males, while region-specific changes included larger changes in the area surrounding the median eminence. Several genes were identified that may provide partial protection to female mice. We also identified diet-induced changes in macrophage migration into the hypothalamus, adipose tissue, and peritoneal cavity, specifically in males. Further, we determined that hypothalamus-infiltrating macrophages express pro-inflammatory markers and markers of metabolically activated macrophages that were identical to markers of adipose tissue macrophages in HFD-fed mice. Employing adipose tissue transplant, we demonstrate that hypothalamic macrophages can originate from the visceral adipose tissue. Conclusion HFD-fed males experience higher neuroinflammation than females, likely because they accumulate more visceral fat, which provides a source of pro-inflammatory macrophages that migrate to other tissues, including the hypothalamus. Our findings may explain the male bias for neuroinflammation and the metabolic syndrome. Together, our results demonstrate a new connection between the adipose tissue and the hypothalamus in obesity that contributes to neuroinflammation and hypothalamic pathologies.

Section: Resultssupporting

confidence: 90%

Visceral adipose tissue imparts peripheral macrophage influx into the hypothalamus

Lainez

Nair

et al. 2021

J Neuroinflammation

Self Cite

“…We demonstrated that females are protected from immunological changes in cytokine levels and neuroendocrine changes in hormone levels regardless of the gonadal status. For example, males on an HFD have increased levels of TNF-a, LIF, and IL-6, whereas in females, unmodified or ovariectomized, TNF-a and LIF are unchanged (19,20). This may indicate that chromosomal differences contribute to intrinsic sex differences in the immune system.…”

Section: Sex Differences In Macrophage Responses To Obesity-mediated ...mentioning

confidence: 99%

Sex Differences in Macrophage Responses to Obesity-Mediated Changes Determine Migratory and Inflammatory Traits

The Journal of Immunology

Lainez

Coss

2021

Self Cite

The mechanisms whereby obesity differentially affects males and females are unclear. Because macrophages are functionally the most important cells in obesity-induced inflammation, we sought to determine reasons for male-specific propensity in macrophage migration. We previously determined that male mice fed a high-fat diet exhibit macrophage infiltration into the hypothalamus, whereas females were protected irrespective of ovarian estrogen, in this study, we show that males accumulate more macrophages in adipose tissues that are also more inflammatory. Using bone marrow cells or macrophages differentiated in vitro from male and female mice fed control or high-fat diet, we demonstrated that macrophages derived from male mice are intrinsically more migratory. We determined that males have higher levels of leptin in serum and adipose tissue. Serum CCL2 levels, however, are the same in males and females, although they are increased in obese mice compared with lean mice of both sexes. Leptin receptor and free fatty acid (FFA) receptor, GPR120, are upregulated only in macrophages derived from male mice when cultured in the presence of FFA to mimic hyperlipidemia of obesity. Unless previously stimulated with LPS, CCL2 did not cause migration of macrophages. Leptin, however, elicited migration of macrophages from both sexes. Macrophages from male mice maintained migratory capacity when cultured with FFA, whereas female macrophages failed to migrate. Therefore, both hyperlipidemia and hyperleptinemia contribute to male macrophage-specific migration because increased FFA induce leptin receptors, whereas higher leptin causes migration. Our results may explain sex differences in obesity-mediated disorders caused by macrophage infiltration.

“…The reason for this discrepancy between the present study and those published studies remains to be determined. By far, although considerable studies have shown that hypothalamic inflammation affected the HPG axis and thus the reproductive system in various inflammation models (Lainez and Coss 2019a;Wu and Wolfe 2012), the underlying mechanism remains elusive. The present study demonstrated in mice that the POMC neurons but not the AgRP neurons mediated the disruption of the HPG axis and thus the sperm production by the hypothalamic inflammation due to PM 2:5 exposure, providing a deep insight into the mechanism for the action of hypothalamic inflammation on the HPG axis and subsequently sperm production.…”

Section: Discussionmentioning

confidence: 99%

PM2.5 Exposure of Mice during Spermatogenesis: A Role of Inhibitor κB Kinase 2 in Pro-Opiomelanocortin Neurons

Qiu

Environ Health Perspect

Wang

et al. 2021

BACKGROUND: Epidemiological studies have shown that exposure to ambient fine particulate matter with aerodynamic diameter less than or equal to 2.5 μm (PM 2:5 ) correlates with a decrease in sperm count, but the biological mechanism remains elusive. OBJECTIVES: This study tested whether hypothalamic inflammation, an emerging pathophysiological mediator, mediates the development of lower epididymal sperm count due to PM 2:5 exposure. METHODS: Inhibitor jB kinase 2 (IKK2) was conditionally knocked out either in all neurons or subtypes of hypothalamic neurons of mice. Effects of concentrated ambient PM 2:5 (CAP) exposure on hypothalamic inflammation, the hypothalamic-pituitary-gonadal (HPG) axis, and epididymal sperm count of these mouse models were then assessed. Furthermore, to test whether hypothalamic inflammation is sufficient to decrease sperm production, we overexpressed constitutively active IKK2 (IKK2ca) either in all neurons or subtypes of hypothalamic neurons and assessed hypothalamic inflammation, the HPG axis, and sperm production of these overexpression mouse models. RESULTS: CAP-exposed wild-type control mice vs. filtered air (FA)-exposed wild-type control mice had a higher expression of hypothalamic inflammatory markers, lower functional indexes of the HPG axis, and a lower epididymal sperm count. In contrast, all these measurements for CAP-vs. FA-exposed mice deficient of IKK2 in all neurons were comparable. We also found that overexpression of IKK2ca in either all neurons or proopiomelanocortin (POMC) neurons only, but not in Agouti-related protein (AgRP) neurons only, resulted in lower functional indexes of the HPG axis and a lower epididymal sperm count. Moreover, we showed that CAP-vs. FA-exposed mice deficient of IKK2 in POMC neurons had a comparable expression of hypothalamic inflammatory markers, comparable functional indexes of the HPG axis, and a comparable epididymal sperm count. DISCUSSION: This mouse model study shows a causal role of IKK2 of POMC neurons in the development of lower epididymal sperm count due to PM 2:5 exposure, providing a mechanistic insight into this emerging pathogenesis.