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Article ; Online: Commentary on the Recent FSH Collection: Known Knowns and Known Unknowns.

Coss, Djurdjica

2019 Volume 161, Issue 1

Abstract: Follicle-stimulating hormone (FSH) is a dimeric glycoprotein secreted by the anterior pituitary gonadotrope that is necessary for reproductive function in mammals. FSH primarily regulates granulosa cells and follicular growth in females, and Sertoli cell ...

Abstract	Follicle-stimulating hormone (FSH) is a dimeric glycoprotein secreted by the anterior pituitary gonadotrope that is necessary for reproductive function in mammals. FSH primarily regulates granulosa cells and follicular growth in females, and Sertoli cell function in males. Since its identification in the 1930s and sequencing in the 1970s, significant progress has been made in elucidating its regulation and downstream function. Recent advances provide deeper insight into FSH synthesis, and effects in the gonads suggest potential roles in extragonadal tissues and examine pharmacological approaches and clinical applications in infertility treatment that now affect 18% of couples. These advances were discussed in detail in a number of reviews published in the last 2 years in Endocrinology. In this brief commentary, we summarize these reviews and point to the outstanding questions that should be answered in the near future to bridge a gap in our understanding of this hormone.
MeSH term(s)	Animals ; Female ; Follicle Stimulating Hormone/genetics ; Follicle Stimulating Hormone/metabolism ; Gene Expression Regulation ; Granulosa Cells/metabolism ; Humans ; Male ; Ovarian Follicle/cytology ; Ovarian Follicle/metabolism ; Protein Binding ; Protein Processing, Post-Translational ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Receptors, FSH/metabolism ; Review Literature as Topic ; Sertoli Cells/metabolism ; Signal Transduction ; Spermatogenesis/genetics
Chemical Substances	Protein Subunits ; Receptors, FSH ; Follicle Stimulating Hormone (9002-68-0)
Language	English
Publishing date	2019-12-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqz035
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Article ; Online: Regulation of reproduction via tight control of gonadotropin hormone levels.

Coss, Djurdjica

Molecular and cellular endocrinology

2017 Volume 463, Page(s) 116–130

Abstract: Mammalian reproduction is controlled by the hypothalamic-pituitary-gonadal axis. GnRH from the hypothalamus regulates synthesis and secretion of gonadotropins, LH and FSH, which then control steroidogenesis and gametogenesis. In females, serum LH and FSH ...

Abstract	Mammalian reproduction is controlled by the hypothalamic-pituitary-gonadal axis. GnRH from the hypothalamus regulates synthesis and secretion of gonadotropins, LH and FSH, which then control steroidogenesis and gametogenesis. In females, serum LH and FSH levels exhibit rhythmic changes throughout the menstrual or estrous cycle that are correlated with pulse frequency of GnRH. Lack of gonadotropins leads to infertility or amenorrhea. Dysfunctions in the tightly controlled ratio due to levels slightly outside the normal range occur in a larger number of women and are correlated with polycystic ovaries and premature ovarian failure. Since the etiology of these disorders is largely unknown, studies in cell and mouse models may provide novel candidates for investigations in human population. Hence, understanding the mechanisms whereby GnRH regulates gonadotropin hormone levels will provide insight into the physiology and pathophysiology of the reproductive system. This review discusses recent advances in our understanding of GnRH regulation of gonadotropin synthesis.
MeSH term(s)	Animals ; Gonadotropin-Releasing Hormone/metabolism ; Gonadotropins/genetics ; Gonadotropins/metabolism ; Humans ; Models, Biological ; Receptors, LHRH/metabolism ; Reproduction/physiology ; Signal Transduction
Chemical Substances	Gonadotropins ; Receptors, LHRH ; Gonadotropin-Releasing Hormone (33515-09-2)
Language	English
Publishing date	2017-03-22
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2017.03.022
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Article ; Online: Obesity alters POMC and kisspeptin neuron crosstalk leading to reduced luteinizing hormone in male mice.

Villa, Pedro A / Ruggiero-Ruff, Rebecca E / Jamieson, Bradley B / Campbell, Rebecca E / Coss, Djurdjica

The Journal of neuroscience : the official journal of the Society for Neuroscience

2024

Abstract: Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms. Herein, we ... ...

Abstract	Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms. Herein, we used mice fed chronic high-fat diet, that mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone (LH), which then regulates testosterone. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. LH pulse frequency is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion. We determined that the LH response to NMDA was lower in obese mice, corresponding to fewer glutamate receptors in kisspeptin neurons, which may be critical for kisspeptin synchronization. Given that kisspeptin neurons also interact with POMC neurons, which regulate satiety and are affected by obesity, we examined their crosstalk, and determined that the LH response to either DREADD-mediated activation of POMC neurons or central injection of αMSH, a product of POMC, is abolished in obese mice. This was accompanied by diminished levels of αMSH receptor, MC4R, in kisspeptin neurons. Together, our studies determined that obesity leads to the downregulation of receptors that regulate kisspeptin neurons, which is associated with lower LH pulse frequency, leading to lower LH and hypogonadism.
Language	English
Publishing date	2024-05-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.0222-24.2024
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Article: Regulation of reproduction via tight control of gonadotropin hormone levels

Coss, Djurdjica

Molecular and Cellular Endocrinology. 2017,

2017

Abstract	Mammalian reproduction is controlled by the hypothalamic-pituitary-gonadal axis. GnRH from the hypothalamus regulates synthesis and secretion of gonadotropins, LH and FSH, which then control steroidogenesis and gametogenesis. In females, serum LH and FSH levels exhibit rhythmic changes throughout the menstrual or estrous cycle that are correlated with pulse frequency of GnRH. Lack of gonadotropins leads to infertility or amenorrhea. Dysfunctions in the tightly controlled ratio due to levels slightly outside the normal range occur in a larger number of women and are correlated with polycystic ovaries and premature ovarian failure. Since the etiology of these disorders is largely unknown, studies in cell and mouse models may provide novel candidates for investigations in human population. Hence, understanding the mechanisms whereby GnRH regulates gonadotropin hormone levels will provide insight into the physiology and pathophysiology of the reproductive system. This review discusses recent advances in our understanding of GnRH regulation of gonadotropin synthesis.
Keywords	amenorrhea ; animal models ; blood serum ; estrous cycle ; etiology ; females ; follicle-stimulating hormone ; gametogenesis ; gonadotropin-releasing hormone ; human population ; hypothalamus ; luteinizing hormone ; mammals ; pathophysiology ; reproductive system ; secretion ; steroidogenesis ; women
Language	English
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2017.03.022
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Article ; Online: Obesity, Neuroinflammation, and Reproductive Function.

Lainez, Nancy M / Coss, Djurdjica

Endocrinology

2019 Volume 160, Issue 11, Page(s) 2719–2736

Abstract: The increasing occurrence of obesity has become a significant public health concern. Individuals with obesity have higher prevalence of heart disease, stroke, osteoarthritis, diabetes, and reproductive disorders. Reproductive problems include menstrual ... ...

Abstract	The increasing occurrence of obesity has become a significant public health concern. Individuals with obesity have higher prevalence of heart disease, stroke, osteoarthritis, diabetes, and reproductive disorders. Reproductive problems include menstrual irregularities, pregnancy complications, and infertility due to anovulation, in women, and lower testosterone and diminished sperm count, in men. In particular, women with obesity have reduced levels of both gonadotropin hormones, and, in obese men, lower testosterone is accompanied by diminished LH. Taken together, these findings indicate central dysregulation of the hypothalamic-pituitary-gonadal axis, specifically at the level of the GnRH neuron function, which is the final brain output for the regulation of reproduction. Obesity is a state of hyperinsulinemia, hyperlipidemia, hyperleptinemia, and chronic inflammation. Herein, we review recent advances in our understanding of how these metabolic and immune changes affect hypothalamic function and regulation of GnRH neurons. In the latter part, we focus on neuroinflammation as a major consequence of obesity and discuss findings that reveal that GnRH neurons are uniquely positioned to respond to inflammatory changes.
MeSH term(s)	Animals ; Female ; Humans ; Hypothalamus/metabolism ; Infertility, Female/etiology ; Infertility, Female/metabolism ; Infertility, Male/etiology ; Infertility, Male/metabolism ; Inflammation/etiology ; Male ; Neurosecretory Systems/metabolism ; Obesity/complications ; Obesity/metabolism ; Reproduction
Language	English
Publishing date	2019-09-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2019-00487
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Article ; Online: PACAP induces FSHβ gene expression via EPAC.

Yeh, Debra M / Coss, Djurdjica

Molecular and cellular endocrinology

2019 Volume 492, Page(s) 110438

Abstract: Gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are heterodimers of a common α subunit and unique β subunits. Regulation of their levels, primarily by GnRH, is critical for reproductive function. Several other hormones ... ...

Abstract	Gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are heterodimers of a common α subunit and unique β subunits. Regulation of their levels, primarily by GnRH, is critical for reproductive function. Several other hormones modulate gonadotropin expression, either independently or by modifying the responsiveness to GnRH. Pituitary adenylate cyclase activating peptide (PACAP) is one such hormone. Four-hour treatment of female mouse primary pituitary cells by either GnRH or PACAP induced FSHβ expression, while 24-h treatment repressed FSHβ. Both PACAP and GnRH caused FSH secretion into the medium. In the gonadotropes, PACAP activates primarily Gαs and increases concentration of cAMP, while GnRH primarily functions via Gαq and increases calcium concentration. Herein, we compared PACAP and GnRH signaling pathways that lead to the induction of FSHβ expression. Interestingly, constitutively active Gαs represses LHβ and induces FSHβ expression, while Gαq induces both β-subunits. We determined that FSHβ induction by PACAP requires functional EPAC, a cAMP sensor protein that serves as a guanine exchange factors for small G proteins that then bridges cAMP signaling to MAPK pathway. We further demonstrate that in addition to the prototypical small G protein Ras, two members of the Rho subfamily, Rac and CDC42 are also necessary for PACAP induction of FSHβ, likely via activation of p38 MAPK that leads to induction of cFOS, a critical transcription factor that is necessary and sufficient for FSHβ induction. Therefore, PACAP-induced cAMP pathway leads to MAPK activation that stimulates cFOS induction, to induce the expression of FSHβ subunit and increase FSH concentration.
MeSH term(s)	Animals ; Cell Line ; Cyclic AMP/metabolism ; Female ; Follicle Stimulating Hormone, beta Subunit/genetics ; Follicle Stimulating Hormone, beta Subunit/metabolism ; Gene Expression Regulation/drug effects ; Gonadotrophs/cytology ; Gonadotrophs/drug effects ; Gonadotrophs/metabolism ; Gonadotropin-Releasing Hormone/pharmacology ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; Mice ; Pituitary Adenylate Cyclase-Activating Polypeptide/pharmacology ; Signal Transduction/drug effects ; cdc42 GTP-Binding Protein/metabolism ; rac GTP-Binding Proteins/metabolism ; ras Proteins/metabolism
Chemical Substances	Cdc42 protein, mouse ; Epac protein, mouse ; Follicle Stimulating Hormone, beta Subunit ; Fshb protein, mouse ; Guanine Nucleotide Exchange Factors ; Pituitary Adenylate Cyclase-Activating Polypeptide ; Gonadotropin-Releasing Hormone (33515-09-2) ; Cyclic AMP (E0399OZS9N) ; cdc42 GTP-Binding Protein (EC 3.6.5.2) ; rac GTP-Binding Proteins (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2019-04-26
Publishing country	Ireland
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2019.04.018
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Article ; Online: Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice.

Lainez, Nancy M / Coss, Djurdjica

Neuroendocrinology

2019 Volume 108, Issue 4, Page(s) 291–307

Abstract: Background: The mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive ... ...

Abstract	Background: The mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive function via reduction in spine density in gonadotropin-releasing hormone (GnRH) neurons. Neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens. Methods: To examine if neuroinflammation-induced cytokines can directly regulate GnRH gene expression, herein we examined signaling pathways and mechanisms in males in vivo and in GnRH-expressing cell line, GT1-7. Results: GnRH neurons express cytokine receptors, and chronic or acute neuroinflammation represses GnRH gene expression in vivo. Leukemia inhibitory factor (LIF) in particular represses GnRH expression in GT1-7 cells, while other cytokines do not. STAT3 and MAPK pathways are activated following LIF treatment, but only MAPK pathway, specifically p38α, is sufficient to repress the GnRH gene. LIF induces cFOS that represses the GnRH gene via the -1,793 site in the enhancer region. In vivo, following high-fat diet, cFOS is induced in GnRH neurons and neurons juxtaposed to the leaky blood brain barrier of the organum vasculosum of the lamina terminalis, but not in the neurons further away. Conclusion: Our results indicate that the increase in LIF due to neuroinflammation induces cFOS and represses the GnRH gene. Therefore, in addition to synaptic changes in GnRH neurons, neuroinflammatory cytokines directly regulate gene expression and reproductive function, and the specificity for neuronal targets may stem from the proximity to the fenestrated capillaries.
MeSH term(s)	Animals ; Gene Expression/physiology ; Gonadotropin-Releasing Hormone/metabolism ; Hypothalamus/metabolism ; Inflammation/metabolism ; Leukemia Inhibitory Factor/metabolism ; Male ; Mice, Inbred C57BL ; Neurons/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Signal Transduction/physiology ; Transcription Factors/metabolism
Chemical Substances	Fos protein, mouse ; Leukemia Inhibitory Factor ; Proto-Oncogene Proteins c-fos ; Transcription Factors ; Gonadotropin-Releasing Hormone (33515-09-2)
Language	English
Publishing date	2019-01-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	123303-8
ISSN	1423-0194 ; 0028-3835
ISSN (online)	1423-0194
ISSN	0028-3835
DOI	10.1159/000496754
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Article: PACAP induces FSHβ gene expression via EPAC

Yeh, Debra M / Coss, Djurdjica

Molecular and cellular endocrinology. 2019 July 15, v. 492

2019

Abstract	Gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are heterodimers of a common α subunit and unique β subunits. Regulation of their levels, primarily by GnRH, is critical for reproductive function. Several other hormones modulate gonadotropin expression, either independently or by modifying the responsiveness to GnRH. Pituitary adenylate cyclase activating peptide (PACAP) is one such hormone. Four-hour treatment of female mouse primary pituitary cells by either GnRH or PACAP induced FSHβ expression, while 24-h treatment repressed FSHβ. Both PACAP and GnRH caused FSH secretion into the medium. In the gonadotropes, PACAP activates primarily Gαs and increases concentration of cAMP, while GnRH primarily functions via Gαq and increases calcium concentration. Herein, we compared PACAP and GnRH signaling pathways that lead to the induction of FSHβ expression. Interestingly, constitutively active Gαs represses LHβ and induces FSHβ expression, while Gαq induces both β-subunits. We determined that FSHβ induction by PACAP requires functional EPAC, a cAMP sensor protein that serves as a guanine exchange factors for small G proteins that then bridges cAMP signaling to MAPK pathway. We further demonstrate that in addition to the prototypical small G protein Ras, two members of the Rho subfamily, Rac and CDC42 are also necessary for PACAP induction of FSHβ, likely via activation of p38 MAPK that leads to induction of cFOS, a critical transcription factor that is necessary and sufficient for FSHβ induction. Therefore, PACAP-induced cAMP pathway leads to MAPK activation that stimulates cFOS induction, to induce the expression of FSHβ subunit and increase FSH concentration.
Keywords	G-proteins ; adenylate cyclase ; calcium ; cyclic AMP ; females ; follicle-stimulating hormone ; gene expression ; gonadotropin-releasing hormone ; luteinization ; luteinizing hormone ; mice ; mitogen-activated protein kinase ; secretion ; signal transduction ; transcription factors
Language	English
Dates of publication	2019-0715
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2019.04.018
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Article ; Online: Sex Differences in Macrophage Responses to Obesity-Mediated Changes Determine Migratory and Inflammatory Traits.

Chen, Kuan-Hui Ethan / Lainez, Nancy M / Coss, Djurdjica

Journal of immunology (Baltimore, Md. : 1950)

2020 Volume 206, Issue 1, Page(s) 141–153

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Cell Movement ; Chemokine CCL2/genetics ; Chemokine CCL2/metabolism ; Fatty Acids, Nonesterified/metabolism ; Female ; Hyperlipidemias ; Inflammation/epidemiology ; Inflammation/immunology ; Leptin/metabolism ; Macrophages/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Multifactorial Inheritance ; Obesity/epidemiology ; Obesity/immunology ; Sex Characteristics ; Sex Factors
Chemical Substances	Chemokine CCL2 ; Fatty Acids, Nonesterified ; Leptin
Language	English
Publishing date	2020-12-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2000490
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Article ; Online: Visceral adipose tissue imparts peripheral macrophage influx into the hypothalamus.

Chen, Kuan-Hui Ethan / Lainez, Nancy M / Nair, Meera G / Coss, Djurdjica

Journal of neuroinflammation

2021 Volume 18, Issue 1, Page(s) 140

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Antigens, CD/analysis ; Cell Movement ; Diet, High-Fat/adverse effects ; Female ; Gene Expression ; Hypothalamus/metabolism ; Hypothalamus/pathology ; Inflammation/metabolism ; Intra-Abdominal Fat/pathology ; Macrophages/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/complications ; Sex Characteristics
Chemical Substances	Antigens, CD
Language	English
Publishing date	2021-06-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-021-02183-2
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