bims-endanx 2025-01-19 papers

bims-endanx

Biomed News

on Endocrine Anxiety

Issue of 2025–01–19
twelve papers selected by
Logan K. Townsend, McMaster University

GDF15 inhibits early-stage adipocyte differentiation by enhancing HOP2 expression and suppressing C/EBPα expression.
Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.
Ablation of PI3Kγ in neurons protects mice from diet-induced obesity MASLD and insulin resistance.
Skeletal and Adipose Manifestations of Stress in a Contemporary Pediatric Sample.
GLP-1 and the Neurobiology of Eating Control: Recent Advances.
Exploring the Complex Relationship Between Psychosocial Stress and the Gut Microbiome: Implications for Inflammation and Immune Modulation.
The immune-inflammatory responses on the hypothalamic-pituitary-adrenal axis and the neurovascular unit in perioperative neurocognitive disorder.
CD44 in myEloid cells is a major driver of liver inflammation and injury in alcohol-related liver disease.
Sex differences in the murine HPA axis after acute and repeated restraint stress.
The immunology of stroke and dementia.
Emerging role of adaptive immunity in diabetes-induced cognitive impairment: from the periphery to the brain.
Chronic traumatic brain injury induces neurodegeneration, neuroinflammation, and cognitive deficits in a T cell-dependent manner.

Mol Cell Endocrinol. 2025 Jan 13. pii: S0303-7207(25)00012-7. [Epub ahead of print] 112461

GDF15 inhibits early-stage adipocyte differentiation by enhancing HOP2 expression and suppressing C/EBPα expression.

Haeng Jun Kim, Sung-Un Kang, Hyo Jeong Kim, Yun Sang Lee, Chul-Ho Kim.

  Excessive adipocyte differentiation and accumulation contribute to the development of metabolic disorders. Growth differentiation factor 15 (GDF15) plays an essential role in energy homeostasis and is considered an anti-obesity factor; however, elevated serum levels of endogenous GDF15 have been reported in certain individuals with obesity. In this study, to gain a better understanding of this complex relationship between GDF15 levels and obesity, we investigated GDF15 expression and function during adipogenesis. Compared with mice fed a normal diet, those fed a short-term high-fat diet exhibited a reduction in epididymal white adipose tissue and serum GDF15 expression. These results were confirmed in human adipose-derived stem cells that showed reduced GDF15 expression during adipogenesis differentiation. During adipogenesis, GDF15 was primarily degraded via the autophagy lysosomal pathway, and GDF15 overexpression in pre-adipocytes inhibited adipogenesis by suppressing CCAAT enhancer binding protein alpha (C/EBPα). Furthermore, whereas we detected a reduction in homologous-pairing protein 2 (HOP2) expression during adipogenesis, expression increased in response to an overexpression of GDF15. Furthermore, following knockdown of HOP2 during GDF15 overexpression, there was no suppression of C/EBPα expression. These findings indicate that GDF15 undergoes lysosomal degradation via an autophagic pathway and suppresses adipocyte differentiation via the HOP2-mediated inhibition of C/EBPα expression. Collectively, our findings indicate that GDF15 could serve as a potential therapeutic target for the treatment of metabolic disorders.

Keywords:  C/EBPα; GDF15; HOP2; adipocyte differentiation; adipogenesis

DOI:  https://doi.org/10.1016/j.mce.2025.112461
Acta Physiol (Oxf). 2025 Feb;241(2): e14283

Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.

Yiyi Zhu, Alexei Verkhratsky, Hui Chen, Chenju Yi.

  The blood-brain barrier (BBB) is a highly selective, semipermeable barrier critical for maintaining brain homeostasis. The BBB regulates the transport of essential nutrients, hormones, and signaling molecules between the bloodstream and the central nervous system (CNS), while simultaneously protecting the brain from potentially harmful substances and pathogens. This selective permeability ensures that the brain is nourished and shielded from toxins. An exception to this are brain regions, such as the hypothalamus and circumventricular organs, which are irrigated by fenestrated capillaries, allowing rapid and direct response to various blood components. We overview the metabolic functions of the BBB, with an emphasis on the impact of altered glucose metabolism and insulin signaling on BBB in the pathogenesis of neurodegenerative diseases. Notably, endothelial cells constituting the BBB exhibit distinct metabolic characteristics, primarily generating ATP through aerobic glycolysis. This occurs despite their direct exposure to the abundant oxygen in the bloodstream, which typically supports oxidative phosphorylation. The effects of insulin on astrocytes, which form the glial limitans component of the BBB, show a marked sexual dimorphism. BBB nutrient sensing in the hypothalamus, along with insulin signaling, regulates systemic metabolism. Insulin modifies BBB permeability by regulating the expression of tight junction proteins, angiogenesis, and vascular remodeling, as well as modulating blood flow in the brain. The disruptions in glucose and insulin signaling are particularly evident in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where BBB breakdown accelerates cognitive decline. This review highlights the critical role of normal glucose metabolism and insulin signaling in maintaining BBB functionality and investigates how disruptions in these pathways contribute to the onset and progression of neurodegenerative diseases.

Keywords:  Alzheimer's disease; Huntington's disease; Parkinson's disease; amyotrophic lateral sclerosis; fenestrated capillaries; glucose transporter; insulin resistance; neurodegeneration

DOI:  https://doi.org/10.1111/apha.14283
iScience. 2025 Jan 17. 28(1): 111562

Ablation of PI3Kγ in neurons protects mice from diet-induced obesity MASLD and insulin resistance.

Angela Molinaro, Arianna Mazzoli, Andrea Usseglio Gaudi, Amit Chand Gupta, Vagner Ramon Rodrigues Silva, Damien Ramel, Muriel Laffargue, Johan Ruud, Barbara Becattini, Giovanni Solinas.

  Mice with genetic ablation of PI3Kγ are protected from diet-induced obesity. However, the cell type responsible for PI3Kγ action in obesity remains unknown. We generated mice with conditional deletion of PI3Kγ in neurons using the nestin promoter to drive the expression of the Cre recombinase (PI3KγNest mice) and investigated their metabolic phenotype in a model of diet-induced obesity. On a chow diet, lean PI3KγNest mice display reduced linear growth and a normal metabolic phenotype. PI3KγNest mice were largely protected from diet-induced obesity and liver steatosis and showed improved glucose tolerance and insulin sensitivity. This phenotype was associated with increased phosphorylation of hormone-sensitive lipase (HSL) at protein kinase A (PKA) sites in white fat. It is concluded that PI3Kγ action in diet-induced obesity depends on its activity in neurons controlling adipose tissue lipolysis. Future clinical studies on PI3Kγ inhibitors capable of crossing the brain-blood barrier will reveal the relevance of these findings to humans.

Keywords:  Molecular biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2024.111562
Am J Biol Anthropol. 2025 Jan;186(1): e25058

Skeletal and Adipose Manifestations of Stress in a Contemporary Pediatric Sample.

Lexi O'Donnell, Louise Corron, Ethan C Hill, Jordan Perez, Michael O'Donnell, Bronwyn Wyatt.

   INTRODUCTION: Adverse experiences leading to physiological disruptions (stress) in early life produce cascade effects on various biological systems, including the endocrine and metabolic systems, which, in turn, shape the developing skeletal system. To evaluate the effects of stress on adipose and skeletal tissues, we examine the relationship between skeletal indicators of stress (porotic hyperostosis [PH] and cribra orbitalia [CO]), bone mineral density (BMD), vertebral neural canal (VNC) diameters, and adipose tissue distribution in a contemporary pediatric autopsy sample.
METHODS: Data is from 702 (409 males, 293 females) individuals from a pediatric (0.5-20.9 years) autopsy sample from New Mexico who died between 2011 and 2022. Data includes visceral adipose tissue (VAT) in the abdomen, heart, and liver, CO/PH, VNC size of the fifth lumbar vertebra, and BMD.
RESULTS: We find that adipose tissue distribution and location are differentially associated with CO/PH, BMD, and VNC size; VNC size is smaller, and liver adiposity is higher in those with CO/PH. Further, increased VAT and small VNC size are associated with PH presence and low BMD. Body mass index categories do not correspond with porous cranial lesion presence.
CONCLUSIONS: This paper provides evidence for the complex relationship between skeletal markers of early-life stress (CO/PH, reduced VNC size, low BMD) and endocrine system function. VAT distribution and VNC size are partly shaped by stressors during gestation, likely through alterations of the HPA axis. It is possible that alterations of the HPA axis due to gestational stress also shape the expression of porous cranial lesions during exposure to childhood stressors.

Keywords:  anemia; cribra orbitalia; fatty liver disease; porotic hyperostosis; stress; visceral adiposity

DOI:  https://doi.org/10.1002/ajpa.25058
Endocrinology. 2025 Jan 15. pii: bqae167. [Epub ahead of print]

GLP-1 and the Neurobiology of Eating Control: Recent Advances.

Lauren A Jones, Daniel I Brierley.

Obesity is now considered a chronic relapsing progressive disease, associated with increased all-cause mortality that scales with bodyweight, affecting more than 1 billion people worldwide. Excess body fat is strongly associated with excess energy intake, and most successful anti-obesity medications (AOMs) counter this positive energy balance through the suppression of eating to drive weight loss. Historically, AOMs have been characterised by modest weight loss and side effects which are compliance-limiting, and in some cases life-threatening. However, the field of obesity pharmacotherapy has now entered a new era of AOMs based on analogues of the gut hormone and neuropeptide glucagon-like peptide-1 (GLP-1). The latest versions of these drugs elicit unprecedented levels of weight loss in clinical trials, which are now starting to be substantiated in real-world usage. Notably, these drugs reduce weight primarily by reducing energy intake, via activation of the GLP-1 receptor on multiple sites of action primarily in the CNS, although the most relevant sites of action, and the neural circuits recruited remain contentious. Here we provide a targeted synthesis of recent developments in the field of GLP-1 neurobiology, highlighting studies which have advanced our understanding of how GLP-1 signalling modulates eating, and identify open questions and future challenges we believe still need to be addressed to aid the prevention and/or treatment of obesity.

DOI: https://doi.org/10.1210/endocr/bqae167
J Appl Physiol (1985). 2025 Jan 15.

Exploring the Complex Relationship Between Psychosocial Stress and the Gut Microbiome: Implications for Inflammation and Immune Modulation.

Komal Marwaha, Ryan Cain, Kathrine Asmis, Katya Czaplinski, Nathan Holland, Darly C Ghislane Mayer, Jessica Chacon.

  There is growing interest in understanding the complex relationship between psychosocial stress and the human gastrointestinal microbiome (GIM). This review explores the potential physiological pathways connecting these two and how they contribute to a pro-inflammatory environment that can lead to the development and progression of the disease. Exposure to psychosocial stress triggers the activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary axis (HPA), leading to various physiological responses essential for survival and coping with the stressor. However, chronic stress in susceptible individuals could cause sustained activation of HPA and SNS, leading to immune dysregulation consisting of redistribution of NK cells in the bloodstream, decreased function of T and B cells, and elevation of proinflammatory cytokines such as IL-1, IL-6, TNF-ɑ, IFN-γ. It also leads to disruption of the GIM composition and increased intestinal barrier permeability, contributing to GIM dysbiosis. The GIM dysbiosis and elevated cytokines can lead to reciprocal effects and further stimulate the HPA and SNS, creating a positive feedback loop that results in a pro-inflammatory state underlying the pathogenesis and progression of stress-associated cardiovascular, gastrointestinal, autoimmune, and psychiatric disorders. Understanding these relationships is critical for developing new strategies for managing stress-related health disorders.

Keywords:  Gastrointestinal Microbiome; Immune Modulation; Inflammation; Microbiota-Gut-Brain Axis; Psychosocial Stress

DOI:  https://doi.org/10.1152/japplphysiol.00652.2024
Exp Neurol. 2025 Jan 11. pii: S0014-4886(25)00010-X. [Epub ahead of print]386 115146

The immune-inflammatory responses on the hypothalamic-pituitary-adrenal axis and the neurovascular unit in perioperative neurocognitive disorder.

So Yeong Cheon, Matthew R Cho, So Yeon Kim, Bon-Nyeo Koo.

  Perioperative neurocognitive disorders (PNDs) refer to a wide spectrum of cognitive impairment persisting days to even after a year postoperative with significant morbidity and mortality. However, despite much efforts involving perioperative managements, PNDs are still prevalent with no standard preventative and therapeutic strategy. To overcome PNDs, a better understanding of pathophysiology of PNDs is crucial and a large number of studies have proven that immune-inflammatory responses from surgical stress are involved in the abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis and destabilization of neurovascular unit (NVU) that lead to PNDs. The HPA axis is one of the key components to maintaining physiological homeostasis in response to stress. Under normal conditions, the HPA axis is involved in multiple roles from memory consolidation to regulating the circadian rhythm by activating adrenal cortex to secret cortisol. However, when overwhelmed with inflammatory response from surgical stress, HPA axis may be abnormally activated to release excessive glucocorticoids to cause PNDs. In addition, NVU, the functional unit of the brain essential for maintaining blood brain barrier and cerebral blood flow, is another possible factor that may lead to PNDs as compromised NVU from inflammatory response can result in disrupted blood brain barrier and impaired brain homeostasis. Therefore, the interaction of immune-inflammatory response with the HPA axis and the NVU seems to play a significant role and therapeutic and/or preventive strategies focused on these interactions may be promising direction for future managements of PNDs.

Keywords:  Hypothalamic-pituitary-adrenal axis; Inflammatory response; Neurovascular unit; Perioperative neurocognitive disorder; Surgery

DOI:  https://doi.org/10.1016/j.expneurol.2025.115146
Hepatology. 2025 Jan 14.

CD44 in myEloid cells is a major driver of liver inflammation and injury in alcohol-related liver disease.

Déborah Rousseau, Stéphanie Bonnafous, Frédéric Soysouvanh, Dorian Sarrail, Manon Bourinet, Axelle Strazzulla, Stéphanie Patouraux, Arnaud Borderie, Bastien Dolfi, Alexandre Gallerand, Marwin A Farrugia, Véronique Orian-Rousseau, Yingzheng Xu, Jesse W Williams, Stoyan Ivanov, Albert Tran, Rodolphe Anty, Carmelo Luci, Philippe Gual.

BACKGROUND AND AIMS: Alcohol-related liver disease (ALD) is one of the leading causes of severe liver disease with limited pharmacological treatments for alcohol-related steatohepatitis (ASH). CD44, a glycoprotein mainly expressed in immune cells, has been implicated in multiple inflammatory diseases but has never been studied in the ALD context. We therefore studied its contribution to ASH development in mice and its expression in ALD patients.
APPROACH AND RESULTS: Here, we report that liver CD44 expression is associated with liver injury and inflammation and its deficiency (Cd44-/-) partially protected mice upon chronic plus binge ethanol feeding (CPB-EtOH). CD44 deletion in myeloid cells (Cd44myel-KO) recapitulated the same protective effects associated with reduced inflammatory monocyte infiltration and neutrophil activation in the liver and diminished blood neutrophil-lymphocyte ratio (NLR). CD44-deficient neutrophils displayed reduced PMA-induced inflammatory mediator expression and increased phagocytosis of live bacteria. Cd44myel-KO mice were also protected against hepatic steatosis mediated by CPB-EtOH or chronic ethanol feeding, due in part to increased SIRT1 mediated fatty acid beta-oxidation. CD44 neutralization with antibodies strongly decreased liver injury and inflammation (hepatic neutrophil frequency) and blood NLR upon CPB-EtOH. In samples from ALD patients, hepatic CD44 expression increased with ALD severity, correlated with hepatic TNFα and CD11b expression, and CD44-expressing neutrophils were enriched in alcohol-associated hepatitis.
CONCLUSIONS: Human and experimental evidence supports CD44 as a marker of hepatic inflammation in ALD. In addition, CD44 modulates neutrophil mobilization and functions and its targeting partially prevents liver inflammation and injury in the context of acute-on-chronic alcohol drinking.

DOI: https://doi.org/10.1097/HEP.0000000000001232
Stress. 2025 Dec;28(1): 2447079

Sex differences in the murine HPA axis after acute and repeated restraint stress.

Isabella Flor Nalepa, Vibeke Nielsen, Tanja Esther Wolf, Chadi Touma, Morten Grupe, Ayodeji A Asuni, Cecilia Ratner.

  Chronic stress and stress-related mental illnesses such as major depressive disorder (MDD) constitute some of the leading causes of disability worldwide with a higher prevalence in women compared to men. However, preclinical research into stress and MDD is heavily biased toward using male animals only. Aberrant activity of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to the development of MDD and several animal models of MDD have been established based on HPA axis dysregulation. In the present study, we compared stress biomarkers and behavior of male and female mice after acute and chronic restraint stress to investigate potential effects of sex differences in the stress response. Further, the validity of the interrupted repeated restraint stress (IRRS) model as an animal model for the HPA axis disturbances seen in MDD was assessed. After acute stress, female mice showed increased corticosterone secretion and changes in molecular markers suggesting increased HPA axis feedback sensitivity. Acute stress-induced signs of anxiety-like behavior were observed in male mice only suggesting that female mice may be more resilient to the anxiogenic effects of acute stress. Males and females responded similarly to IRRS with no sustained perturbations in HPA axis biomarkers. The IRRS model did not adequately translate to the changes reported in MDD with HPA axis overactivity and more severe perturbation models are likely needed. However, in alignment with previous studies, these data support that there are important sex differences in the HPA axis and that these may contribute to the etiology of stress-related psychiatric disorders.

Keywords:  HPA axis; Stress; corticosterone; major depressive disorder; restraint stress; sex

DOI:  https://doi.org/10.1080/10253890.2024.2447079
Immunity. 2025 Jan 14. pii: S1074-7613(24)00572-7. [Epub ahead of print]58(1): 18-39

The immunology of stroke and dementia.

Costantino Iadecola, Josef Anrather.

  Ischemic stroke and vascular cognitive impairment, caused by a sudden arterial occlusion or more subtle but protracted vascular insufficiency, respectively, are leading causes of morbidity and mortality worldwide with limited therapeutic options. Innate and adaptive immunity have long been implicated in neurovascular injury, but recent advances in methodology and new experimental approaches have shed new light on their contributions. A previously unappreciated dynamic interplay of brain-resident, meningeal, and systemic immune cells with the ischemic brain and its vasculature has emerged, and new insights into the frequent overlap between vascular and Alzheimer pathology have been provided. Here, we critically review these recent findings, place them in the context of current concepts on neurovascular pathologies and Alzheimer's disease, and highlight their impact on recent stroke and Alzheimer therapies.

Keywords:  ARIA syndrome; Alzheimer’s disease; RNA-seq; cerebral circulation; ischemic brain injury; meningeal immunity; vascular cognitive impairment

DOI:  https://doi.org/10.1016/j.immuni.2024.12.008
Metab Brain Dis. 2025 Jan 16. 40(1): 102

Emerging role of adaptive immunity in diabetes-induced cognitive impairment: from the periphery to the brain.

Genhui Yang, Runtao Su, Jie Bu, Ying Li, Xueling Lin, Jiahui Jin, Yanjun Zhang, Pengwei Zhuang, Hong Guo, Qingsheng Yin.

  Diabetic cognitive impairment (DCI) is a central nervous system complication induced by peripheral metabolic dysfunction of diabetes mellitus. Cumulative studies have shown that neuro-immune crosstalk is involved in the pathological progression of DCI. However, current studies mostly focus on the interaction between innate immunity cells and neurons, while ignoring the role of adaptive immunity cells in DCI. Notably, recent studies have revealed adaptive immune cells are involved in cognitive development and the progression of neurodegenerative diseases. Equally important, accumulated past studies have also shown that diabetic patients experience imbalanced peripheral adaptive immune homeostasis and disrupted transmission of adaptive immune cells to the central system. Therefore, this review first updated the cognitive mechanism of adaptive immune regulation, and then summarized the contribution of adaptive immunity to DCI from the aspects of peripheral adaptive immune homeostasis, transmission pathways, and brain tissue infiltration. Furthermore, we also summarized the potential of anti-diabetic drugs to regulate adaptive immunity, and looked forward to the potential value of regulatory adaptive immunity in the prevention and treatment of DCI, to provide a new strategy for the prevention and treatment of DCI.

Keywords:  Adaptive immunity; B cells; Blood-brain barrier; Blood-cerebrospinal fluid barrier; Diabetic cognitive impairment; T cells

DOI:  https://doi.org/10.1007/s11011-025-01532-x
Brain Res. 2025 Jan 10. pii: S0006-8993(25)00004-6. [Epub ahead of print] 149446

Chronic traumatic brain injury induces neurodegeneration, neuroinflammation, and cognitive deficits in a T cell-dependent manner.

Leyre Ayerra, Kirill Shumilov, Allen Ni, Maria S Aymerich, Stuart H Friess, Marta Celorrio.

  Traumatic brain injury (TBI) can lead to chronic neuroinflammation, and neurodegeneration associated with long-term cognitive deficits. Following TBI, the acute neuroinflammatory response involves microglial activation and the release of proinflammatory cytokines and chemokines which induce the recruitment of peripheral immune cells such as monocytes and ultimately T cells. Persistent innate and adaptive immune cells response can lead to chronic neurodegeneration and functional deficits. Therefore, understanding the dynamic interaction between chronic immune responses and TBI-related pathogenesis and progression of the disease is crucial. We hypothesized that T cells have an essential role in TBI severity and recovery. We used generic T cell deletion mice (TCRβ-/-δ-/-) vs Wild-type mice that underwent to controlled cortical impact assessing behavioral, histological, and immune system response outcomes at 3 months post-TBI. The absence of T cells reduced neurodegeneration and was associated with improved neurological outcomes 3 months post-injury. Furthermore, the absence of T cells enhanced an anti-inflammatory phenotype in peripheral myeloid cells in the injured brain. Collectively, these data indicate that T cells promote persistent neuropathology and functional impairments chronically after TBI.

Keywords:  And fear memory; Monocytes; Neurodegeneration; T cells; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.brainres.2025.149446