AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

Deferasirox exerts anti-epileptic effects by improving brain iron homeostasis via regulation of ITPRIP.

Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.

Dopamine­iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease.

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment resulted in increased expression of the transmembrane iron transporters transferrin receptor 1 (TFR1), ferroportin (FPN), and mitoferrin2 (MFRN2) and intracellular iron accumulation, suggesting that dopamine may promote iron uptake. Furthermore, dopamine supplementation led to reduced mitochondrial fitness including decreased mitochondrial respiration, increased cytochrome c control efficiency, reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore the disturbed regulatory network in PD cells.

How gut microbiota may impact ocular surface homeostasis and related disorders.

Changes in the bacterial flora in the gut, also described as gut microbiota, are readily acknowledged to be associated with several systemic diseases, especially those with an inflammatory, neuronal, psychological or hormonal factor involved in the pathogenesis and/or the perception of the disease. Maintaining ocular surface homeostasis is also based on all these four factors, and there is accumulating evidence in the literature on the relationship between gut microbiota and ocular surface diseases. The mechanisms involved are mostly interconnected due to the interaction of central and peripheral neuronal networks, inflammatory effectors and the hormonal system. A better understanding of the influence of the gut microbiota on the maintenance of ocular surface homeostasis, and on the onset or persistence of ocular surface disorders could bring new insights and help elucidate the epidemiology and pathology of ocular surface dynamics in health and disease. Revealing the exact nature of these associations could be of paramount importance for developing a holistic approach using highly promising new therapeutic strategies targeting ocular surface diseases.

Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice.

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis.

Xiphoid nucleus of the midline thalamus controls cold-induced food seeking.

Maintaining body temperature is calorically expensive for endothermic animals1. Mammals eat more in the cold to compensate for energy expenditure2, but the neural mechanism underlying this coupling is not well understood. Through behavioural and metabolic analyses, we found that mice dynamically switch between energy-conservation and food-seeking states in the cold, the latter of which are primarily driven by energy expenditure rather than the sensation of cold. To identify the neural mechanisms underlying cold-induced food seeking, we used whole-brain c-Fos mapping and found that the xiphoid (Xi), a small nucleus in the midline thalamus, was selectively activated by prolonged cold associated with elevated energy expenditure but not with acute cold exposure. In vivo calcium imaging showed that Xi activity correlates with food-seeking episodes under cold conditions. Using activity-dependent viral strategies, we found that optogenetic and chemogenetic stimulation of cold-activated Xi neurons selectively recapitulated food seeking under cold conditions whereas their inhibition suppressed it. Mechanistically, Xi encodes a context-dependent valence switch that promotes food-seeking behaviours under cold but not warm conditions. Furthermore, these behaviours are mediated by a Xi-to-nucleus accumbens projection. Our results establish Xi as a key region in the control of cold-induced feeding, which is an important mechanism in the maintenance of energy homeostasis in endothermic animals.

A closer look at the role of iron in glioblastoma.

Glioblastoma (GBM) is among the deadliest malignancies facing modern oncology. While our understanding of certain aspects of GBM biology has significantly increased over the last decade, other aspects, such as the role of bioactive metals in GBM progression, remain understudied. Iron is the most abundant transition metal found within the earth's crust and plays an intricate role in human physiology owing to its ability to participate in oxidation-reduction reactions. The importance of iron homeostasis in human physiology is apparent when examining the clinical consequences of iron deficiency or iron overload. Despite this, the role of iron in GBM progression has not been well described. Here, we review and synthesize the existing literature examining iron's role in GBM progression and patient outcomes, as well as provide a survey of iron's effects on the major cell types found within the GBM microenvironment at the molecular and cellular level. Iron represents an accessible target given the availability of already approved iron supplements and chelators. Improving our understanding of iron's role in GBM biology may pave the way for iron-modulating approaches to improve patient outcomes.

The hypothalamus as a key regulator of glucose homeostasis: emerging roles of the brain renin-angiotensin system.

The regulation of plasma glucose levels is a complex and multifactorial process involving a network of receptors and signaling pathways across numerous organs that act in concert to ensure homeostasis. However, much about the mechanisms and pathways by which the brain regulates glycemic homeostasis remains poorly understood. Understanding the precise mechanisms and circuits employed by the central nervous system to control glucose is critical to resolving the diabetes epidemic. The hypothalamus, a key integrative center within the central nervous system, has recently emerged as a critical site in the regulation of glucose homeostasis. Here, we review the current understanding of the role of the hypothalamus in regulating glucose homeostasis, with an emphasis on the paraventricular nucleus, the arcuate nucleus, the ventromedial hypothalamus, and lateral hypothalamus. In particular, we highlight the emerging role of the brain renin-angiotensin system in the hypothalamus in regulating energy expenditure and metabolic rate, as well as its potential importance in the regulation of glucose homeostasis.

Cerebrovascular and cardiovascular responses to the Valsalva manoeuvre during hyperthermia.

BACKGROUND: During hyperthermia, the perturbations in mean arterial blood pressure (MAP) produced by the Valsalva manoeuvre (VM) are more severe. However, whether these more severe VM-induced changes in MAP are translated to the cerebral circulation during hyperthermia is unclear. METHODS: Healthy participants (n = 12, 1 female, mean ± SD: age 24 ± 3 years) completed a 30 mmHg (mouth pressure) VM for 15 s whilst supine during normothermia and mild hyperthermia. Hyperthermia was induced passively using a liquid conditioning garment with core temperature measured via ingested temperature sensor. Middle cerebral artery blood velocity (MCAv) and MAP were recorded continuously during and post-VM. Tieck's autoregulatory index was calculated from the VM responses, with pulsatility index, an index of pulse velocity (pulse time) and mean MCAv (MCAvmean ) also calculated. RESULTS: Passive heating significantly raised core temperature from baseline (37.9 ± 0.2 vs. 37.1 ± 0.1°C at rest, p < 0.01). MAP during phases I through III of the VM was lower during hyperthermia (interaction effect p < 0.01). Although an interaction effect was observed for MCAvmean (p = 0.02), post-hoc differences indicated only phase IIa was lower during hyperthermia (55 ± 12 vs. 49.3 ± 8 cm s- 1 for normothermia and hyperthermia, respectively, p = 0.03). Pulsatility index was increased 1-min post-VM in both conditions (0.71 ± 0.11 vs. 0.76 ± 0.11 for pre- and post-VM during normothermia, respectively, p = 0.02, and 0.86 ± 0.11 vs. 0.99 ± 0.09 for hyperthermia p < 0.01), although for pulse time only main effects of time (p < 0.01), and condition (p < 0.01) were apparent. CONCLUSION: These data indicate that the cerebrovascular response to the VM is largely unchanged by mild hyperthermia.

Spectro-spatial features in distributed human intracranial activity proactively encode peripheral metabolic activity.

Mounting evidence demonstrates that the central nervous system (CNS) orchestrates glucose homeostasis by sensing glucose and modulating peripheral metabolism. Glucose responsive neuronal populations have been identified in the hypothalamus and several corticolimbic regions. However, how these CNS gluco-regulatory regions modulate peripheral glucose levels is not well understood. To better understand this process, we simultaneously measured interstitial glucose concentrations and local field potentials in 3 human subjects from cortical and subcortical regions, including the hypothalamus in one subject. Correlations between high frequency activity (HFA, 70-170 Hz) and peripheral glucose levels are found across multiple brain regions, notably in the hypothalamus, with correlation magnitude modulated by sleep-wake cycles, circadian coupling, and hypothalamic connectivity. Correlations are further present between non-circadian (ultradian) HFA and glucose levels which are higher during awake periods. Spectro-spatial features of neural activity enable decoding of peripheral glucose levels both in the present and up to hours in the future. Our findings demonstrate proactive encoding of homeostatic glucose dynamics by the CNS.

Zinc: From Biological Functions to Therapeutic Potential.

The trace element zinc (Zn) displays a wide range of biological functions. Zn ions control intercellular communication and intracellular events that maintain normal physiological processes. These effects are achieved through the modulation of several Zn-dependent proteins, including transcription factors and enzymes of key cell signaling pathways, namely those involved in proliferation, apoptosis, and antioxidant defenses. Efficient homeostatic systems carefully regulate intracellular Zn concentrations. However, perturbed Zn homeostasis has been implicated in the pathogenesis of several chronic human diseases, such as cancer, diabetes, depression, Wilson's disease, Alzheimer's disease, and other age-related diseases. This review focuses on Zn's roles in cell proliferation, survival/death, and DNA repair mechanisms, outlines some biological Zn targets, and addresses the therapeutic potential of Zn supplementation in some human diseases.

Zinc Homeostasis: An Emerging Therapeutic Target for Neuroinflammation Related Diseases.

Zinc is an indispensable trace element in the human body and plays an important role in regulating normal growth and development. Zinc homeostasis in the central nervous system is closely related to the development of neuroinflammation, and synaptic zinc homeostasis disorders affect zinc homeostasis in the brain. Under the condition of synaptic zinc homeostasis, proper zinc supplementation improves the body's immunity and inhibits neuroinflammation. Synaptic zinc homeostasis disorder in the brain promotes the occurrence and development of neuroinflammation. Cerebral ischemia and hypoxia cause a massive release of synaptic Zn2+ into the synaptic cleft, resulting in neurotoxicity and neuroinflammation. Synaptic zinc homeostasis disorder is a high-risk factor for neurodegenerative diseases. Maintaining cerebral zinc homeostasis suppresses the progression of neuroinflammation-mediated neurodegenerative diseases. This article reviews the relationship between brain zinc homeostasis and neuroinflammation and proposes that maintaining synaptic zinc homeostasis prevents neuroinflammation.

Interactions between the regulatory peptide 26RFa (QRFP) and insulin in the regulation of glucose homeostasis in two complementary models: The high fat 26RFa-deficient mice and the streptozotocin insulin-deficient mice.

The regulatory peptide 26RFa (QRFP) is involved in the control of glucose homeostasis at the periphery by acting as an incretin, and in the brain by mediating the central antihyperglycemic effect of insulin, indicating the occurrence of a close relationship between 26RFa and insulin in the regulation of glucose metabolism. Here, we investigated the physiological interactions between 26RFa and insulin in two complementary models i.e. a model of obese/hyperglycemic mice deficient for 26RFa and a model of diabetic mice deficient for insulin. For this, transgenic 26RFa-deficient mice were made obese and chronically hyperglycemic by a 3-month high fat diet (HFD) and second group of mice was made diabetic by destruction of the ß cells of the pancreatic islets using a single injection of streptozotocin. Our data reveal that 26RFa deficiency does not impact significantly the "glycemic" phenotype of the HFD mice. The pancreatic islets, liver, white adipose tissue masses are not altered by the lack of 26RFa production but the brown adipose tissue (BAT) weight is significantly increased in these animals. In diabetic insulin-deficient mice, the injection of 26RFa does not exhibit any beneficial effect on the impaired glucose homeostasis characterizing this model. Finally, we show that streptozotocin diabetic mice display lowered plasma 26RFa levels as compared to untreated mice, whereas the expression of the peptide in the duodenum is not affected. Taken together, the present results indicate that dysregulation of glucose homeostasis in obese/hyperglycemic mice is not aggravated by the absence of 26RFa that may be compensated by the increase of BAT mass. In diabetic insulin-deficient mice, the antihypergycemic effect of 26RFa is totally blunted probably as a result of the impaired insulin production characterizing this model, avoiding therefore the action of the peptide.

Selenium in Bodily Homeostasis: Hypothalamus, Hormones, and Highways of Communication.

The ability of the body to maintain homeostasis requires constant communication between the brain and peripheral tissues. Different organs produce signals, often in the form of hormones, which are detected by the hypothalamus. In response, the hypothalamus alters its regulation of bodily processes, which is achieved through its own pathways of hormonal communication. The generation and transmission of the molecules involved in these bi-directional axes can be affected by redox balance. The essential trace element selenium is known to influence numerous physiological processes, including energy homeostasis, through its various redox functions. Selenium must be obtained through the diet and is used to synthesize selenoproteins, a family of proteins with mainly antioxidant functions. Alterations in selenium status have been correlated with homeostatic disturbances in humans and studies with animal models of selenoprotein dysfunction indicate a strong influence on energy balance. The relationship between selenium and energy metabolism is complicated, however, as selenium has been shown to participate in multiple levels of homeostatic communication. This review discusses the role of selenium in the various pathways of communication between the body and the brain that are essential for maintaining homeostasis.

Understanding the aging hypothalamus, one cell at a time.

The hypothalamus is a brain region that integrates signals from the periphery and the environment to maintain organismal homeostasis. To do so, specialized hypothalamic neuropeptidergic neurons control a range of processes, such as sleep, feeding, the stress response, and hormone release. These processes are altered with age, which can affect longevity and contribute to disease status. Technological advances, such as single-cell RNA sequencing, are upending assumptions about the transcriptional identity of cell types in the hypothalamus and revealing how distinct cell types change with age. In this review, we summarize current knowledge about the contribution of hypothalamic functions to aging. We highlight recent single-cell studies interrogating distinct cell types of the mouse hypothalamus and suggest ways in which single-cell 'omics technologies can be used to further understand the aging hypothalamus and its role in longevity.

Neuroendocrine microRNAs linked to energy homeostasis: future therapeutic potential.

The brain orchestrates whole-body metabolism through an intricate system involving interneuronal crosstalk and communication. Specifically, a key player in this complex circuitry is the hypothalamus that controls feeding behaviour, energy expenditure, body weight and metabolism, whereby hypothalamic neurons sense and respond to circulating hormones, nutrients, and chemicals. Dysregulation of these neurons contributes to the development of metabolic disorders, such as obesity and type 2 diabetes. The involvement of hypothalamic microRNAs, post-transcriptional regulators of gene expression, in the central regulation of energy homeostasis has become increasingly apparent, although not completely delineated. This review summarizes current evidence demonstrating the regulation of feeding-related neuropeptides by brain-derived microRNAs as well as the regulation of specific miRNAs by nutrients and other peripheral signals. Moreover, the involvement of microRNAs in the central nervous system control of insulin, leptin, and estrogen signal transduction is examined. Finally, the therapeutic and diagnostic potential of microRNAs for metabolic disorders will be discussed and the regulation of brain-derived microRNAs by nutrients and other peripheral signals is considered. Demonstrating a critical role of microRNAs in hypothalamic regulation of energy homeostasis is an innovative route to uncover novel biomarkers and therapeutic candidates for metabolic disorders.

Contribution of the co-chaperone FKBP51 in the ventromedial hypothalamus to metabolic homeostasis in male and female mice.

OBJECTIVE: Steroidogenic factor 1 (SF1) expressing neurons in the ventromedial hypothalamus (VMH) have been directly implicated in whole-body metabolism and in the onset of obesity. The co-chaperone FKBP51 is abundantly expressed in the VMH and was recently linked to type 2 diabetes, insulin resistance, adipogenesis, browning of white adipose tissue (WAT) and bodyweight regulation. METHODS: We investigated the role of FKBP51 in the VMH by conditional deletion and virus-mediated overexpression of FKBP51 in SF1-positive neurons. Baseline and high fat diet (HFD)-induced metabolic- and stress-related phenotypes in male and female mice were obtained. RESULTS: In contrast to previously reported robust phenotypes of FKBP51 manipulation in the entire mediobasal hypothalamus (MBH), selective deletion or overexpression of FKBP51 in the VMH resulted in only a moderate alteration of HFD-induced bodyweight gain and body composition, independent of sex. CONCLUSIONS: Overall, this study shows that animals lacking and overexpressing Fkbp5 in Sf1-expressing cells within the VMH display only a mild metabolic phenotype compared to an MBH-wide manipulation of this gene, suggesting that FKBP51 in SF1 neurons within this hypothalamic nucleus plays a subsidiary role in controlling whole-body metabolism.

The central nervous system control of energy homeostasis: High fat diet induced hypothalamic microinflammation and obesity.

Obesity is believed to arise through the imbalance of energy homeostasis controlled by the central nervous system, where the hypothalamus plays the fundamental role in energy metabolism. In this review, we will provide an overview regarding the functions of POMC neurons and AgRP neurons in acute nucleus of the hypothalamus which mediated the energy metabolism, highlighting their interactions with peripheral organs derived hormones in control of energy homeostasis. Furthermore, the role of high fat diet induced hypothalamic microinflammation in the pathogenesis of obesity will be discussed. We hope this review could help researchers to understand the mechanism of hypothalamus in control of energy metabolism, and design related drugs to block the pathways involving in the impaired metabolism in obese patients.

Neuroendocrine mechanisms of reproductive dysfunctions in undernourished condition.

It is well known that undernourished conditions disturb female reproductive functions in many species, including humans. These alterations are mainly caused by a reduction in gonadotrophin-releasing hormone (GnRH) secretion from the hypothalamus. Evidence from the literature suggests that some hypothalamic factors play pivotal roles in the coordination of reproductive functions and energy homeostasis in response to environmental cues and internal nutritional status. Generally, anorexigenic/satiety-related factors, such as leptin, alpha-melanocyte-stimulating hormone, and proopiomelanocortin, promote GnRH secretion, whereas orexigenic factors, such as neuropeptide Y, agouti-related protein, orexin, and ghrelin, attenuate GnRH secretion. Conversely, gonadotrophin-inhibitory hormone, which exerts anti-GnRH and gonadotrophic effects, promotes feeding behavior in many species. In addition, the activity of kisspeptin, which is a potent stimulator of GnRH, is reduced by undernourished conditions. Under normal nutritional conditions, these factors are coordinated to maintain both feeding behavior and reproductive functions. However, in undernourished conditions their activity levels are markedly altered to promote feeding behavior and temporarily suppress reproductive functions, in order to prioritize the survival of the individual over that of the species.

Dietary nitrate supplementation effect on dynamic cerebral autoregulation in normoxia and acute hypoxia.

We tested the hypothesis that increasing the nitric oxide (NO) bioavailability by dietary nitrate would recover the hypoxia-induced reduction in dynamic cerebral autoregulation (CA). Twelve healthy males (age 21 ± 2 years) completed four days of dietary supplementation with a placebo or inorganic nitrate drink (140-ml beetroot juice per day) followed by 60-min of normoxia or hypoxia (fraction of inspired oxygen [FiO2] = 13%). Duplex ultrasonography was used to perform volumetric change-based assessment of dynamic CA in the internal carotid artery (ICA). Dynamic CA was assessed by rate of regulation (RoR) of vascular conductance using the thigh-cuff method. Four days of beetroot supplementation increased circulating nitrate by 208 [171,245] µM (mean difference [95% confidence interval]) compared with placebo. Dynamic CA was lower in hypoxia than normoxia (RoR Δ-0.085 [-0.116, -0.054]). Compared with placebo, nitrate did not alter dynamic CA in normoxia (RoR Δ-0.022 [-0.060, 0.016]) or hypoxia (RoR Δ0.017 [-0.019, 0.053]). Further, nitrate did not affect ICA vessel diameter, blood velocity or flow in either normoxia or hypoxia. Increased bioavailability of NO through dietary nitrate supplementation did not recover the hypoxia-induced reduction in dynamic CA. This suggests the mechanism of hypoxia-induced reduction in dynamic CA does not relate to the availability of NO.