Review on the role of hypothalamic astrocytes in the neuroendocrine control of metabolism

Abstract

Astrocytes are the most numerous type of glial cells found in the nervous system. They regulate energy homeostasis in collaboration with the neuronal circuits involved in energy balance. These glial cells are equipped with sensors and receptors for nutrients and metabolic hormones in order to control energy homeostasis. Astrocytes, like hypothalamic appetite-regulating neurons, are vulnerable to the negative consequences of a high-fat diet (HFD) feeding, which is associated with an inflammatory response and transforms them into a reactive astrocyte state, consequently leading to the disruption of energy balance. Additionally, these cells have sexually dimorphic characteristics, which will lead to different metabolic outcomes in males and females. In this review, we will discuss the various physiological and pathophysiological roles of astrocytes in regulating energy balance. Finally, we will discuss the sexual dimorphism in astrocytes and the impact of estrogen on eliciting distinct responses.

Introduction

Astrocytes, the most abundant glial cells in the brain, participate in brain homeostasis in many ways, including the formation of the blood-brain barrier (BBB), providing structural, functional, and metabolic support to neurons [1]. In addition to supplying energy for neurons, these cells can detect nutrient availability and regulate nutrient transport to neighboring neurons [2, 3]. Furthermore, astrocytes possess receptors for metabolic hormones, including insulin, ghrelin, and leptin. Therefore, they mediate metabolic connections between the peripheral environment and the central nervous system [4].

There is growing evidence from animal models that consumption of a HFD is associated with hypothalamic inflammation and astrocyte reactivity (molecular and morphological changes within astrocytes) [5–7], These changes include increased expression of glial fibrillary acidic proteins (GFAP), which is a marker of astrocyte reactivity [8], as well as an increase in the number and size of astrocytes [6]. This can result in the development of some metabolic disorders such as obesity and type 2 diabetes. Astrocytes become hypertrophic only 24 h after HFD feeding, before the onset of dysfunctional firing patterns of neurons and neuroinflammation [6, 9, 10], suggesting that they participate in the pathophysiology of metabolic disorders. Therefore, it is necessary to understand the underlying mechanisms through which reactive astrocytes contribute to the disruption of energy balance in order to develop effective therapeutic strategies to combat obesity.

Sexual dimorphism in astrocytes is present in different brain regions, impacting their number, morphology, and function [11, 12]. One possible reason for this is the exposure of cells to different sex hormones during development [13]. Estradiol, as a mediator of sexual differences, plays a crucial role in the neuroendocrine regulation of metabolism, such as modulating the sensitivity of certain metabolic hormones [14, 15], regulating body weight [16], and suppressing inflammation caused by a high-calorie diet [17, 18]. Although there is a wealth of information on how estrogen influences energy balance, the specific mechanisms through which estrogen mediates the neuroendocrine regulation of energy balance are yet to be fully understood.

In this review, we provide a summary of the role of astrocytes in the neuroendocrine regulation of energy balance, as well as their involvement in developing pathophysiological processes such as diet-induced obesity. Additionally, we discuss the action of estrogen as a mediator of sexual dimorphism in astrocytes, contributing to the regulation of energy homeostasis.

The role of hypothalamic astrocytes in the Central Control of Metabolism

The hypothalamus, specifically the arcuate nucleus (ARC), is a crucial region of the brain responsible for regulating appetite and metabolism [19]. The ARC is located near the median eminence (ME), a circumventricular organ with fenestrated capillaries that allow molecules to freely move from the periphery to the central nervous system (CNS). This makes the ARC a metabolically sensitive area in the brain. Hypothalamic astrocytes located in the ARC-ME region, are responsible for sensing the metabolic state from the periphery and transmitting metabolic signals to the ARC neuronal population involved in the regulation of energy homeostasis (Fig. 1).

Fig. 1.

A schematic representation illustrates how astrocytes facilitate the exchange of metabolic signals between the periphery and the brain, which plays a crucial role in regulating the energy balance. Astrocytes participate in the control of energy balance by transporting and sensing nutritional signals, as well as expressing several receptors for metabolic hormones including, Insulin receptor (IR), leptin receptor (LEPR), glucagon- like peptide 1 (GLP-1), glucagon- like peptide 1 receptor (GLP-1R). Astrocytes transport glucose, fatty acids, and ketone bodies via glucose transporter 1(GLUT1), cluster of differentiation 36 (CD36), and monocarboxylate transporter1 (MCT1), respectively and transfer lactate and ketone body to neuron via MCT1, and MCT2, respectively

Astrocytes and central glucose sensing

Glucose is the most important source of energy for the brain. There is increasing evidence that astrocytes actively participate in the detection, uptake, metabolism, and storage of glucose [20, 21]. Glucose enters the astrocyte through glucose transporters and then converts into pyruvate and lactate by glycolysis, finally transfer to neurons as an energy source via monocarboxylate transporters (MCTs) (Fig. 1). Additionally, excess glucose is stored in the form of glycogen in astrocytes, serving as an energy source [22]. Astrocytes not only transport glucose and store it as an energy source, but they can also sense glucose. Previous studies have shown that hypothalamic astrocytes cooperate with glucose-sensitive neurons to detect glucose [23]. For example, increasing the level of glucose in the brain following carotid injection of glucose stimulates both neurons and astrocytes within the ARC [24]. Glucose transporters 1, and Glucose transporters 2 (GLUT1 and GLUT2) in astrocytes are critical for glucose sensing [25]. Persistent hyperglycemia in uncontrolled diabetes impairs hypothalamic glucose sensing through changes in glial GLUT1 [26]. Furthermore, down-regulated expression of GLUT1 in db/db mice (the mice have a mutation in the gene that encodes the leptin receptor), type 2 diabetes (T2DM) patients, and Alzheimer’s disease (AD) mouse model probably indicates that GLUT1 dysfunction could be a pathophysiological basis of T2DM and AD [27]. Therefore, GLUT1 could be considered an important therapeutic strategy for treating both T2DM and AD. In addition to GLUT1, GLUT2 in hypothalamic astrocytes, especially in the feeding center, has a crucial role in sensing glucose (Fig. 2) [21, 28–30]. It has been demonstrated that the inhibition of GLUT2 in the astrocytes impairs central glucose sensing and also changes insulin secretion in response to an increased glucose level in the brain [31]. Additionally, changes in astroglial connexin expression in fasting and feeding states confirm the role of astrocytes in glucose sensing [23]. Connexins are in gap junctions between astrocytic networks and play a prominent role in the transport of nutrients over long distances [32]. Removing connexin 43 from the ARC decreases insulin secretion from the pancreas in response to an increase in central glucose [23].

Fig. 2.

The figure shows a comparison between normal and impaired metabolic signals mediated by the astrocytes of the hypothalamus. In the normal state, there are metabolic sensors, which include glucose transporters (GLUTs), peroxisome proliferator-activated receptor gamma (PPARγ), and lipoprotein lipase (LPL). Additionally, there are metabolic receptors such as the leptin receptor (LEPR), glucagon-like peptide1 receptor (GLP-1R), and insulin receptor (IR) in astrocytes that contribute to maintaining energy homeostasis. In an impaired metabolic state, the deletion of these sensors and receptors leads to a disruption of energy homeostasis and the development of metabolic disorders

Astrocytes and lipids

Changes in plasma lipid concentration following meal consumption can be detected by the central nervous system and act as a signal to regulate energy balance [33]. Both neurons and astrocytes have been found to express several fatty acid transporters (FATPs), such as FATP1, FATP4, and cluster of differentiation 36 (CD36). In addition to that, these cells express lipid sensors, such as peroxisome proliferator-activated receptor gamma (PPARγ) and lipoprotein lipase (LPL) [34]. The PPARs are nuclear receptor proteins that function as transcription factors. They play a crucial role in regulating cell differentiation, development, and the metabolism of proteins, and lipids [35]. There are three subtypes of PPARs α, δ/β, and γ. All three subtypes of PPARs are found in the brain. PPARγ serves as the main sensor of lipids and regulator of metabolism [36, 37]. The results of a recent study showed that astrocytic-specific deletion of PPARγ leads to changes in the expression of genes involved in lipid transport and metabolism, as well as increased appetite and body weight gain in HFD mice (Fig. 2) [38].

Brain LPL also contribute to brain lipid sensing [39, 40]. Astrocytes can uptake and store lipids through LPL [41]. Significant functions of astrocytic LPL in the control of lipid homeostasis were shown by changing the expression of LPL in response to saturated and unsaturated fatty acids, as well as various nutrient stimuli. The results of a recent study have shown that postnatal deletion of astrocytic LPL disrupts lipid sensing and contributes to dietary obesity, as well as glucose intolerance in HFD mice (Fig. 2). Also, it was discovered that LPL knockout mice showed an increase in ceramide accumulation, specifically in hypothalamic neurons. Therefore, according to Gao et al. (2017), astrocytic LPL is not only required for lipid metabolism and the detection of lipid levels, but also contributes to whole-body energy metabolism [40].

Astrocytes and ketone bodies

In addition to the astrocytes’ role in lipid homeostasis, they also play a role in the homeostasis of ketone bodies. Many studies have shown that astrocytes are the exclusive source of ketone body production in the brain [39, 42]. Astrocytes not only uptake ketone body but also synthesize them from fatty acids and deliver them to neurons. The main transporters of ketone bodies in the brain are monocarboxylate transporters (MCTs), specifically MCT1, MCT2, and MCT4 [43]. During fasting and under high-fat diet conditions, levels of free fatty acids (FFA) increase and are metabolized by astrocytes [39]. A previous study has shown that levels of fatty acids and ketone bodies can influence feeding behaviors. Consuming a high-fat diet for a short period of time leads to an increased production of ketone bodies in astrocytes and a decrease in feeding. Additionally, pharmacological inhibition of ketone body production suppresses HFD-induced satiety [44]. Thus, ketone bodies play a significant role in the regulation of feeding.

Astrocytes and Leptin

Leptin, a hormone weighing 16 KDa, is secreted by adipose tissue. Its primary function is to regulate energy balance by acting on the central nervous system [7]. Leptin is transported across the BBB through a saturable transport system [45]. It stimulates the release of appetite-suppressing neuropeptides while also inhibiting the release of hunger-inducing neuropeptides, thus effectively reducing food intake [16, 46]. In addition to neurons and endothelial cells, astrocytes are also able to mediate the central effects of leptin [47, 48]. Astrocytes express four major forms of the leptin receptor (ObR) splice variants, including ObRa, ObRb, ObRc, and ObRe [49]. It has been shown that diet-induced obesity can increase the expression of leptin receptors in hypothalamic astrocytes [50] and induce gliosis and increased levels of GFAP, which could be related to increased leptin signaling in astrocytes [49, 51]. More studies indicate the importance of astrocytes, along with neurons, in the regulation of central leptin responsiveness [50, 52]. Furthermore, knocking out all isoforms of ObR in astrocytes leads to mild changes in the morphology of glial cells, a higher percentage of body fat, hyperleptinemia, and the development of diet-induced obesity (Fig. 2). Therefore, leptin signaling in astrocytes is essential for the neuroendocrine regulation of obesity [52].

Astrocytes and GLP-1

Glucagon-like peptide-1 (GLP-1) is a proglucagon-derived peptide that is released from the enteroendocrine L-cells. It stimulates glucose-dependent insulin secretion and inhibits glucagon secretion in pancreatic islets. Hence, it is important as an attractive therapeutic strategy for the treatment of T2DM [53, 54]. Furthermore, GLP-1 is produced by proglucagon-expressing neurons in the nucleus of the solitary tracts (NTS) nuclei of the brain and is projected to other areas of the brain, including the hypothalamus [53]. Little research has been done on the role of astrocytic GLP-1 and its function in energy homeostasis. Astrocytes express the glucagon-like peptide receptor [55]. Results of a recent study have shown that NTS astrocytic GLP-1R signaling is important for controlling energy balance and reducing food intake [56, 57]. Additionally, the results of Timper et al.’s study showed that GLP-1 inhibits glucose uptake and increases beta oxidation in astrocyte primary cell culture [58]. Furthermore, the results of this study showed that postnatal deletion of astrocytic GLP-1 receptor leads to increased brain glucose availability, which is associated with improvements in systemic glucose homeostasis and memory formation (Fig. 2) [58].

Astrocytes and Ghrelin

Ghrelin regulates appetite, energy balance, and glucose homeostasis [59, 60]. There have been few studies on ghrelin’s actions on astrocytes. The in vitro results of the study conducted in 2016 showed that ghrelin modulates glucose uptake in hypothalamic astrocytes. Additionally, in vivo studies showed that intracerebroventricular injection of ghrelin quickly decreases the expression of glucose transporters in astrocytes. This rapid decline in glucose transporters can reduce astrocytes’ ability to detect glucose, thereby increasing food intake [21]. Therefore, these results suggest that some effects of ghrelin in the neuroendocrine control of metabolism are mediated by astrocytes [21].

Astrocytes and insulin

Astrocytic insulin signaling has been proven to be important for regulating hypothalamic glucose sensing and modulating systemic glucose metabolism [61, 62]. The results of a previous study showed that deletion of the astrocytic insulin receptor decreased glucose-induced neuronal activation in the hypothalamus, particularly in pro-opio-melanocortin (POMC) neurons, and impaired the physiological response to changes in glucose availability [61]. Additionally, mice lacking the astrocytic insulin receptor were unable to readjust systemic glucose levels following intraperitoneal glucose injection [61]. Furthermore, there is evidence that insulin and insulin-like growth factor IGF-1, through coordinated action on astrocytes, modulate brain glucose metabolism by translocating GLUT-1 to the plasma membrane [63]. The physiological importance of insulin signaling in astrocytes has been clearly demonstrated in genetically engineered mice. Mice with insulin receptor deletion develop brain insulin resistance, along with impaired coupling between brain glucose uptake and blood flow, as well as disturbed astrocytic mitochondrial function [61, 64]. In addition to the regulation of glucose homeostasis, insulin signaling in astrocytes plays a pivotal role in the regulation of energy balance. The results of studies have shown that the ablation of insulin receptors in astrocytes leads to decreased energy expenditure and decreased normal body temperature in astrocyte-specific insulin receptor deletion (IRKO^GFAP₎ mice (Fig. 2) [62].

Astrocytes and development of hypothalamic inflammation

Inflammation is considered an important cellular event in the pathogenesis of obesity [65, 66]. Several studies have shown an association between the consumption of a high-fat diet, inflammation, and obesity [1, 7]. Long-term exposure to a HFD induces chronic low-grade inflammation and gliosis, which is responsible for the development of central leptin and insulin resistance [9, 67]. HFD-induced hypothalamic inflammation provokes inflammatory signals through the up-regulation of inflammatory mediators; including IκB kinase-β/nuclear factor-κB (IKKβ-NFκB) and endoplasmic reticulum stress markers that suppress downstream mediators of leptin pathways [1, 66, 68]. Multiple studies have indicated that astrocytes, microglia, and neurons play a crucial role in promoting hypothalamic inflammation and the development of metabolic disorders [66, 69–71]. The results of a study have shown that only a few days after consuming a high-fat diet, hypothalamic inflammatory responses and reactive astrocytes were observed in the hypothalamus of mice and rats [9]. Indeed, this is part of an acute homeostatic response after consuming a HFD, which constrains food intake and ultimately leads to the maintenance of energy homeostasis [72]. However, chronically, increased production of pro-inflammatory cytokines by activated astrocytes induces neuronal damage and disrupts energy homeostasis [73].

Inflammatory signaling in astrocytes

Multiple studies indicate that consuming a high-fat diet has the potential to activate inflammation in the hypothalamus, leading to alterations in glial cells [1]. Results of in vitro studies have shown that saturated fatty acids (palmitic acid, stearic acid) induce reactivity in astrocyte culture and also release pro-inflammatory cytokines from the culture [74]. In addition, the presence of saturated fatty acids promotes the accumulation of lipids in the hypothalamus [75]. Sugiyama et al. showed that after the initiation of a high-fat diet, hypothalamic astrocytes suppress inflammation, partly by increasing the anti-inflammatory cytokine interleukin-10. However, prolonged consumption of a high-fat diet impairs the inflammation-suppressing function of glial cells [76].

Various studies have shown that there is a significant relationship between IKKβ/NFκB astrocytic signaling and the development of metabolic disorders in HFD rodents [9, 77, 78]. IKKβ/NFκB is an important intracellular pro-inflammatory pathway that plays a crucial role in regulating the development of neuroinflammatory related diseases [79]. Results of the study conducted by Buckman et al. showed that the inhibition of NFκB signaling in astrocytes prevented astrocyte reactivity in high-fat diet mice. Additionally, this inhibition resulted in an increase in food intake on the first day following the high-fat diet feeding [72]. Also, the results of previous studies have shown that up-regulation of astrocytic IKKβ/NFκB results in glucose intolerance, body weight gain, and body fat accumulation (Fig. 3) [80]. However, deletion of IKKβ from astrocytes of DIO mice improves astrocyte reactivity and hypothalamic inflammation and also results in weight loss through reducing food intake [78].

Fig. 3.

The schematic representation shows the relationship between chronic high-fat diet feeding and the development of metabolic disorders. Consuming a high-fat diet induces reactive astrocyte, the production of inflammatory cytokines, increased expression of inflammatory mediators such as IκB kinase-β/nuclear factor-κB (IKKβ/NFκB), toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), which results in the development of leptin resistance and obesity

Long-term HFD feeding also up-regulates Myd88 (myeloid differentiation primary response 88) in hypothalamic astrocytes. Myd88 signaling is an adapter molecule that links toll-like receptor (TLR4) to the intracellular signaling cascade, such as IKKβ/NF-κβ [1, 81]. Astrocyte-specific deletion of Myd88 ameliorates the metabolic phenotype associated with HFD-induced obesity [65]. It should be mentioned that, in addition to consuming a high-fat diet, intracerebroventricular injection of saturated free fatty acids induces gliosis in the ARC of the hypothalamus of control mice. However, this effect was not present in mice that specifically had the Myd88 gene knocked out in their astrocytes. These results suggest that MyD88 in hypothalamic astrocytes is a critical molecule in obesity pathogenesis that mediates HFD signals for gliosis and leptin resistance (Fig. 3) [65]. Therefore, these results show the critical role of astrocytes in the pathophysiological response to a high-fat diet.

Sexual dimorphism in astrocytes and the role of Estrogen in astrocyte-mediated neuroendocrine action

Sexual dimorphism is observed in the number, morphology, gene expression, and function of astrocytes in various brain regions [11, 82]. Sex differences in astrocytes between males and females can be influenced by several factors, including sex hormones [83]. The results of the study have demonstrated that there is sexual dimorphism in the response to a high-fat diet in male and female mice. Hence, in males the level of pro-inflammatory cytokines is higher than in females [84]. Other examples of sex differences between males and females include the higher level of fatty acids in the brain and ketone bodies in the plasma of male mice fed a HFD [84–86]. Additionally, the prevalence of obesity in female rodents following a high-fat diet is lower than in males [87–89]. Therefore, it is suggested that there are sexually dimorphic properties in hypothalamic neurons and glial cells involved in the regulation of energy balance, and these differences are likely mediated through sex steroids, particularly estrogen [90–92].

Estrogen Action on astrocytes in the control of metabolism

Estrogen, an essential hormone for sexual reproduction, has metabolic activities and contributes to modulating sensitivity to some metabolic hormones [17, 68, 93]. The biological function of estrogen is mediated through three receptors: estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein coupled receptor (GPER) [94]. ERα is the primary functional mediator of estrogen effects on energy balance. It is expressed in POMC neurons within the ARC, ventromedial hypothalamus, and brainstem [95]. Estrogen is able to decrease food intake and increase energy expenditure through ERα. As a result, the anti-obesity effects of estrogen are mediated through ERα [17, 96]. Furthermore, estrogen has been shown to possess anti-inflammatory and neuroprotective properties, with ERα playing a critical role in mediating these effects [17]. A recent study has shown that ovariectomy (removal of ovaries) leads to a reduction in ERα expression and an increase in brain inflammation in mice fed a high-fat diet, while activation of ERα reverses these effects [17]. Ovariectomy in mice fed a HFD also leads to leptin resistance (decreased responsiveness to the appetite-suppressing effects of leptin) and increased body weight gain, while estrogen therapy restores leptin sensitivity and decreases body weight by increasing the expression of the anorexigenic neuropeptide Alpha-Melanocyte-Stimulating Hormone (α-MSH) and decreasing the expression of the orexigenic neuropeptides Neuropeptide Y (NPY) and Agouti-Related Protein (AgRP) [17, 93].

Astrocytes also express estrogen receptors, including ERα, ERβ, and GPER [91, 97]. Results of HFD in in vivo and palmitic acid in in vitro studies show that estrogen reduces inflammatory markers in astrocytes of female mice, and this action is probably mediated through ERα [84, 98]. Furthermore, estrogen decreases the expression of some inflammatory responses such as IL-6 and NF-κB in astrocytic cell culture [84, 99]. Moreover, estrogen protects over-nutrition female Wistar rats from hypothalamic gliosis and inflammation induced by circulating fatty acids [100]. Therefore, estrogen acts, at least in part, through astrocytes to exert its neuroprotective effects. As mentioned previously, estrogen reduces the increased hypothalamic inflammation induced by a high-fat diet and also improves central leptin sensitivity. Nevertheless, the exact mechanism of estrogen’s central effects and whether astrocytic estrogen receptors contribute to improving hypothalamic inflammation caused by a high-fat diet to restoring sensitivity to leptin has not been investigated precisely. Further studies are required to interrogate the action of estrogen on astrocytes and how it interacts with neuronal circuits to control energy homeostasis.

Conclusion and perspectives

The purpose of the review was to emphasize the role of astrocytes in regulating energy metabolism. It is crucial to understand the molecular mechanism involved in sensing and conveying metabolic signals in hypothalamic astrocytes because many metabolic disturbances, particularly those related to obesity such as insulin resistance, are linked to these pathways. Therefore, it is important to recognize the significance of astrocytes as a target in combating obesity and metabolic disorders.

The protective effects of estrogen against high-fat diet and resulting metabolic disorders in females have been extensively studied in hypothalamic neurons. Studies have demonstrated that estrogen not only affects neurons but also exerts its protective effects through astrocytes, which are the most abundant non-neuronal cells in the nervous system. Since the effects of estrogen on astrocytes and the mechanisms by which it alleviates metabolic disorders are still poorly understood, future studies should focus on surveying the role of different types of estrogen receptors (ERα, ERβ, and GPER30) through pharmacological interventions, as well as elucidating how selective ligands can act through any of the three ERs. This would be valuable in understanding the underlying mechanisms of action of estrogen.

Funding

This research did not receive any specific grant from funding agencies.

Declarations

Competing interest

The authors have no competing interests to declare that are relevant to the content of this article.