Hypothalamic AMP-Activated Protein Kinase as a Whole-Body Energy Sensor and Regulator

Article information

Endocrinol Metab. 2024;39(1):1-11

Publication date (electronic) : 2024 February 14

doi : https://doi.org/10.3803/EnM.2024.1922

Se Hee Min ¹^,^*

, Do Kyeong Song ²^,^*

, Chan Hee Lee ³^,^*

, Eun Roh ⁴^,^*

, Min-Seon Kim^,¹

¹Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

²Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea

³Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon, Korea

⁴Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Korea

Corresponding author: Min-Seon Kim. Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-3245, Fax: +82-2-3010-6962, E-mail: mskim@amc.seoul.kr

*These authors contributed equally to this work.

Received 2024 January 2; Revised 2024 January 5; Accepted 2024 January 9.

Abstract

5´-Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a cellular energy sensor, is an essential enzyme that helps cells maintain stable energy levels during metabolic stress. The hypothalamus is pivotal in regulating energy balance within the body. Certain neurons in the hypothalamus are sensitive to fluctuations in food availability and energy stores, triggering adaptive responses to preserve systemic energy equilibrium. AMPK, expressed in these hypothalamic neurons, is instrumental in these regulatory processes. Hypothalamic AMPK activity is modulated by key metabolic hormones. Anorexigenic hormones, including leptin, insulin, and glucagon-like peptide 1, suppress hypothalamic AMPK activity, whereas the hunger hormone ghrelin activates it. These hormonal influences on hypothalamic AMPK activity are central to their roles in controlling food consumption and energy expenditure. Additionally, hypothalamic AMPK activity responds to variations in glucose concentrations. It becomes active during hypoglycemia but is deactivated when glucose is introduced directly into the hypothalamus. These shifts in AMPK activity within hypothalamic neurons are critical for maintaining glucose balance. Considering the vital function of hypothalamic AMPK in the regulation of overall energy and glucose balance, developing chemical agents that target the hypothalamus to modulate AMPK activity presents a promising therapeutic approach for metabolic conditions such as obesity and type 2 diabetes mellitus.

Keywords: AMP-activated protein kinases; Hypothalamus; Energy metabolism; Glucose metabolism; Hormones

The Namgok Award is the highest scientific award of the Korean Endocrine Society, and is given to honor an individual who has made excellent contributions to progress in the field of endocrinology and metabolism. The Namgok Award is named after the pen name of Professor Hun Ki Min, who founded the Korean Endocrine Society in 1982. Professor Min-Seon Kim received the Namgok Award at the 11th Seoul International Congress of Endocrinology and Metabolism of the Korean Endocrine Society in October 2023.

INTRODUCTION

Our comprehensive understanding of the mechanisms underlying body weight homeostasis and energy metabolism has significantly evolved over the last three decades. The hypothalamus plays a central role in regulating energy homeostasis [1,2]. Specific neuronal populations within this brain region respond to changes in food availability, energy reserves, and nutritional needs, thereby initiating compensatory actions that maintain whole-body energy balance [3-7]. Disruptions in the homeostatic mechanisms of energy balance have been implicated in the pathogenesis of both obesity and cachexia [5].

5´-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase that serves as a critical regulator of cellular energy homeostasis [8,9]. AMPK monitors the cellular energy status and becomes activated in response to a decline in intracellular adenosine triphosphate (ATP) levels, which can be precipitated by metabolic stressors such as physical activity, hypoxia, or fasting [10]. Evidence suggests that AMPK modulates the whole-body energy balance, playing a crucial role in the regulation of feeding behavior and energy expenditure, primarily in the hypothalamus [11-14]. Hypothalamic AMPK also exerts a substantial influence on glucose homeostasis, which is another key aspect of homeostatic regulation by the hypothalamus [11,12].

This review aims to provide a concise overview of the function and regulators of hypothalamic AMPK in food intake, energy expenditure, and glucose homeostasis and to discuss the therapeutic potential of targeting AMPK pathways in the treatment of metabolic diseases.

AMPK: MECHANISM OF CELLULAR ENERGY SENSING

AMPK is a heterotrimeric complex composed of three distinct subunits: α, β, and γ. Each of these subunits plays a crucial role in the function and regulation of this enzyme. The catalytic α (α1, α2) subunit is responsible for the enzyme’s catalytic activity, while β (β1, β2) and γ (γ1, γ2, γ3) are regulatory subunits. The β subunit acts as a scaffold that holds the complex together, while the γ subunit primarily regulates AMPK activity.

AMPK regulation is multifaceted, involving allosteric activation, phosphorylation, and dephosphorylation processes [13]. The primary mechanism for AMPK activation is the phosphorylation of Thr172 on the α subunit, which can be allosterically induced by AMP (but not adenosine diphosphate [ADP]) binding to the γ subunit [8]. This phosphorylation is predominantly carried out by upstream kinases, such as liver kinase B1 (LKB1) and Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ) [14]. Moreover, both AMP and ADP can induce a conformational change that protects AMPK from dephosphorylation and enhances its activity [14].

Functioning as an energy sensor, AMPK is activated in response to decreases in intracellular ATP levels and to increases in the AMP:ATP ratio, which are often the result of metabolic stressors such as exercise, hypoxia, or nutrient deprivation [8-10]. AMPK activation can also occur in the absence of a detectable increase in the AMP:ATP ratio, as seen with hyperosmolar stress [15] and during metformin treatment [16]. Once activated, AMPK phosphorylates a wide array of substrates. This action inhibits ATP-consuming anabolic pathways, including fatty acid and protein synthesis, and activates ATP-generating catabolic pathways, such as fatty acid oxidation and glycolysis [13]. The activation of AMPK generates ATP and restores the AMP:ATP and ADP:ATP ratios, thereby maintaining energy homeostasis.

ROLE OF HYPOTHALAMIC AMPK IN REGULATING WHOLE-BODY ENERGY HOMEOSTASIS

Hypothalamic AMPK has been suggested to be a key sensor and integrator of nutritional and hormonal signals and a regulator of the whole-body energy balance (Fig. 1) [17,18]. AMPK is present in the central nervous system, with high expression levels in hypothalamic nuclei including the arcuate nucleus (ARC), dorsomedial hypothalamus, paraventricular nucleus (PVH), ventromedial nucleus (VMH), and lateral hypothalamic area (LHA). These regions are involved in controlling food intake and maintaining energy homeostasis [19].

Fig. 1.

The regulators and conditions that alter hypothalamic 5´-adenosine monophosphate-activated protein kinase (AMPK) activity and their associated physiological outcomes. (A) Conditions and regulators inducing hypothalamic AMPK activation. (B) Conditions and regulators inducing hypothalamic AMPK inactivation. GLP-1, glucagon-like peptide-1; SNS, sympathetic nervous system; BAT, brown adipose tissue.

Alterations in hypothalamic AMPK activity influence both food intake and energy metabolism. When constitutively active (CA)-AMPK is expressed via adenovirus in the medial hypothalamus, there is an increase in food consumption and body weight. In contrast, expression of dominant-negative (DN)-AMPK in the mediobasal hypothalamus leads to reduced food intake and body weight in normal mice [20]. Similarly, activating hypothalamic AMPK by injecting the activator 5-amino4-imidazole carboxamide riboside (AICAR) into the third ventricle or the PVH results in increased food intake and body weight [21]. Conversely, reducing AMPK activity in the hypothalamus through the administration of the chemical inhibitor compound C leads to a suppression of food intake [22].

Although the exact mechanism by which hypothalamic AMPK regulates energy homeostasis remains elusive, it is thought to mediate changes in the expression of key appetite-regulating neuropeptides in the hypothalamus, which vary according to the feeding state and the overall energy status of the body. When hypothalamic AMPK is inhibited by DN-AMPK, there is a suppression of the mRNA expression of the orexigenic neuropeptides Agouti-related peptide (AgRP) and neuropeptide Y (NPY) in the ARC during ad libitum feeding conditions. Conversely, the activation of hypothalamic AMPK by CA-AMPK expression enhances the fasting-induced increases in AgRP and NPY mRNA levels in the ARC, as well as melanin-concentrating hormone mRNA levels in the LHA [19]. Interestingly, the stimulation of AgRP and NPY mRNA expression by AMPK occurs, in part, through an autophagy-dependent mechanism [23].

AMPK appears to regulate energy homeostasis in a hypothalamic neuron-specific manner [24,25]. When AMPK was selectively deleted from neurons expressing either proopiomelanocortin (POMC) or AgRP, both of which are pivotal for energy homeostasis, opposing effects on energy balance were observed. The deletion of the AMPKα2 catalytic subunit in POMC neurons (POMC-α2KO mice) led to obesity, characterized by increased food consumption and decreased energy expenditure. Conversely, deleting AMPKα2 in AgRP neurons (AgRP-α2KO mice) resulted in a mild, age-dependent lean phenotype, with no significant changes in food intake or energy expenditure under ad libitum feeding conditions [26]. These results imply that AMPK activity in POMC neurons may protect against obesity by reducing appetite and increasing energy expenditure, acting as a preventative mechanism. Meanwhile, the role of AMPK in AgRP neurons appears to be associated with increased adiposity through mechanisms that remain to be elucidated.

Hypothalamic AMPK regulates energy homeostasis by modulating thermogenesis. It has been reported that several homeostatic signals target the VMH to suppress AMPK activity, which in turn promotes thermogenesis in brown adipose tissue (BAT) and the browning of white adipose tissue via the sympathetic nervous system (SNS) [20,21]. When estradiol (E2) was administered centrally, it triggered BAT thermogenesis by reducing AMPK activation in the VMH, followed by the activation of the SNS. In contrast, the genetic activation of AMPK in the VMH, using CA-AMPK adenoviruses, blocked the E2-induced enhancement of BAT thermogenesis and the associated weight loss [27]. Similarly, central administration of triiodothyronine (T3) in the VMH decreased adiposity and increased BAT thermogenesis through the SNS. However, overexpressing CA-AMPK in the VMH negated the effects of central T3 on body weight [28].

ROLE OF HYPOTHALAMIC AMPK IN REGULATING WHOLE-BODY GLUCOSE METABOLISM

Hypothalamic AMPK acts as a critical sensor and integrator of whole-body glucose homeostasis, with its activity being regulated by glucose levels [25]. Intracerebroventricular (ICV) glucose administration suppresses AMPK activity in hypothalamic regions, including the ARC, PVH, and LHA [22]. In contrast, insulin-induced hypoglycemia and the inhibition of intracellular glucose utilization through 2-deoxyglucose administration lead to the activation of hypothalamic AMPK [12,22]. This activation of AMPK in response to hypoglycemia is significant in the ARC, VMH, and PVH [12].

Several studies have suggested that hypothalamic AMPK is necessary for the hypothalamic regulation of hepatic glucose production. When conducting a pancreatic euglycemic clamp in rats, both molecular and pharmacological inhibition of hypothalamic AMPK activity led to a suppression of hepatic glucose production. This effect was mediated through the vagal motor complex pathways and the hepatic innervation of the vagus nerve [29]. Conversely, the activation of hypothalamic AMPK counteracted the glucose-lowering effects of infusing glucose or lactate directly into the hypothalamus [11].

In addition, hypothalamic AMPK may affect whole-body insulin action through the SNS. ICV infusion of an AMPK activator, AICAR, increased insulin-stimulated muscle glycogen synthesis and insulin sensitivity when a hyperinsulinemic clamp was placed in mice [30]. Furthermore, AMPK may play a role in regulating insulin secretion through the hypothalamus. In a knockout mouse model lacking the AMPKα2 catalytic subunit gene, glucose-induced insulin secretion was found to be impaired, attributed to alterations in the autonomic nervous system [31].

Conversely, hypothalamic AMPK also regulates the hormonal responses that counteract hypoglycemia [24]. The inhibition of hypothalamic AMPK activity with compound C diminishes these counter-regulatory responses, resulting in severe and prolonged hypoglycemia [11]. These findings indicate that hypothalamic AMPK is essential for recovery from hypoglycemia.

REGULATION OF HYPOTHALAMIC AMPK ACTIVITY BY METABOLIC HORMONES

AMPK activity in hypothalamic neurons is regulated by important metabolic hormones, wherein AMPK acts as a downstream signaling molecule mediating their effects in the hypothalamus.

Leptin

Leptin, the first adipokine discovered, mediates communication between the hypothalamus and adipose tissues, which is essential for regulating food intake and energy expenditure [32]. High levels of leptin receptor expression are found in many regions of the hypothalamus [33-35]. Mutations in either the leptin receptor gene or the ob gene, which encodes leptin, lead to severe obesity in both rodents and humans, primarily due to hyperphagia [36-38]. While leptin promotes the activation of AMPK in skeletal muscle, it conversely inhibits AMPK activity in the hypothalamus [39]. Notably, the traditional leptin signaling pathway involving Janus kinase 2-signal transducer and activator of transcription 3 is not implicated in the suppression of AMPK activity [19].

AMPK interacts with other signaling pathways, including phosphoinositide 3-kinase and the mammalian target of rapamycin complex 1, to regulate the effects of leptin in the hypothalamus [19,35,39]. Leptin stimulates POMC neurons, leading to increased production of β-endorphin and α-melanocyte-stimulating hormone by suppressing AMPK activity [36-38]. Furthermore, acetyl-CoA carboxylase (ACC), a well-established downstream target of AMPK, seems to play a role in AMPK’s influence on food intake [40]. ACC facilitates the transformation of acetyl-CoA into malonyl-CoA, while AMPK reduces ACC activity by phosphorylating it [40]. Thus, leptin-induced hypothalamic AMPK inhibition would be expected to increase malonyl-CoA levels by upregulating ACC activity [41]. Elevated malonyl-CoA levels result in increased cellular palmitoyl-CoA levels by inhibiting carnitine palmitoyl transferase-1 (CPT1) activity and subsequently suppressing mitochondrial fatty acid oxidation [41]. Increased malonyl-CoA and palmitoyl-CoA levels in hypothalamic neurons are known to suppress food intake [41]. Supporting this pathway’s role as downstream of leptin’s effects, leptin-induced inhibition of AMPK elevated malonyl-CoA levels in the ARC and palmitoyl-CoA in the PVH [39]. The pharmacological blockade of these anorexigenic fatty acids attenuated leptin’s appetite-suppressing effects.

Insulin

Insulin is secreted postprandially in response to various dietary cues, including glucose, fatty acids, and amino acids. It possesses lipogenic and glucose-lowering properties, and it also exerts anorexigenic effects by influencing brain activity. Animals deficient in insulin demonstrate hyperphagia [42,43]. Furthermore, mice with neuron-specific knockouts of the insulin receptor consume more food and are more susceptible to diet-induced obesity [44]. Conversely, ICV injections of insulin or its analogues produce the opposite effect [45-48].

Insulin exerts a broad inhibitory effect on AMPKα2 activity across various regions of the hypothalamus, including the PVH, ARC, and LHA [35]. This suppression of hypothalamic AMPK by insulin is responsible for its anorexigenic effect [49]. Conversely, insulin-induced hypoglycemia increases AMPKα2 activity in the hypothalamus, a critical component of the counter-regulatory hormone response to low blood sugar levels, as previously mentioned [16]. Furthermore, insulin deficiency caused by streptozotocin leads to hyperphagia through the activation of AMPK and elevated NPY expression in the rat hypothalamus [12]. In this diabetic model, either insulin treatment or the pharmacological or molecular inhibition of AMPK in the hypothalamus can reverse hyperphagia [12], indicating that the activation of hypothalamic AMPK may be a key factor in driving hyperphagia in diabetes. The suppressive effect of insulin on hypothalamic AMPK is diminished by cold exposure, which could explain why cold conditions reduce the effectiveness of insulin in inhibiting feeding [50].

Ghrelin

Ghrelin is the first gastrointestinal hormone known to promote appetite. This hormone is produced in the stomach and is secreted during fasting [51]. The orexigenic effect of ghrelin is mediated by hypothalamic AgRP/NPY-producing neurons [52]. Central or peripheral administration of ghrelin in rats increases AMPK activity in the ARC and the VMH through the growth hormone secretagogue receptor expressed in these brain regions [53-56]. Ghrelin’s orexigenic effect is eliminated when hypothalamic AMPK activation is inhibited [54,57-59].

The orexigenic effect of ghrelin seems be mediated by hypothalamic AMPK through multiple downstream targets. For example, ghrelin releases Ca²⁺ from the endoplasmic reticulum to activate NPY neurons via AMPK-dependent mechanisms [60-62]. Additionally, ghrelin stimulates NPY neuronal activity by activating AMPK in presynaptic neurons and by regulating synaptic plasticity in NPY neurons [36]. In another pathway, ghrelin activates NPY neurons and enhances food intake by promoting hypothalamic mitochondrial function through a mechanism dependent on uncoupling protein 2 (UCP2) [62]. Ghrelin was also found to increase UCP2 expression in hypothalamic neurons via the AMPK-ACC-CPT1-fatty acid oxidation pathway [62]. The orexigenic action of ghrelin is closely associated with fatty acid metabolism in hypothalamic VMH neurons [55]. Additionally, ghrelin downregulates fatty acid synthase in the VMH through an AMPK-dependent mechanism, which is a key factor in fasting-induced hyperphagia [55].

Glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L cells [63,64]. It is also a neuropeptide generated by preproglucagon neurons in nucleus tractus solitarius in the brainstem, which stimulates the hypothalamus to suppress appetite [63,64]. In fasted rats, the hypothalamic GLP-1 level decreased, while central GLP-1 injection inhibited food intake [65,66]. The anorectic effect of GLP-1 is achieved by its inhibitory action on hypothalamus AMPK activation [66,67]. Targeted injection of the GLP-1 receptor agonists exendin-4 or liraglutide into the VMH has been found to decrease food intake in mice and humans [68,69]. Pre-injection of AICAR in the VMH counteracted the anorexic effect of exendin-4 [69], confirming that GLP-1 induces anorexia by suppressing hypothalamic AMPK activity.

Adiponectin

Adiponectin, the most abundant adipokine, exerts anti-inflammatory and insulin-sensitizing effects [70,71]. People with obesity and diabetes have lower levels of circulating adiponectin than their counterparts [72,73]. Adiponectin inhibits glucose production in the liver and increases glucose uptake and fatty acid oxidation in the skeletal muscle [70,71]. In addition to its peripheral endocrine actions, adiponectin also influences food intake and energy balance through its effects on the hypothalamus. The enzyme AMPK is pivotal in mediating adiponectin’s central metabolic functions [70,71,74]. Intravenous infusion of full-length adiponectin activates AMPK in the hypothalamus, which in turn increases food consumption and reduces energy expenditure following a period of fasting [75]. The beneficial effects of adiponectin are abrogated when either DN-AMPK is overexpressed or adiponectin receptor 1 (AdipoR1) expression is silenced in the hypothalamus using adenovirus-mediated techniques or small inhibitory RNA, respectively. Additionally, the hypothalamic AdipoR1-AMPK signaling pathway is implicated in the modulation of food intake and energy expenditure by pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist [50].

THE THERAPEUTIC POTENTIAL OF AMPK REGULATORS FOR METABOLIC DISORDERS

Systemic AMPK stimulation is an effective approach for combating metabolic disorders, such as type 2 diabetes and obesity [76]. Activation of AMPK in adipose tissues enhances thermogenesis, fatty acid oxidation, mitochondrial function, and insulin sensitivity. This is achieved by suppressing the activity of ACC and 3-hydroxy-3-methylglutaryl coenzyme A reductase or by stimulating the phosphorylation of hormone-sensitive lipase and adipose triglyceride lipase [77,78]. In skeletal muscle, AMPK activation increases glucose uptake by promoting the translocation of glucose transporter 4 to the plasma membrane [79].

Due to its metabolic benefits, AMPK has emerged as one of the most promising therapeutic targets for diabetes and obesity. Various drugs have been shown to enhance glucose and lipid metabolism by directly or indirectly activating AMPK signaling. Indirect activators, including biguanides (metformin), thiazolidinediones (TZDs), and α-lipoic acid (ALA), induce AMPK activation by promoting the accumulation of AMP or calcium. Direct activators, such as AICAR, thienopyridones (A-769662), and salicylate, stimulate AMPK by binding to specific subunits of the AMPK.

Indirect AMPK activators, particularly biguanides such as metformin and phenformin, elevate cellular AMP:ATP and ADP:ATP ratios. This elevation is due to the inhibition of ATP synthesis by targeting mitochondrial electron transport chain (ETC) complex 1 [80]. As a result of decreased glycolysis and gluconeogenesis in the liver, biguanide therapy has become a mainstay in the management of type 2 diabetes [81,82]. Unlike its impact on AMPK activity in the peripheral organs, metformin inhibits AMPK activity in cultured hypothalamic neurons, thereby decreasing NPY expression and suppressing food intake [83]. Consistently, ICV administration of metformin counteracts ghrelin-induced hypothalamic AMPK activation and hyperphagia [84].

TZDs, such as pioglitazone, rosiglitazone, and troglitazone, improve insulin sensitivity by activating PPARγ and AMPK in the skeletal muscle, liver, and adipose tissues [85,86]. TZDs activate AMPK by inhibiting the ETC complex 1, thereby increasing AMP, like biguanides [87]. Pioglitazone treatment improves insulin sensitivity and glucose tolerance by indirectly activating hypothalamic AMPK via adiponectin-AdipoR1-dependent mechanisms [50].

ALA exerts beneficial effects on metabolic syndrome, lipotoxicity, and endothelial dysfunction through CaMKKβ-mediated intracellular calcium signaling, which is responsible for AMPK activation [88-91]. Unlike peripheral tissues, however, the central administration of ALA reduced appetite and yielded anti-obesity effects by suppressing hypothalamic AMPK activity [22]. This indicates that ALA exerts tissue-specific opposing effects on AMPK activation [22].

Direct AMPK activators are categorized into two types: AMP mimetics and non-nucleoside activators that bind to AMPK indirectly. Unlike indirect activators, direct AMPK activators do not alter the AMP:ATP ratio or mitochondrial function, leading to the assumption that they may have fewer side effects. AICAR functions as an AMP analog; upon entering cells, it is phosphorylated by adenosine kinase to form 5-aminoimidazole-4-carboxamide ribotide (ZMP). ZMP, bearing a structural resemblance to AMP, binds to the same site on the AMPK subunit as AMP does [92]. Allosteric AMPK changes induced by ZMP promote its phosphorylation via upstream kinases such as LKB1 or CaMKKβ [93]. However, some AICAR effects are AMPK-independent [94].

AICAR treatment has been shown to improve metabolic abnormality in mice fed a high-fat diet [95]. In human subjects, intravenous administration of AICAR reduces hepatic glucose production and inhibits lipolysis throughout the body in patients with type 2 diabetes [96]. However, although AICAR has been used clinically in cases of coronary artery disease, the therapeutic benefits have been minimal or almost negligible [97,98]. Moreover, high doses of AICAR (210 mg/kg) have been associated with renal toxicity in some patients with myelodysplastic syndrome, which suggests that caution is warranted when considering AICAR for clinical use [99].

A-769662 has been developed as a new AMPK activator that decreases blood glucose and triglyceride levels, as well as hepatic triglyceride content [100,101]. This compound activates AMPK by binding to and phosphorylating Thr-172 in the AMPK α subunit, a key step for AMP-dependent AMPK activation [100]. Additionally, A-769662 phosphorylates Ser-108 in the AMPK α1 subunit, promoting fatty acid oxidation through phosphorylation-induced ACC inhibition [102].

Despite the numerous beneficial effects observed in mouse models, clinical evidence supporting the use of AMPK activators for metabolic diseases remains limited. Furthermore, caution is warranted when utilizing AMPK activators because of the different metabolic outcomes observed in peripheral tissues and the brain.

CONCLUSIONS

Evidence indicates that the regulation of AMPK activity in hypothalamic neurons is essential for maintaining whole-body energy balance and glucose homeostasis. AMPK acts as a key signaling molecule for various hormones and nutrients. Changes in AMPK activity within these neurons can significantly impact cellular signaling pathways, mitochondrial functions, autophagy, neuroelectrical properties, and transcriptional activity. These alterations are crucial for the neuronal functions that are involved in the central regulation of metabolic homeostasis.

Although this review focuses on hypothalamic neuronal AMPK, it is important to note that AMPK in hypothalamic non-neuronal cells, such as microglia and astrocytes, may also play a role in maintaining metabolic homeostasis and preventing metabolic diseases. For instance, activation of AMPK has been shown to induce anti-inflammatory responses in microglia [103], which could help alleviate hypothalamic inflammation and obesity caused by a high-fat diet. Additionally, the anti-hypertensive drug telmisartan has been found to prevent lipopolysaccharide-induced microglial activation through CaMKKβ-induced AMPK activation [104]. In astrocytes, AMPK activation protects against hypoxia-induced cell death [105] and promotes glycolysis and lactate production via the lactate shuttle [106]. Therefore, AMPK inhibition in astrocytes causes neuronal loss [106]. To date, the role of glial AMPK in energy metabolism has not been thoroughly investigated, and the significance of AMPK in hypothalamic glial cells warrants further research.

Given that AMPK is a key integrator and regulator of energy homeostasis, there have been ongoing trials to develop AMPK activators with beneficial metabolic effects. However, despite the identification and preclinical testing of several direct AMPK activators, only a handful have advanced to clinical trials. The results of these trials have been underwhelming, and safety concerns have emerged, especially at higher doses of AMPK activators. AMPK activation promotes positive metabolic outcomes by targeting peripheral metabolic organs. However, these benefits may be counterbalanced by AMPK activation in the brain, which could lead to increased food intake and decreased energy expenditure. Consequently, the creation of tissue-specific delivery systems for AMPK regulators may be crucial to improve metabolic outcomes and mitigate potential side effects.

Notes

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Acknowledgements

This study was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT of Korea (2020R1A2C3004843, 2022M3E5E8017213 to Min-Seon Kim, 2022R1C1C1012590 to Se Hee Min, 2022 R1C1C1004187 to Chan Hee Lee; 2022R1F1A1071743 to Do Kyeong Song).

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