Neuropsychological and metabolic interconnectivity in obesity, anorexia and bulimia nervosa – an integrative literature review

Abstract

A dysfunctional bi-directional signalling of plural neural networks expresses distinct metabolic disruption with mental health consequences in obesity, anorexia nervosa and bulimia nervosa. Maladaptive brain-gut connectivities lead to multifactorial contributing factors raising the interest of researchers in an effort to address their neurobiological, psychological and metabolic factors to improved mental health outcomes. The first aim of this review was to collate clinical evidence on brainstem-hypothalamus pathways in obesity, anorexia nervosa and bulimia nervosa. Further, it sought to describe the chief brain-based interactions within both the brain-gut and brain-gut-adipose axis in these conditions. Another aim was to explore the interactions of prominent peptides within the brain-gut and brain-gut-adipose axes. The final aim was to integrate the knowledge of maladaptive neural, peptide and hormonal signalling interactions with the mental faculty. According to integrative review guidelines, the multileveled information was grouped into three superordinate themes: the brain neurofeedback, the stomach neurofeedback and the sympathoadrenal neurofeedback, with seven subordinate themes: brain stem, lateral nucleus of the hypothalamus, arcuate nucleus of the hypothalamus, mechanism of appetite regulation, short-term satiety and long-term satiety signalling as well as the mechanisms of glucoprivation and lipoprivation, presented in Table 1. Their interconnectivites are synthesised in seven Figures, presented at each subtheme section. This paper augmented our understanding of brain maladaptive interactions with gut peptides and hormones among people with obesity and eating disorders and may serve a roadmap to neurobiological and metabolic influences on physical and mental health. Limitations identify qualitative areas of research towards evidence-informed psychiatric and health counselling support.

Introduction

The neural connectivity between the brain and body weight through food intake, energy expenditure, body fat stores, and endogenous glucose production has been of interest to the health professionals for a long time. Obesity, anorexia nervosa and bulimia nervosa are complex conditions with low rates of detection and low treatment uptake, requiring an understanding of their neurometabolic and mental health factors to enable early recognition of patterns and lead to early interventions, essential in prevention of further psychopathology and a reduction of relapse (Austin et al. 2021; Fatt et al. 2020; Koreshe et al. 2023).

Epidemiological studies suggest that obesity factors are on increase, with comorbidities and increased mortality sequelae (Hruby & Hu 2015). While genetic predisposition to abnormal metabolism is one well-known contributing factor, stress-induced, uncontrolled food intake is an emerging major contributor to weight gain with some individuals inherently more susceptible to the negative effects of stress than others (Diz Chaves 2011; Tomiyama 2019; van der Valk et al. 2018). Because the brain-gut neural axis is involved in the disruption of goal-directed behaviors (Yamada et al. 2018), the growing understanding of the brain-based influences on eating behaviours indicates a derangement across various layers of brain-gut axis and a coherent presentation of these mechanisms could contribute to more precise choices to treatment. A correct understanding and application to this complex condition of abnormal emotional functioning, and depressive symptomatology is important, because research is clear that obese people avoid seeking treatment largely due to wide-spread stigmatisation and associated shame (Chakravorty 2021; Dallman, 2010).

In Australia, there has been a six-fold increase in prevalence of eating disorders since the late 1990 s (National Eating Disorders Collaboration 2023). Eating disorders adversely affect a person’s physical and mental health with neuroscience research indicating altered brain structure and function as a common features of both anorexia nervosa and bulimia nervosa (McAdams and Smith 2015). Anorexia nervosa is characterised by a low body mass index (BMI), starvation due to fear of gaining weight, denial of current low weight and by serious negative impact on mental health (American Psychiatric Association [APA] 2013), with amenorrhea occurring in the majority of female patients (Mustelin et al. 2016). Despite the evidence of neurophysiological malfunctions, anorexia -afflicted individuals do not feel any change in themselves and do not appear distressed, further lacking acknowledgement of their condition during consults and refusing treatment for underweight (Casper 2022). Physiologically, bulimia nervosa’s characteristic symptoms include large amounts of food intake (binge-eating behaviour) after prolonged fasting, following episodes of self-induced vomiting (purge behaviour) (Albracht-Schulte et al. 2023) or excessive use of laxatives (APA 2013). However, bulimia nervosa patients eat normally with friends and family and only binge-eat when alone with more severe cases, altering their daily routines to make time for the binge and purge outlets (Rushing et al. 2003).

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) suggests medical treatment interventions in late discovery or advanced cases of eating disorders (APA, 2013). Theoretically, serotonin fluctuations are known to disturb appetite, simultaneously leading to anxious and obsessive behaviours, both chiefly based on lack of impulse control (Cloninger 1987). Brain imaging research in both these conditions has repeatedly implicated activation of the brain structures related to meal-sizes, taste-reward and salience-processing regions (Berthoud et al. 2006; Donnely et al. 2018; Frank et al. 2016; South and Ritter 1983). However, starvation is known to increase stress by activating the HPA axis (Schmalbach et al. 2020) and the symptoms of anorexia nervosa are based on increased HPA axis functions, displaying elevated hunger-signalling neuropeptides (Comeras et al. 2019; Pannicke et al. 2021), simultaneously demonstrating fear and avoidance behaviours (Steinglass et al. 2011). The neuroscientific view of such outcomes is based on feedback from the brain, stomach and sympathoadrenal system hunger-satiety malfunctional pathways, affecting adequate production of brain-gut-adipose axis hormones and peptides, resulting in pathogenesis of eating disorders (Smitka et al. 2013).

Methodology

Methods and data evaluation

A narrative integrative literature review structure is based on five stages, namely problem identification, literature search, data evaluation, data analysis and presentation of findings, fundamental to the rigor of the integrative studies (Ferrari 2015; Sukhera 2022; Whittemore and Knafl 2005). The main search was conducted with a primary focus on clinical studies, systematic reviews, meta-analyses and other integrative reviews, seeking to meet the four aims of this study such as gathering clinical evidence to inform all the to-date neural, metabolic and mental health factors, known to be prevalent across studies on both obesity and eating disorders. While seeking to present brain-based mechanisms for food intake, the peptide and hormonal interactions within the brain-gut and brain-gut-adipose axes, the review further at creating a platform for evidence-informed, person-centered treatment. Such platform was considered to best suit the focus on pragmatic understanding and the empirical application of outcomes (Jahan et al. 2016). This provided a platform for the next aim which was achieving thoroughness in an effort to create an overarching holistic perspective (Hopia et al. 2016), recommended in both psychiatric and health counselling work. As the bi-directional effects of the neurometabolic as well as mental health changes involve a complex understanding of both the client and the formation of clinical approach, the final aim of this work centred only on the prominent tenets for practicality and feasibility, particularly for the novice psychiatric and counselling practitioners. As such, this narrative integration does not claim to be exhaustive however, focus remained on selected medical and biological literature that supported clear statements aiming to make way for qualitative inquiries in the field (Chigbu 2019).

A narrative integrative literature review accommodates for insights into the current progress of a given field and typically, does not adhere to inclusion and exclusion criteria (Sukhera 2022). For the purpose of practicality, this study kept clear boundaries between thinking and interpretation (Greenhalgh et al. 2018) which however, were specific enough to allow for a subjective direction during data evaluation (Sukhera 2022) such as asking the question: “Could the psychiatric or health counselling professional use the outcomes of this work in their practice?” Adhering to this structure, another aim of this study was to capitalise on critical thinking and interpretation of evidence-informed rather than evidence-based work (Nevo and Slonim-Nevo 2011). This factor alone supported the rationale behind the structure of this review as evidence-informed health outcomes are conducive to the novice clinicians, critical thinking in their decision-making and referral processes.

Literature search

This literature review began in March 2022 and was completed in October 2025, using the Boolean phrasing with the key words: (eating disorder OR obesity OR anorexia OR bulimia) AND (neurobiology) AND (brain OR “brain metabolism” OR “brain area’ OR gastro* OR “brain gut” OR “brain-gut-adipose”) AND (hunger OR “hunger mechanism” OR satiety) AND (hormon* OR neuro* OR peptide). The key search terms were applied across PubMed and Google Scholar and included journal articles published in English between 1990 and 2025. The complex information was grouped into three superordinate themes and seven subthemes, presented in Table 1.

Table 1.

Themes to neurometabolic factors in obesity, anorexia nervosa and bulimia nervosa

Superordinate Themes	Subthemes
1. Brain neurofeedback	1.1. The brain stem 1.1.1. Dorsal vagal complex 1.1.1.1. Nucleus of solitary tract 1.1.1.2. Area postrema 1.1.1.3. Vagal dorsal motor nucleus (see Figure 1). 1.2. The hypothalamus 1.2.1. Lateral nucleus of hypothalamus 1.2.1.1. α-MSH, MCH, AgP and PYY signals in starting a meal (see Figure 2). 1.2.2. Arcuate nucleus of hypothalamus 1.2.2.1. NPY, POMC, CART and MCH signals in regulation and completion of a meal (see Figure 3).
2. Stomach neurofeedback	2.1. Starting of a meal: Ghrelin, NPY, CART and AgP signals in appetite regulation (see Figure 4). 2.2. Completion of a meal: Cholecystokinin and PYY signals in short-term satiety from stomach, duodenum and liver (see Figure 5). 2.3. Fasting: Leptin signalling in long-term satiety from adipose tissue (see Figure 6).
3. Sympathoadrenal system	3.1. Chronic changes in glucose levels and fatty acid oxidation: the mechanisms of glucoprivation and lipoprivation (see Figure 7).

Box 1: Table 1

Neurometabolic connectivities in in obesity, anorexia and bulimia nervosa

Brain neurofeedback

The role of the brainstem

Brain stem contains neurons that detect hunger and satiety signals and produce behaviours of acceptance or rejection of food. Connections from brain stem to forebrain directly influence metabolic rate and impulse for or rejection of, food intake (Miller 2019). Nucleus of solitary tract, area postrema and vagal dorsal motor nucleus are the three chief parts of brain stem that connect peripheral nervous system with hypothalamus (Da Silva and Bloom 2012) and they are referred to as dorsal vagal complex (Cheng et al., 2022; Mirza and Das 2019).

Nucleus of solitary tract

Nucleus of solitary tract receives taste input from the cranial nerves and receives afferent signals from various organs via vagus connections (Mirza and Das, 2019). It was found to exhibit particular affinity to glucose modification by demonstrating firing rates corresponding to varied glucose intake levels from stomach, duodenum, and liver (Roberts et al. 2017). Because nucleus of solitary tract receives afferent impulses not only from vagus nerve but from the spinal cord as well, it has a capacity to be activated by a number of psychogenic stimuli (Holt 2022). As a result, it modulates the autonomic nervous system output towards a motivated behaviour (Maniscalco and Rinaman 2018). Motivated behaviour is an important point in obesity and eating disorders, because of its explicit focus on self-imposed critical attitudes to image accompanied with low self-esteem (Casper 2022), as seen in Fig.1

Fig. 1.

Brain neurofeedback via brainstem dorsal vagal complex: Nucleus of solitary tract, area postrema and vagal dorsal motor nucleus. ANS: autonomic nervous system; PNS: peripheral nervous system; SNS: sympathetic nervous system

Area postrema

Area postrema is adjacent to the nucleus of solitary tract and plays a crucial part in hunger by facilitating neuronal connections between the gut hormones, brainstem and forebrain circuitry (Ahima and Anthwi 2008). Its neuronal communication is largely facilitated by the absence of a full blood–brain barrier which increases molecular permeability (Da Silva and Bloom 2012). The fenestrated capillaries of hypothalamic median eminence allow hormonal and nutrient access to both the brainstem and hypothalamus, contributing to energy homeostasis (Miller 2019; Peruzzo et al. 2000). Area postrema plays a prominent role in controlling nausea and vomiting, chiefly because of its dense population with glucagon-like protein receptor-1 from the gut, processing sensory information and invoking intestinal discomfort (Kawatani et al. 2018; Trapp and Brierley 2022). Glucagon-like protein receptor-1 is of emerging research interest due to its large neural population in the nucleus of solitary tract, with current studies linking its aberrant signalling in that area, to low impulse control, resulting to pathways of binge eating conditions such as obesity and bulimia nervosa (Alhadeff et al. 2017), as shown in Fig. 1.

Vagal dorsal motor nucleus

The vagal dorsal motor nucleus regulates ingestion and glucose metabolism (Holt 2022). Its activity is mainly parasympathetic and as such, it stimulates the function of the organs of the abdominal cavity (Zsombok et al. 2014). Vagus nerve receptors densely populate gastrointestinal area and link the peripheral nervous system with the central nervous system (Browning et al., 2017; Greene, 2014). Since vagal dorsal motor nucleus is downregulated via overactive sympathetic activity (Breit et al. 2018), it reduces the adequate function of leptin receptors. Such disrupted exchange downregulates the gut-brain axis signalling and impairs leptin transportation across the blood–brain barrier, causing hypothalamic inflammation along with neuronal autophagic activity (Meng and Cai, 2011; Myers et al., 2012). Such maladaptive signalling results in overconsumption of highly palatable food and excessive drinking, accompanied by a consistent low body weight (South and Ritter 1983) as well as an increased duration of feeding time (de Silva and Bloom 2012), as shown in Fig 1.

Box 2: Fig. 1

The role of the hypothalamus

The hypothalamus moderates homeostasis by connecting central nervous system (CNS) to the enteroendocrine and sympathoadrenal systems, and modulates heart rate, appetite, thirst, temperature, and the release of gut peptides ghrelin and leptin as well as the hormone insulin (Thau et al. 2022). Two hypothalamic areas play role in hunger and satiety: the lateral nucleus of hypothalamus, connected to acceleration of hunger and the arcuate nucleus of hypothalamus related to both appetite stimulation and inhibition (Roger et al. 2022).

Lateral nucleus of the hypothalamus: α-MSH, MCH, AgP and PYY signals in starting a meal

The circuitry of the lateral nucleus of the hypothalamus chiefly consists of orexin and melanin-concentrating hormone (MCH) neural populations (Dilsiz et al. 2020). Orexins are of neuromodulating activities (Nixon et al. 2012) and are regulated by neurotransmitter systems and environmental stimuli, both related to reward-seeking behaviours, including food intake (Mohammadkhani et al. 2024). MCH is a neurological complex that maintains energy intake and expenditure to promote energetic balance after caloric consumption (Lord et al. 2021). Together with orexin, MCH maintains a pivoting role in engagement and regulation of food intake (Hahn 2010). As shown in Fig. 2, the processes of food intake and appetite suppression are bi-directional because the peripheral peptides and hormones influence sympathetic nervous system (SNS) that in turn, activates the metabolic phases (Austin and Marks 2009). For example, as both sensory and motor activator of the brain-gut neural axis, the bi-directional signalling of the vagus nerve plays a role in moderation of energy intake and expenditure (Yahagi 2017). Further, as orexigenic pathways play a vital role in energy balance, their interaction with the gut peptide ghrelin is focused on moderation of energy expenditure (Ferno et al. 2015). Because ghrelin signalling occurs simultaneously with the neuropeptide signals for lowering fat metabolism, the ghrelin effects, transmitted via vagal nerve, are to trigger thoughts of food.

Fig. 2.

Lateral nuclei of hypothalamus: α-MSH, MCH, AgP and PYY signals in starting a meal

α-MSH: alpha-melanocyte-stimulating hormone; AgP: agouti-related protein; CART: cocaine- and amphetamine-regulated transcript; MCH: melanin-concentrating hormone; PYY: peptide tyrosine tyrosine; SNS: sympathetic nervous system

Hypersecretion of orexins translates into two systems affect: disturbances in sleep–wake cycles (Hara et al. 2005; Kotz et al. 2012), and deficiencies in energy balance (Dahmen et al. 2008), (see Fig. 2). This could be due to the conflictual signaling between two dysfunctional pathways - one of an acute and one of a chronic depletion of orexin signalling. For example, higher levels of serum orexin interfere with spontaneous physical activity and the non-exercise thermogenesis, contributing to the development of oxidative stress, common in ischaemic conditions which are considered the underlying mechanism to obesity resistance transcription factors (Butterick et al. 2013). Increased concentrations of MCH lead to hyperphagic behaviours as the acute phase of MCH neuron firing increases food intake (Noble et al. 2019) while MCH chronic signalling leads to expansions in body weight, overtime (Mul et al. 2010). (see Fig. 2).

MCH participates in stress responses as well as in mood modulation (Al-Massadi et al. 2021) and is involved in reduction of appetite and increased energy expenditure via its connectivity with the melanocortin receptor 4 (Tao 2010). As MCH has simultaneous connectivity with the dopamine receptor 2 (Concetti et al. 2023), it acts as a specific dopamine depressant (Conductier et al. 2011). Given these dual signalling, MCH neuronal activation is responsible for feelings of rewards from food and for the reinforcement of ongoing food intake (Dilsiz et al. 2020) with its aberrant signalling having selective effects on the mesolimbic dopamine pathways (Pissios et al. 2008). Since both melanocortin receptor 4 and dopamine receptor 2 interact to respond to food rewards (Yoon and Baik 2015) and both densely populate the mesolimbic dopamine pathway, their abnormal connectivity reinforces compulsive behaviours, generating motivation for food reward via binge eating accompanied with choices of highly palatable foods (di Bonaventura et al. 2020). Due to MCH prominent bi-directional signalling in obesity and eating disorders, low thermogenesis, oxidative stress and ischaemic conditions suggest possible connectivity to somatic depressive symptomatology on account of pro-inflammatory cytokine signalling from the adipose tissue, increasing production of reactive oxygen species (Marseglia et al. 2014; Turner 2024). Figure 2 shows how in such connectivity, the neuronal circuits in reward-based feeding increase motivation for palatable foods intake. The resultant pleasure from this process leads to surrendering to the impulse for food intake thereby prioritising sleep deprivation in favour of eating (Soltanieh et al. 2021).

Box 3: Fig. 2

Arcuate nucleus of the hypothalamus: NPY, POMC, CART and MCH signals in regulation and completion of a meal

The arcuate nucleus of hypothalamus has strategic systems that regulate appetite by expressing several neuronal groups. Neuropeptide Y (NPY) and agouti-related proteins (AgP) act as neuromodulators (Hirsch and Zukowska 2012) as well as behavioural modulators (Ferno et al. 2015; Tanaka et al. 2021) as shown in Fig. 3. NPY is a major hunger activator, linked to the brain nutrient status (Comeras et al. 2019). In normal conditions, the role of AgP is to detect nutrient requirements, overcome food-suppressive signalling, decrease activity of anorexigenic neurons and initiate food-seeking behaviour (Essner et al. 2017). AgP is a neuropeptide that holds a dual role: firstly, it interacts with NPY to increase eating and decrease body metabolic rate and secondly, it acts on melanocortin receptors 4 to maintain appetite and thermogenesis by lowering energy expenditure (Ilnytska and Argyropoulos 2008). NPY and AgP both play a pivotal role in energy balance and maintenance of body weight (Jackson et al. 2006; Vohra et al. 2022) (see Fig. 3).

Fig. 3 .

Arcuate nucleus of hypothalamus: NPY: neuropeptide Y; CART: cocaine- and amphetamine-regulated transcript; POMC – pro-opiomelanocortin; MCH: melanin-concentrating hormone; BMI – body mass index

The neuropeptides pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) inhibit feeding (Murphy and Bloom 2006; Neudorfer et al. 2020). CART exhibits appetite suppression effect becasue its receptors are chiefly located in arcuate nucleus of hypothalamus, where its terminal connections send and receive satiety responses (Thim et al. 1998). CART holds a neuronal affinity to central and peripheral glucose-sensing sites, and fires for selective food intake to an increased energy expenditure (Lau and Herzog 2014). The CART network chiefly involves the melanotropin (α-melanocyte-stimulating hormone), which is an anorexigenic (appetite-suppressing) complex (Tian et al. 2004). This hormone is related to adrenocortical hormonal secretions and in particular, to the production of the glucocorticoid hormone cortisol (Anderson et al. 2016). CART inhibits food intake and modulates both insulin secretion and lipid metabolism (Morgan and Cone 2006). As AgP, NPY and CART are sensitive to cortisol (Schwartz et al. 2017), they exchange signals across the brain-gut neural axis, influencing the brainstem and vagus nerve (Grill and Hayes 2012), thus affecting cognitive complexes such as values of food, food preferences as well as invoking food-related memories (Kanoski et al. 2011). Studies suggest that anorexia nervosa exhibits a continuously elevated levels of NPY, indicating a permanent status of a search for food as well as ability to consume large amounts of it (Södersten et al. 2008; Tyszkiewicz-Nwafor et al. 2021). This mechanism keeps noradrenergic signalling from the brain stem to the arcuate nucleus of hypothalamus at a constant operation (Nagatani et al. 1996), given that CART is well-known contributor linked to anorexia nervosa hyperactivity factor (Jean et al. 2012). POMC has recently been confirmed to contribute to stress-induced hypophagia resulting in overall anhedonia (Qu et al. 2020). Because CART and POMC signals involve both the motor and sensory neuronal activities, the body stress levels are kept permanently high (Lach et al. 2018). As ghrelin plasma levels have been positively associated with physical exercise, hyperactivity is likely to be a strong predictor of elevated ghrelin levels (Schalla and Stengel 2018). The brain-gut neural axis connectivity translates this process in mental symptomatology such as fear-based emotional vulnerabilities leading to self-inflicted food restrictions and resulting in low body mass index (Strober 2004). Hyperactivity and depressive moods resulting from voluntary food suppressions increase the risks of stress-exacerbated neural, physiological and psychopathologies in eating disorders as shown in Fig. 3.

Box 4: Fig. 3

Stomach neurofeedback

Starting of a meal: Ghrelin, NPY, CART and AgP signals in appetite regulation

Two major signals are of physiological significance in controlling food intake: the first is whether the stomach is empty, determining return of hunger and the second is how much food has been already eaten (Tack et al. 2021). When the stomach is empty, it releases peptide ghrelin which is an orexigenic hormone and a short-term hunger stimulus peptide that is physiologically related to production of growth hormone (Wang et al. 2008). Blood plasma ghrelin increases before meal intake times and it is generally activated with food entrance in the duodenum along with rise of the acidic gastric secretion (Diz Chavez 2011). Ghrelin is predominantly suppressed via glucose-ghrelin axis neurotransmission during short-term metabolic phase when the amount of food consumed has been determined sufficient for the body’s needs (Mani et al. 2019). Some of the glucose is utilised and some of it is stored in the liver in form of short-term energy reservoir, until the next food intake (Chun-Xia and Tschop 2012) (see Fig. 4).

Fig. 4 .

Starting of meal: Ghrelin, NPY, CART and AgP signals in appetite regulations AgP: agouti-related protein; CART: cocaine- and amphetamine-regulated transcript; NPY neuropeptide Y

In obesity and eating disorders, brain-gut neurocircuitry chiefly involves dopamine cells of ventral tegmental area and their projection to nucleus accumbens, both strongly activating food-rewarding behaviours (di Bonaventura et al. 2020), simultaneously increasing ghrelin release for hunger thusenhancing motivation for food (Smitka et al. 2013). As short-term feeding phase is observed to enhance the production of cortisol and insulin, it simultaneously reduces aberrant brain activity related to stress-responses (Kumar et al. 2022; Tyszkiewicz-Nwafor et al. 2021). This behavioural mechanism is of a particular interest in obesity research, as ghrelin activation in dopamine mesolimbic pathway directly stimulates motivation and food reward circuits and results in hyperphagic behaviour with a contribution to adipose tissue growth (Hanssen et al. 2022). Hyperphagic behaviours further increase the concentration of the glucose-dependent cortisol in the blood, that may result in uncontrollable, stress-based, obesity-enhancing behaviours (Dallman 2010). Simultaneously, raise of blood serum glucocorticoids stimulates corticotropin-releasing hormone in the amygdala and other limbic sites, impacting the monoaminergic neurons in the brainstem to initiate motivated behaviours (Dallman 2010; Ulrich-Lai and Herman 2009). Further, hunger is primarily perceived by AgP in the arcuate nucleus of hypothalamus, as ghrelin receptors on AgP neurons increase plasma concentration of ghrelin (Méquinion et al. 2013). This mechanism activates brain-gut pathway as both peptides and neurotransmitters increase eating (Diz-Chavez 2011)(see Fig. 4).

AgP, NPY and CART are sensitive to ghrelin release (Morrison et al. 2005). As AgP is known to facilitate a range of behaviours such as motivation, locomotion, anxiety and overall negative reinforcement, people with anorexia nervosa show increased activity across ghrelin signalling pathways, resulting in thoughts of food (Jerlhag et al. 2006). However, the prolonged food restriction symptom of anorexia nervosa leads to a possible long-term ghrelin insensitivity (Schalla and Stengel 2018), resulting in a dysfunctional signalling with metabolic consequences such as a negative energy balance on the brain-gut axis (Grill and Hayes 2012) (see Fig. 4). This neurobiological observation was linked to mental health deviations such as hyperactivity and addiction to self-starvation (Méquinion et al. 2013).

Box 5: Fig. 4

Completion of a meal: Cholecystokinin and PYY signals in short-term satiety from stomach, duodenum and liver

Two types of satiety signalling stop a meal: the first is short-term satiety signal, involving the brain, stomach, duodenum and liver and the second is long-term satiety signal, involving the adipose tissue (Barakat et al. 2024). During short-term satiety, insulin secretion is increased, allowing the body to absorb nutrients other than glucose. Certain amount of insulin is required to travel through blood–brain barrier in order to trigger action in the insulin receptors. Located in the anterior hypothalamic region, their neuronal population detects the rising levels of insulin in the body, and releases signal, inhibiting hunger (Blasquez et al. 2014). During food ingestion, the stomach nutrient receptors to satiety detect the levels of food taken, and signal termination of intake when the body needs have been met. Once the food is mixed with bile and pancreatic enzymes, cholecystokinin is released. Metabolically, cholecystokinin is known as hormone that breaks down the fatty acids by triggering simultaneous pylorus constriction and gastric contraction inhibition (Raybould 2007). Since cholecystokinin has neuronal receptors that inhibit hunger by signalling meal satiety, its secretion increases gallbladder activity, simultaneously preventing duodenum from giving more food, thus terminating eating behaviours (Okonkwo et al. 2020). The action of cholecystokinin across the brain -gut axis remains primarily dependent on the vagus nerve, assuming to lead to decreased duration of food intake, smaller sizes and functional cues to induction of satiety (Peters et al. 2006). Cholecystokinin interactions are shown in Fig. 5.

Fig. 5 .

Completion of a meal: Cholecystokinin and PYY signals in short-term satiety. GLP-1: glucagon-like peptide 1; PYY: peptide tyrosine tyrosine

Various clinical research during 90’s indicated that cholecystokinin is elevated during eating disorders (Geracioti et al 1992; Fujimoto et al. 1997; Phillipp et al. 1991). For example, metabolically high levels of cholesystokinin were linked to increased levels of cholesterol and physiology-based abnormalities (Powell-Wiley et al. 2021). While on a neural level, the vagus nerve afferent connectivity signals low satiation levels and continued intrinsic enforcement for high saturated and trans-fat foods intake to energetic balance (de Lartigue et al. 2011), with both factors leading to obesity. In the gastrointestinal tract, cholecystokinin acts as a major peptide and its elevated levels have been implicated in a number of gastrointestinal pathologies. such as reduced ability to downregulate SNS to relaxation with CNS disturbances, thus increasing stress-based mood alterations in anorexia psychopathology (Breit et al. 2018; Greene 2014; Schorr and Miller 2017; Sjolund et al. 1996).

Another example is self-restriction behaviours, effecting increase of serum cholecystokinin simultaneously reducing satiation rates (Bailer and Kaye 2003). Because of the interconnectivity of arcuate nucleus of hypothalamus via brain-gut axis (see Fig. 3), anorexia nervosa individuals are vulnerable to binge eating episodes with a prominent loss of self-control when presented with food (Cuntz et al. 2013). Along with the impredictability of altered mood levels, the cholecyctokinin mechanism malfunction plays a role in anorexia nervosa irregular and idiopathic bowel movements and functional bowel disorders as well as pathogenesis of inflammatory bowel disease (Larsen et al. 2021; Tang et al., 1998) as seen in Fig. 5.

The anorexigenic peptide, PYY is normally low after a prolonged starvation, indicating a need for food intake (de Silva and Bloom 2012). It is found in adipose tissue as well as in the small intestine and it is the chief activator of L-cells located between stomach and duodenum (Lach et al. 2018). Since L-cells’ only response is to decrease the size of meals ingested, their signalling inhibits the feeding process, leading to decreased bodily metabolism (Vincent and le Roux 2008). Because L-cells produce glucagon-like peptide (GLP-1) that signals satiety, this mechanism of action terminates food intake, making it essential for glucose homeostasis, pivotal in formulation of anti-obesity treatments (Oertel et al. 2024). PYY mechanics however, were not the same in anorexia nervosa individuals as during an episode of self-restraint from food, plasma PYY levels were elevated (Haines 2023), indicating that the restriction from food was linked specifically to a lack of acknowledgement of bodily needs and absence of self-awareness (Casper 2022). PYY interactions are shown on Fig. 5.

Box 6: Fig. 5

Fasting: Leptin signals in long-term satiety from adipose tissue

During the long-term satiety, blood sugar levels drop due the termination of insulin secretion and the start of secretion of glucagon. This process stimulates hepatocytes to initiate the chain of glycogenolysis, enabling glycerol and fatty acids to be metabolised within the SNS and deposit the remainder of nutrients into the adipose tissue (Martini et al. 2012). The liver glucose trasporters initiate signals for the short-term preserved glucose from previous meal, to fuel the brain (Blasquez et al. 2014). This phase activates gut-brain-adipose neural axis however, it only operates when the digestive system is empty (Chun-Xia and Tschop 2012). Long-term metabolic phase in eating disorders is of interest because during it is only when the stomach is empty, the adipose tissue cells begin to secrete leptin – a peripheral peptide, known as the anti-obesity hormone (Morrison et al. 2005). During long-term satiety, leptin secretion results in hunger reduction and it contributes to the maintenance of a healthy fat tissue while mediating replenishment of bodily energy reservoirs, to the CNS (Bates and Myers 2003). Leptin is a hormone, secreted in pulsatile patterns during this long-term metabolic phase, with its lowest levels in the mid-afternoon hours and highest at midnight with significantly higher release in obese people, during those times (Licinio et al. 1997). Due to this maladaptive pathway, leptin secretion forms a resistance that promotes obesogenic behaviours via affecting peripheral insulin sensitivity therefore increasing the desire for food (Coppari and Bjørbæk 2012). Additionally, if the person maintains the intake of food during night hours, the circadian rhythms are impaired and their replacement with eating behaviours, promotes obesity (Grossjean et al., 2023). Leptin interactions are shown in Fig. 6.

Fig. 6 .

Fasting: GLUT: glucose transporters, MsLimbP: mesolimbic pathway, NStrP – nigrostriatal pathway, FSts: frontostriatal cortex, AgP: agouti-related protein, NPY: Neuropeptide Y; HPA – hypothalamic–pituitary–adrenal axis, CNS: Central nervous system; SNS: sympathetic nervous system

Malfunctioning of leptin receptor results in increased energy storage by exhibiting continuous hyperphagic behaviours, leading to various metabolic syndromes (Bingham et al. 2008). Research recommends restoration of brain-gut disrupted patterns via weight loss endeavours (Strohacker et al. 2014) as well as examination of the quantities and the duration of food intake, feed only when hungry and avoid sleep deprivation in favour of food intake (Soltanieh et al. 2021). Possibly mediated by leptin deficiencies is the dysfunction of the CART system, linked to chronic obesity in some studies (de Macedo et al. 2016). While CART activity impacts the dopamine mesolimbic pathway (see Fig. 4), fasting results in a significant reduction in dopamine expression and less interest in food intake (Kim et al., 2002; Kristensen et al., 1998). However, research shows that CART-firing was significantly increased while presented with highly palatable foods with simultaneous activation of the reward-seeking complex (Hunter et al. 2004), presenting with important implications of the CART complex to hyperactivity and psychopathology (Jean et al. 2012). Another example is with the nature of leptin function, known to inhibit AgP and NPY neuronal connectivity (see Fig 2). It is expected that leptin mechanism of action should exacerbate anorexic signalling (Hasan and Hasan 2011), however, anorexia afflicted people actually are of low leptin levels (Bluher and Mantzoros 2004). This facts confirms abnormal connectivity during food-restrictive behaviours, suggesting anorexia nervosa, psychosomatic origins (Abbate-Daga et al. 2013) (see Fig. 6).

In normal conditions, leptin signalling reduces the rate of dopaminergic neuronal firing in the mesolimbic and striatal areas and across nucleus accumbens, suggesting a decrease in the amount and the duration of feeding (Krugel et al. 2003). High fat intake suppression levels during fasting reduces leptin storage, and increases frequency of binge eating episodes, raising the frequency of food-based reward system responses (Bodell and Keel 2015). Despite increased serum leptin across some conditions such as autoimmune disorders, in bulimia nervosa leptin production is reduced and because leptin levels are sensitive to the reduction of catecholamine reserves (Homan et al. 2014), capacity to self-regulation is obstructed. Apart from the psychiatric complications, this fact is also suggestive of the risk of pathogenesis of autoimmune origin (Raevuori et al., 2014). Further, because leptins require adequate connectivity with leptin-receptor neurons in order to activate hypothalamic structures, the optimal function of HPA axis is lowered (Park and Ahima 2015). As hypothalamic structures normal function depends on the amounts of circulating leptin, such lowered levels of activation further impede self-control and decrease individual's resilience (Aschbacher et al. 2014). Sub-optimal function of leptin pathways dysregulate the signalling of growth hormone, reduce biochemical balance to coping capacity and initiate binge eating episodes, along with an uncontrollable weight gain (Smitka et al. 2013) (see Fig. 6).

In normal conditions, the frontostriatal cortex activity is responsible for control and organisation therefore promoting behavioural flexibility. Frontostriatal metabolism is of research interest due to its prominent activity in bulimia nervosa (Donnely et al. 2018) with functional brain images displaying disorganised firing and marked hypoactivity in the attention-focusing circuits, conveying habitual, reward seeking-behaviours, adversely affecting capacity for self-regulation (Berner and Marsh 2014). These findings form the rationale for bulimia nervosa disordered eating patterns that have been found to persist even after recovery (Steiger et al. 2001). These outcomes could be further linked to risk of autoimmune pathologies with Smitka et al. (2013) studies confirming decreased levels of autoantibodies against both serotonin and dopamine that could potentially explain symptoms of excessive hunger (Smitka et al. 2013). Fig. 6 shows how the regulation of the reward-seeking mechanisms stands out in harnessing the positive autoimmune responses in the pathogenesis of bulimia nervosa (Bodell and Keel 2015; di Bonaventura et al. 2020).

Box 7: Fig. 6

Sympathoadrenal neurofeedback

Chronic changes in glucose levels and fatty acid oxidation: the mechanisms of glucoprivation and lipoprivation

Glucose and fatty acid oxidation are two neurometabolic processes of the sympathoadrenal system (Jordan et al., 2010), responsible for energy homeostasis. Their signalling is primarily set to increase enteroendocrine production of ghrelin, resulting in potent impulse for hunger and beginning of food intake (Mani et al. 2019). In normal functioning, when the glucose levels reach lower than the required for energy homeostasis, glucoprivation occurs. Its mechanism of action begins with the activation of glucose transporter-insulin receptor cells, signalling hypoglycemic state and triggering impulse for re-feeding (Blasquez et al. 2014). The lipoprivation state is activated when fatty acid oxidation reaches below the level of the organism requirements (Simsek et al. 2014). As the brain is the highest lipid-containing organ after the adipose tissue, the fatty acid metabolism is another prominent neural mechanism in energy homeostasis (Jordan et al. 2010). The lipid content in the brain is derived from both local fatty acid synthesis via lipoprotein receptors as well as from plasma and it influences hypothalamic pathways to regulation of food intake (Kim et al. 2002) (see in Fig. 7). Both glucoprivation and lipoprivation are of interest in studying obesity and anorexia nervosa due to expression of aberrant dopamine neurotransmission (Blum et al. 2014; Sajapitak et al. 2008; Simsek et al., 2014). The mechanism of glucoprivation plays a significant part in the anorexia pathology as it leads to stress-induced hypophagia resulting in chronic hypoglycaemia (Brown and Mehler 2015), that translates into psychological symptom of anhedonia (Qu et al. 2020). Because lipoprivation is related to hypothalamus-regulated energy production and expenditure (Morgan et al. 2004), low energy production further results in chronically increased stress levels, leading to hypercortisolaemia (Lawson et al. 2011) (see Fig. 7).

Fig. 7 .

Chronic changes in glucose levels and fatty acids oxidation: the mechanisms of glucoprivation and lipoprivation, CART: cocaine- and amphetamine-regulated transcript; HPA: hypothalamic-pituitary-adrenal axis; GABA: gamma-aminobutyric acid; GLUT: glucose transporters, NPY: neuropeptide Y; POMC: pro-opiomelanocortin

Physiologically, NPY is significantly involved in the neuromodulation in both glucoprivation and lipoprivation (Kozak et al. 2005), and the alteration of its pathways has been shown to lead to obesity, chiefly from prominent high carbohydrate and fat intake (Li et al. 2020; Rattanajearakul et al. 2025). Neurobiologically, NPY connections activate pathways that inhibit oxytocin release and activate gamma-aminobutyric acid (GABA) pathways which is a connectivity that holds significance to impaired attachment patterns, various somatic symptomatology as well as sleep disturbances as well as implication to psychiatric disorders such as depression (Chaulagain et al. 2025; Huang et al. 2021; Lach et al. 2018; Lawson et al. 2011; Schür et al. 2016). These findings are significant because they show evidence to eating disorders high co-occurence with mood disorders (McAulay et al., 2019), leading to chronic stress adaptation (Herman and Tasker, 2016).

Studies demonstrate a significant relationship between dopamine release and insulin firing on the dopamine-hypothalamus pathway (Stagkourakis et al. 2019). In the brain, glucoprivation is expressed via an enhanced dopamine signalling, associated with intensified metabolic stress (Blum et al. 2014). Since glucose levels are dependent on the optimal function of dopaminergic circuitries, lowered glucose levels inhibit dopamine release, leaving the body dependent on the endogenous dopamine for basal metabolic functions (Adler et al. 2000). As such, chronic states of dopamine depletion in obesity are evidenced by hyperphagic behaviours, in an effort to prevent brain from oxygen starvation (Trugman and James 1993). In anorexia the mechanism of glucoprivation results in hypersecretion of POMC across the CART system and its action lasts longer than in a normal neurometabolic phase (Stoving et al. 1999). Apart from the weight loss, this neural connectivity induces bouts of pleasant mood during appetite-suppressing episodes, resulting in creation of food- avoidance behavioural patterns, and leading to a state of adaptive starvation (Yeomans and Gray 2002).

The interconnectivity with HPA pathway and its degree of activation depends on the levels of lipoprivation (Sajapitak et al. 2008). In anorexia, nervosa, the lipoprivation mechanism malfunctions due to starvation, resulting in increasing serum macrophage inhibitory cytokine-1, inducing inflammatory responses (Karczewska-Kupczewska et al. 2012). As most of the energy needed to initiate gluconeogenesis is obtained from fat oxidation, starvation-induced lipoprivation increases plasma glucose levels (Simsek et al. 2014), carrying both metabolic and neural complications. For example, Ohwada et al. (2006) have found that hypoglycemia-induced inflammation had a simultaneous presence of hyperlipidemia, further indicating accelerated cholesterol metabolism. Some research reports that chronic upgrades in cholesterol accumulation has resulted in tumour formations in lateral hypothalamic area in postmortem hypoglycaemic anorexia nervosa patients (Lewin et al. 1972; Mattingly and Bhanji 1995). These outcomes highlight the necessity of restoring gluconeogenesis and fatty acid metabolism in their simplest form of regulated nutrition, as a beneficial starting point in anorexia treatment (Rosen et al. 2017) (see Fig. 7).

Box 8: Fig. 7

Limitations and considerations for future practice

This paper had some methodological limitations. One of the those was the complexity of problem identification. This study was a preliminary effort to explore the connectivities of neuropathophysiological conditions that have explicit mental health implications. In order maintain validity and reliability of the information, the literature search question had to keep very narrow focus, as some other narrative integrative and descriptive works, with similar topic investigation, have done. Limiting the selection papers to such publications was a restriction however, the narrative integrative literature reviews are designed to address the current state of development of a given topic and to provide a synthesis of the published literature on it (Ferrari 2015). In this light, this narrative presentation is content to offer a practical yet succinct format for the novice clinicians in practice.

Another limitation we faced was through data analysis. According to Rumrill and Fitgerald (2001), narrative approach provides room for subjective perceptions in the given field. This review’s goal is to encourage development of newer qualitative perspectives across the domains of the topic. Although this aim could be interpreted as a frivolous change across a methodology by some members of scholarly community, such direction does not necessarily indicate a lack of methodological rigour or flaws in the design (Sukhera 2022), particularly because phenomenological angle in approaching obesity and eating disorders work has recently been recognized as beneficial in exploring newer treatment perspectives (Burns et al. 2017; Chimpen-Lopez and Ariazu-Munoz 2021; Knio and Sridhar 2025).

The emerging field of neuropathophysiology is an area of knowledge that deals with obesity as a class of medical conditions (Kessler et al. 2016). The key understandings are currently carried out in the emergent research field of hypothalamic neuronal interaction with hormones and gut peptides. This knowledge gives vital information with studies on obesogenic behaviours during periods of stress that involve the brain-gut-adipose neural axis (Agustí et al. 2018; Chun-Xia and Tschop 2012; Weltens et al. 2018). On one hand, NPY is observed to moderate stress centrally, with mechanics of adrenocorticotropic hormone secretion causing corticotropin-releasing hormone to rise across the HPA axis (see Fig. 3), while on the other, this mechanism amplifies stress coping responses peripherally via the activities of the adrenal medulla and sympathetic nerves (Hirsch and Zukowska 2012). This translated into the fact that both obesity and eating disorders remain primarily stress-related conditions and because feeding processes involve production of corticotropin-releasing hormone, directly responsible for energy levels in the body, the eating behaviours during stressful conditions are normally inhibited, as part of normal physiological response to stress. However, it should be cautioned that chronically increased stress levels degrade frontal cortex’ rational executive functions and promotes an emotion-led, stress-based feeding mode (Dallman 2010; George et al. 2010).

The food choices during obesity and eating disorders are generally made during acute emotional episodes where capacity to self-control is reduced. Activation of HPA-induced neuronal firing exacerbates the potential of energy dense and nutrient poor food intake (Pannicke et al. 2021). In hyperphagia, both plasma and fat tissue present with elevated NPY, inducing ravenous desire for food, despite the presence of obesity (Kuo et al. 2008; Lemmens et al. 2011). In obese people, depressive moods such as sadness, feelings of boredom and internal tension have been found to increase habit-based choices of fatty and sweet-tasting, as well as processed foods in contrast to the happy states that favoured dry fruit choices (Dallman 2010; Diz Chaves 2011: Keast et al. 2011). Such examples suggest nutritional recommendation for increased intake of fruits and vegetables due to their verified capacity to positively influence mental health (Głąbska et al. 2020).

Another consideration to obesity prevention are the choices of nutrient-specific foods. For example, oleic fatty acids found in nuts and seeds, avocado and others, were associated with lower adiposity measures, standing against obesity-promoting behaviours (Bauer et al. 2009; Schwartz et al. 2008). Further, oleic fatty acids intake increased production of anti-inflammatory cytokines and secretion of glucagon, resulting in lowering glucose production and leading to overall hunger reduction (Hung et al. 2023), thus, inhibiting food intake and decreasing the release of AgP, reducing the chances for fasting-induced hyperphagia (Quiñones et al. 2015). Furhter, clinical studies demonstrate that neurons in the arcuate nucleus of hypothalamus were affected by the type and the concentration levels of fatty acids (Vohra et al. 2022). For example, oleic acid fails to affect AgP while it depolarises and increases the firing rate of POMC (Michael and Watt, 2020), with both connectivities beneficial to obesity reduction. As the arcuate nucleus of hypothalamus stimulates food intake via hunger-stimulating AgP and inhibits it via hunger-inhibiting POMC (Neudorfer et al. 2020; Roger et al. 2022) (see Fig. 3), oleic acid intake may be of benefit to the treatment of obesity (Tutunchi et al. 2020).

Elenolic acid found in olives and extra virgin olive oil, were confirmed to stimulate PYY release from L-cells (Suzuki et al. 2012). Because PYY is the main nutrient detector organ that sends short-term satiety signal is the liver, its signalling will be maintained for as long as nutrients from stomach and duodenum are received - as it happens during the short-term satiety. However, elenolic acid simultaneously induces secretion of glucagon-like peptide -1 called liraglutide in the arcuate nucleus of hypothalamus, effecting upregulations in signalling of the anorexigenic POMC and CART peptides, mediating weight loss processes (Jelsing et al. 2012; Secher et al. 2014). Further, elenolic acid acts as an appetite suppressant towards reduction of food intake volume as well as is of a restorative effect on the stomach tissue, carrying strong implications to maintenance of selected food choices in obesity treatment (Wang et al. 2022).

During trauma recovery, a high level of fatty acids is essential to accelerate the process of generating ketone bodies as an alternative energy source, generally obtained from an increased consumption of fatty acids and decreased carbohydrate intake (Frank and Scolnick 2024). Ketosis has been shown to exert an anorexigenic effect as it increases cholecystokinin signalling and reduces orexigenic signalling such as suppression of hormone ghrelin (Paoli et al. 2015) (see Figs. 4 and 5). Some in vitro studies of brain injuries show such accelerated production of ketones (Cahill Jr. 2006; Dilliraj et al. 2022) with explicit clinically significant results of a reduced onal apoptosis, increase in cognitive capacity, and upregulation across sensorimotor functions (Simeone et al. 2017; Stubbs et al. 2020). As the levels of ketone bodies stands at its highest following bodily starvation during severe traumatic experiences (Daines 2021), the ketogenic diet, combined with low carbohydrate consumption may be recommended for both obesity and bulimia nervosa (Sethi et al. 2020).

Anorexia nervosa’ neuro-endocrine pathologies are an area of continued research interest (Brown and Mehler, 2015; Casper, 2022; Cuntz et al., 2013; Fatt et al., 2020). While hypothalamus influences anorexia' metabolic phases by modifying the humoral and neuronal signals towards energy homeostasis, the modification remains dependent on the level of affect, becasue normally, all emotional, environmental, psychological and physical stresses influence the activity of brain-gut-adipose axis (Yi and Tschop 2012). For example, during an significant emotional stress, traumatic affect or a physically demanding situation, the limbic system initiates autonomic nervous system responses of fight or flight. During these stages, the triglycerides provide up to eighty percent of the bodily energy necessary for the recovery from trauma (Simsek et al. 2014) as evident by a decreased sympathetic activity (Schumann et al. 2017) and the increased rate of lipolysis, both triggered by activation of cortisol and insulin secretions (Polito et al., 2021). Because anorexia nervosa’ psychotic symptomatology is amongst the primary concerns involving increased levels of anxiety along with perpetual alertness (Smitka et al. 2013), evidence-informed psychotherapy interventions (Bower and Irwin, 2016) combined with anxiolytic drug interventions are the prioritised treatment options (Lock and Fitzpatrick 2009).

Because bulimia nervosa significantly affects mental health, the use of standardised clinical questionnaires creates difficulties in some psychotic patients due to the cognitive and emotional aspects of the interviewing protocols (de Beaurepaire 2021). Further, patients with comorbid schizophrenia may misinterpret the purpose of the questions (Palmese et al. 2013) while patients with vagus nerve pathophysiologies could end up feeling depressed, confused or emotionally demanded upon (Faris et al. 2006). Both anorexia nervosa and bulimia nervosa are accepted to largely follow parental autoimmune or autoinflammatory conditions, (Zerwas et al. 2017). Medical literature agrees that eating disorders are complex metabolic, neuroendocrine and psychiatric conditions, with distinct subtypes, involving culture-related differential diagnoses (Hay & Bacaltchuk 2001; Smitka et al. 2013; Zerwas et al. 2017), recommending explorations of heredity, focus on psychoeducation and psychotherapy (Hay 2020).

Conclusion

Neuroscience is increasingly taking an interest in analytical studies of obesity and eating disorders as conditions of interrelated neural, immune, gastric and mental health factors, with the understanding that brain-gut neurofeedback can inform essential biochemical methods of assessment in support of best treatment choices. A true holistic approach involves consolidation of knowledge within the field of neuropathophysiology while incorporating the essential elements of person-centered counselling, individually tailored nutritional planning and the appopriate consideration of medical management.

Author contributions

This study has been conceptualised, designed, structured, researched and written by Malini Turner (corresponding Author). The Table and the Figures were created by Malini Turner (corresponding Author). Critical analysis, final edits and proofread of the manuscript were done by Malini Turner (corresponding Author). Dr Mansi Dass Singh supervised, validated and added various specialised content to nutritional and methodology sections. Provided final suggestions to the manuscript overall structure. Dr Ian Evans supervised, validated and provided specialised content to neuroscience content. Provided final critical revision to the manuscript.

Funding

Open Access funding enabled and organized by CAUL and its Member Institutions. The authors declare no funding was received for this paper.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Use of AI

The authors declare there has been no AI used in this review.

Competing interests

The authors declare no competing interests.