Anorexia Nervosa: Unraveling the Metabolic Mysteries Behind Self-Starvation and Anxiety Relief
Anorexia nervosa (AN) remains one of the most challenging psychiatric disorders to model and understand, partly because of its multifaceted origins. Genetic predispositions intertwine with environmental pressures, social influences, and cultural nuances to sculpt the complex pathology of AN. Traditional animal models have not sufficiently captured the breadth of these factors or the intricate neurobiological underpinnings that contribute to this life-threatening condition. However, recent advances leveraging genetic, dietary, and behavioral manipulations in mice have started to shed light on the metabolic and neurological pathways underlying AN, offering promising avenues for future research.
Among the models developed, the activity-based anorexia (ABA) paradigm stands out as a prolific tool in dissecting AN-like behaviors in rodents. This paradigm mimics core features of human AN, including compulsive self-starvation, hyperactivity, intense weight loss, disrupted reproductive cycles, hypothermia, and hormonal imbalances such as elevated ghrelin and diminished leptin levels. In the ABA model, adolescent mice are isolated with continuous access to running wheels but restricted access to food for limited hours. Intriguingly, these animals often engage in relentless running, prioritizing wheel activity over feeding even when food is available, paralleling the compulsive exercise and food aversion observed in human AN.
Several studies using the ABA model have revealed a protective role for dietary fat in mitigating self-starvation and subsequent mortality. High-fat, low-carbohydrate diets appear to disrupt the cascade of metabolic changes leading to extreme weight loss and physical decline. The underlying mechanism seems tightly linked to how fat content influences peripheral metabolism and neuroregulatory circuits, preventing onset and even reversing established self-starvation in these rodents. This discovery aligns with an emerging perspective that alterations in fat metabolism and energy substrate utilization are key players in the pathophysiology of AN.
At the neural circuit level, the arcuate nucleus of the hypothalamus, home to Agouti-related peptide (AgRP) neurons, has been identified as a central regulator of starvation adaptation and behavior modulation. These neurons orchestrate nutrient partitioning, optimize substrate preference, and mediate the body’s response to energy deficits. Intriguingly, AgRP neurons also modulate non-feeding behaviors linked with reward, anxiety, and compulsive activities. Experimental disruption of AgRP signaling in the ABA model results in catastrophic failure to maintain food intake and 100% lethality. This dire outcome is accompanied by marked drops in circulating free fatty acids and glucose—vital energy substrates—highlighting the indispensable role of AgRP circuits in survival during caloric restriction.
Conversely, chemogenetic stimulation of AgRP neurons promotes the development of compulsive exercise behaviors without exacerbating anxiety-like symptoms in mice. Importantly, administering a high-fat diet rescues animals with impaired AgRP circuitry from fatal consequences and curbs long-term compulsive behaviors associated with starvation. These findings position the AgRP neuron network as a critical nexus linking metabolic cues with maladaptive behavioral outputs akin to AN. Beyond preclinical models, patients with AN show elevated circulating AgRP levels, which have been correlated with cognitive rigidity, suggesting a translational relevance that bridges rodent studies with human pathology.
Anxiety closely intertwines with AN, perpetuating a vicious cycle that complicates treatment and recovery. The onset of AN frequently coincides with heightened levels of anxiety, which can predate the disorder and serve as a risk factor for its development. Starvation itself is hypothesized to exert anxiolytic effects in susceptible individuals, possibly explaining the compulsive drive to maintain caloric restriction despite detrimental health consequences. Notably, conventional anxiolytic medications such as selective serotonin reuptake inhibitors (SSRIs) often show limited efficacy during states of starvation, presumably due to altered synaptic serotonin dynamics and impaired glucose metabolism within the brain.
Recent advances emphasize metabolic and mitochondrial dysfunction in the brain as foundational elements in anxiety disorders. Ketogenic diets (KDs), characterized by low carbohydrate and high fat intake, have gained traction as experimental interventions for anxiety and mood dysregulation. These diets enhance bioenergetic efficiency, stabilize neuronal membranes, and optimize substrate transport within critical brain regions like the medial prefrontal cortex, known for regulating anxiety responses. While clinical data remain preliminary and heterogeneous, emerging reviews highlight the potential benefits of ketogenic approaches in managing psychiatric disorders marked by anxiety and metabolic dysregulation.
In the context of AN, ketone bodies (KBs)—metabolic products generated during fat catabolism—may play a paradoxical role. Starvation-induced ketosis provides an alternative energy source when glucose is scarce, sustaining cerebral metabolism under nutritional duress. Beyond fulfilling energy demands, KBs possess membrane-stabilizing properties and may exert direct anxiolytic effects, thereby attenuating the distress associated with starvation. This neurochemical milieu potentially reinforces the persistence of starvation behavior by mitigating anxiety, inadvertently fostering a self-perpetuating cycle where metabolic adaptations support maladaptive psychological states.
Moreover, starvation is known to disturb peripheral metabolism and compromise mitochondrial function within the brain, contributing further to neurocircuitry dysfunction and aberrant behavior. Compulsive exercise—a common feature of AN—may amplify these metabolic perturbations by promoting the systemic release of ketone bodies, particularly beta-hydroxybutyrate (D-BHB). This metabolite not only fuels energetic demands but may modulate neural circuits regulating anxiety and reward, perpetuating the cycle of self-starvation and hyperactivity. Hence, the maintenance of AN symptoms might stem in part from these ketone-mediated anxiolytic effects, complicating interventions aimed at refeeding and behavioral normalization.
The implications of these findings are profound for therapeutic strategies aimed at treating AN. Traditional refeeding protocols may falter because they neglect the neurochemical and metabolic feedback loops sustaining the disorder. Specifically, discontinuing ketosis could inadvertently remove its anxiolytic benefits, increasing anxiety and resistance to nutritional rehabilitation. Therefore, interventions that either mimic the anxiolytic effects of ketosis or gradually transition metabolism away from ketone dependence may represent a critical frontier in improving AN outcomes.
On a translational front, the elucidation of AgRP neuron circuits and their metabolic interactions opens new vistas for pharmacological targeting. Manipulating these neural pathways could recalibrate the balance between energy homeostasis and compulsive behavior, offering a precision medicine approach to tackle the neurobiological roots of AN. Coupled with dietary modulation strategies emphasizing fat metabolism, such interventions might effectively interrupt the vicious cycle described.
The convergence of metabolic, behavioral, and neuronal evidence underscores a paradigm shift in understanding anorexia nervosa—from a purely psychiatric illness to a complex bioenergetic disorder involving brain-periphery crosstalk. The highlighted research champions the need for integrative models that address both metabolic substrate availability and neural circuit adaptations to devise more effective treatments.
Future research directions must aim to refine ABA models further, incorporating genetic and environmental variables to mirror human heterogeneity in AN manifestation. Investigations into ketone signaling, mitochondrial dynamics, and neuroinflammation will be critical in delineating causative versus consequential changes in disease progression. Moreover, clinical studies assessing ketogenic or modified high-fat diets in AN patients could validate preclinical observations and potentially revolutionize nutritional therapy.
Understanding how ketones modulate anxiety within starvation contexts invites broader inquiries into developing brain-targeted metabolic therapies for psychiatric conditions beyond AN, including generalized anxiety disorder and depression. The neuroprotective and anxiolytic potential of ketone bodies places them at the forefront of emerging psychobiological research.
In summary, the intricate interplay between metabolic adaptations, hypothalamic neural circuits, and anxiety-related behaviors in the anorexia nervosa model reveals a previously underappreciated dimension of this disorder’s pathogenesis. Ketones, acting as alternative fuels with neuromodulatory capacities, emerge as key mediators in sustaining starvation behaviors through anxiety mitigation. Unlocking these mechanisms will be essential to breaking the debilitating cycle of anorexia and guiding innovative therapeutic paradigms.
As this exciting field evolves, interdisciplinary collaboration between neuroscientists, psychiatrists, and metabolic researchers promises to unravel the enigmas of anorexia nervosa, ultimately transforming patient care through metabolic-targeted and circuit-specific interventions.
Subject of Research: The neurobiological and metabolic mechanisms underlying anorexia nervosa, emphasizing the role of ketones and hypothalamic Agouti-related peptide neurons in modulating starvation behaviors and anxiety.
Article Title: Providing alternative fuel for the brain in anorexia nervosa: a review of the literature on ketones and their effects on metabolism and the brain.
Article References: Micali, N., Miletta, M.C., Clemmensen, C. et al. Providing alternative fuel for the brain in anorexia nervosa: a review of the literature on ketones and their effects on metabolism and the brain. Transl Psychiatry 15, 412 (2025). https://doi.org/10.1038/s41398-025-03591-1
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41398-025-03591-1
