Glucose is the primary energy substrate for most tissues and the almost exclusive fuel for the brain in both rodent and human. As noted by Mergenthaler et al. (2013) (1), the mammalian brain depends on glucose to sustain neuronal activity, neurotransmitter synthesis, and overall cognitive function. Thus, precise control of glucose metabolism is essential for brain and systemic health. To ensure a constant energy supply, plasma glucose concentrations are tightly regulated through highly coordinated mechanisms, a process known as glucose homeostasis (1, 2).

Traditionally, glucose homeostasis has been attributed to the balance between insulin and glucagon secretion by the pancreas (2). However, growing evidence highlights a pivotal role of the central nervous system (CNS) in sensing metabolic status and actively orchestrating systemic glucose regulation, shifting the paradigm from a passive to an integrative control system (3, 4). Key determinants of glucose homeostasis, such as insulin and glucagon secretion, peripheral insulin sensitivity, and glucose utilization, are under central modulation by the brain.

Within the brain, the hypothalamus and brainstem act as neuroendocrine hubs that integrate hormonal, nutritional, and neural signals to regulate feeding, autonomic tone, and endocrine outputs. Specialized hypothalamic glucose-sensing neurons detect changes in glucose availability through mechanisms shared with pancreatic β-cells and translate this information into adaptive autonomic and behavioral responses to maintain glucose stability. Through reciprocal connections with other brain regions, the hypothalamus and brainstem coordinate food intake, thermogenesis, and systemic energy balance.

Disruption of these regulatory circuits is increasingly recognized as a key contributor to metabolic disease. Central insulin and leptin resistance, hypothalamic inflammation, and impaired brainstem autonomic control are implicated in the pathogenesis of obesity and T2DM (4). Importantly, these alterations often precede overt hyperglycemia, suggesting that neuroendocrine dysfunction constitutes an early, causal step in metabolic deterioration (5) and may accelerate brain aging (6, 7) in both rodents and humans. Diet-induced hypothalamic stress, particularly from high-fat diets, further amplifies inflammatory and oxidative pathways, exacerbating both metabolic and cognitive decline.

Understanding how the hypothalamus and brainstem sense and integrate metabolic signals is therefore essential for elucidating the mechanisms underlying metabolic disease and identifying new therapeutic strategies. In this review, we summarize current insights into the neuroendocrine control of glucose homeostasis, discuss mechanisms of central dysfunction in metabolic disease, and highlight emerging therapies targeting brain pathways to restore systemic glucose balance. Much of the available evidence comes from rodent studies, as functional validation in humans remains limited.

While the hypothalamus is a central hub for energy balance and glucose regulation, the brainstem provides essential autonomic control that maintains glucose homeostasis within narrow physiological limits (44, 45). Key regions in the brainstem include the dorsal vagal complex (DVC), comprising the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus (DMV), and area postrema (AP), as well as the rostral ventrolateral medulla (RVLM), which together integrate visceral and hormonal signals and coordinate autonomic outputs to regulate pancreatic hormone secretion, hepatic glucose production, and peripheral glucose utilization (Figure 2).

The vagus nerve contains the primary sensory neurons that monitor the gastrointestinal environment and transmit this information to the brainstem. The NTS serves as a major integrative center for visceral afferents from the gastrointestinal tract, liver, and pancreas. Vagal and sympathetic afferents from the gut synapse in the NTS, where neuronal activity modulates insulin secretion and hepatic glucose output (46, 47).

Recent advances have refined our understanding of gut-brain communication as a central regulator of metabolic homeostasis. Using intersectional genetic approaches, Borgmann et al., demonstrated that distinct populations of gut-innervating vagal afferents exert differential control over food intake and glucose metabolism by engaging separate neural circuits in the brain (48). Consistently, activation of intestinal mechanoreceptors during feeding generates satiety signals transmitted via vagal afferents to the nucleus tractus solitarius (NTS), where they inhibit hypothalamic AgRP/NPY neurons and activate anorexigenic pathways (49). By modulating autonomic balance-reducing sympathetic drive and enhancing parasympathetic signaling-gut-derived sensory inputs lower hepatic glucose output and improve insulin sensitivity. These findings highlight vagal sensory pathways as key integrators of intestinal, hepatic, and hypothalamic signals in the neurohormonal control of glucose homeostasis (Figure 2).

Within this framework, catecholaminergic circuits in the NTS integrate visceral afferent inputs to adapt feeding and glucose metabolism to changing energy states. Epinephrine/NPY-expressing neurons promote feeding, norepinephrine neurons suppress it, and a subset of tyrosine hydroxylase–expressing neurons drives glucoprivic feeding through hypothalamic AgRP and POMC neurons, revealing an orexigenic role for the vagal-NTS circuit beyond its classical satiety function (50–53) (Figure 2).

The NTS also receives descending projections from hypothalamic PVN, LH, and ARC neurons, allowing bidirectional communication that integrates circulating signals such as glucose, ghrelin, GLP-1, and leptin to coordinate autonomic and neuroendocrine regulation. Parallel brainstem centers, including the RVLM and the area postrema, contribute to sympathetic outflow that promotes hepatic gluconeogenesis, inhibits insulin secretion, and regulates feeding and lipolysis. Collectively, hypothalamic and brainstem neurons, together with sympathetic preganglionic circuits, form an integrated network that coordinates feeding behavior and glucose balance, whose dysfunction contributes to impaired hypoglycemia awareness, hyperglycemia in type 2 diabetes, and hormonal resistance (54–60).

The gut microbiota interfaces with the gut-liver-brain axis through bidirectional communication encompassing neural, immune, and endocrine pathways. This network involves vagal signaling, microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids that influence host physiology, and immune responses elicited by microbial byproducts like lipopolysaccharides (LPS) reaching the liver and brain. While these interactions are essential for maintaining metabolic homeostasis, microbial dysbiosis can disrupt this equilibrium, promoting systemic inflammation, hepatic insulin resistance, and neuroendocrine dysfunction (61).

Future studies should further elucidate how the gut microbiota shapes neural, endocrine, and metabolic control within this interconnected system. Although SCFAs and bile acids have been identified as major mediators, the vast genetic and functional diversity of the microbiome likely conceals additional mechanisms influencing glucose homeostasis. Integrative approaches combining microbiomics, metabolomics, and neurophysiology will be crucial to bridge this gap (61).

Together, these insights into the gut-liver-brain network underscore how peripheral signals converge on central circuits to regulate glucose metabolism, an integrative framework that extends to the brain-pancreas axis, discussed next.

Extending beyond incretin-mediated pathways, the brain-pancreas axis exemplifies how neuroendocrine circuits integrate peripheral metabolic cues with central control mechanisms to maintain glucose and energy homeostasis. The brain and peripheral nerves coordinate with pancreatic islets to regulate glucose. Glucose-sensing neurons in the hypothalamus, including AgRP/NPY, POMC and VMH, form the core of brain–pancreas connections. These neurons project to the PVN and the brainstem, ultimately communicating with the NTS and DMV. Through these pathways, brainstem structures control vagal and/or spinal outputs to the pancreatic islets, thereby regulating insulin and glucagon secretion (62–64).

Mammals have the capability to maintain blood glucose levels within strikingly narrow ranges under normal conditions. The maintenance of glucose homeostasis relies not only on the intrinsic sensing properties of pancreatic islet cells but also on complex neuroendocrine circuits and autonomic inputs from the sympathetic and parasympathetic nervous systems.

The vagus nerve, a major parasympathetic pathway, further modulates glucose metabolism by influencing both insulin release and hepatic glucose production (65). Direct evidence of autonomic control over islet function was provided by Rodriguez-Díaz et al., who demonstrated in mice with islets transplanted into the eye that autonomic axons innervating the islet directly regulate glucose homeostasis (65).

Pancreatic islets are thus under dual autonomic control. Sympathetic fibers, originating from thoracolumbar spinal segments, stimulate glucagon release from α-cells and suppress insulin secretion from β-cells, largely through modulation of islet blood flow (66).

Parasympathetic vagal input, under hypothalamic regulation, promotes insulin secretion during the cephalic phase of feeding by integrating sensory cues (taste, smell, vision) and responding to gut-derived hormones such as CCK and serotonin. While vagal signaling is dispensable for basal insulin secretion in fasting conditions, it becomes crucial for glucose-stimulated insulin release in the fed state. This dynamic interplay between sympathetic inhibition and parasympathetic stimulation coordinates islet hormone output according to metabolic state (67).

The gut microbiota also influences glucose homeostasis by communicating with the pancreas through various microbial metabolites like the SCFAs and branched-chain amino acids (BCAAs). In both type 1 and type 2 diabetes, microbial imbalance (dysbiosis) alters metabolite profiles, impacting pancreatic islet function. This can lead to effects like increased inflammation, insulin resistance, and the development or progression of diabetes (68). Understanding these complex gut-liver-pancreas-brain circuits could lead to new treatments to prevent or reverse metabolic dysfunction and improve insulin sensitivity.

Neuroendocrine circuits that regulate glucose homeostasis are highly vulnerable to disruption in obesity, type 2 diabetes, and aging. Insulin resistance in the CNS impairs metabolic control, while autonomic dysregulation alters pancreatic function. Reduced vagal tone further limits insulin secretion and weakens counter-regulatory responses to hypoglycemia. Evidence from human and animal studies shows that these disturbances are accompanied by neuroinflammation, neurotransmitter imbalance, and structural brain changes, all of which contribute to progressive metabolic derangements and increased risk of cognitive decline (69).

Hypothalamic inflammation, characterized by gliosis and microglial activation in the ARC nucleus interferes with PI3K-Akt and STAT3 signaling and blunts POMC and AgRP neuronal responsiveness, thereby favoring orexigenic tone and systemic insulin resistance (70, 71).

In leptin-deficient models, chronic inflammatory signaling further exacerbates hyperphagia and metabolic dysfunction. Mechanistic studies implicate mitochondrial dysfunction and endoplasmic reticulum (ER) stress as key contributors, exemplified by POMC-specific Mitofusin 2 (Mfn2) deletion, which induces ER stress, leptin resistance, and obesity (72, 73).

Beyond inflammation, dysregulation of orexigenic neuropeptides such as neuropeptide Y (NPY) and melanin-concentrating hormone (MCH) worsens metabolic disease. In this regard, ablation of NPY Y2 receptors improves glucose and lipid profiles in ob/ob mice, whereas MCH deletion increases energy expenditure and glycemic control (74, 75).

Moreover, novel pituitary-brain circuits contribute to systemic glucose regulation, as a subset of AgRP-expressing neurons in the anterior pituitary, which responds to bile acid signals and regulates glucose tolerance independently of food intake; silencing these neurons improves glucose-stimulated insulin secretion (76).

However, the precise mechanisms linking brain activity to peripheral glucose handling in humans remain poorly defined, representing a critical frontier for translational research in metabolic regulation.

The identification of central mechanisms governing glucose homeostasis has opened new therapeutic avenues for obesity, insulin resistance, and diabetes. For instance, intranasal insulin bypasses the blood-brain barrier to enhance central insulin action, improving hepatic glucose production and peripheral glucose disposal without raising systemic insulin levels (77).

Dual and triple incretin receptor agonists, such as tirzepatide and retatrutide, combine peripheral and central actions that target mechanisms underlying sex differences in metabolic homeostasis and disease. These agents not only improve glycemic control and promote weight loss but also partially restore leptin sensitivity through microbiota-derived metabolites such as inosine (78, 79).

Systematically incorporating sex as a biological variable in both preclinical and clinical research will be essential to uncovering mechanistic differences, improving translational accuracy and ultimately guiding the development of sex-adapted therapies for diabetes and other metabolic disorders (80).

Neuromodulatory strategies, including vagus nerve stimulation, selective hepatic-celiac vagal modulation, optogenetics, and chemogenetics, also show promise in improving glycemic control and reducing inflammation (81, 82).

Lifestyle interventions, including intermittent fasting and time-restricted feeding, engage hypothalamic and autonomic pathways to reduce hepatic gluconeogenesis and enhance metabolic flexibility, while early-life nutritional modulation can shape hypothalamic plasticity and long-term glucose control (83).

Emerging therapies targeting mitochondrial quality control, inflammatory signaling, and post-translational modifications (e.g., neddylation) also hold potential to restore central metabolic function. Moreover, multi-omics approaches, integrating proteomics, metabolomics, epigenomics, and microbiomics, combined with artificial intelligence and circuit-level mapping, are accelerating biomarker discovery and precision therapeutic design (84).

Non-invasive neuroimaging tools, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), complement these approaches by enabling longitudinal monitoring of brain metabolism and activity in humans (85–87).

Central regulation of glucose homeostasis arises from the coordinated activity of neuroendocrine and autonomic circuits integrating hormonal and nutrient-derived signals from adipose tissue, gut, liver, and pancreas. Within this network, leptin, insulin, and incretin pathways converge on AgRP/NPY and POMC neurons in the ARC to control feeding, hepatic glucose output, and insulin sensitivity (4–14).

These hypothalamic circuits are developmentally programmed yet remain modifiable during early life. Maternal obesity, overnutrition, or inflammation can durably alter AgRP and POMC connectivity through microglial activation and impaired perineuronal net (PNN) maturation, establishing a “metabolic memory” that predisposes offspring to lifelong glucose dysregulation (29–35).

The brainstem complements hypothalamic control by integrating visceral feedback within the gut-liver-brain axis, central to metabolic homeostasis and a target for novel therapies (60–64). Chronic overnutrition and neuroinflammation exacerbate these impairments, promoting hypothalamic leptin and insulin resistance, hallmarks of metabolic disease and contributors to cognitive decline (70, 71).

Next-generation incretin mimetics and neuromodulatory interventions capitalize on these central-peripheral interactions to enhance metabolic flexibility and restore hormonal sensitivity (78, 79, 81–83). Integrating multi-omics and high-resolution neurocircuit mapping will refine biomarker discovery, improve translational fidelity, and inform precision strategies linking metabolic, neuroendocrine, and immune systems (84).

In summary, glucose homeostasis is governed by a distributed, plastic neuroendocrine network whose developmental and inflammatory plasticity shapes the trajectory of metabolic health. Leveraging this integrative understanding, bridging developmental neurobiology, incretin pharmacology, and neuromodulation, will be key to achieving durable metabolic restoration in obesity and diabetes.

Despite major advances, translating mechanistic insights from animal models to humans remains a key challenge. Standardization across strains, diets, and experimental designs is needed to improve reproducibility and cross-study comparability. Longitudinal human cohorts combining neuroimaging, biofluid omics, and hormonal profiling will be instrumental to map central-peripheral interactions in metabolic control.

Future studies should incorporate sex as a biological variable, as estrogens acting through ERα signaling improve insulin sensitivity, β-cell survival, and central metabolic regulation, providing protection before menopause. Developing biomarkers to monitor central interventions will also accelerate translation into effective therapies.