Beyond Pleasure: Unraveling the Multifaceted Role of Dopamine in Obesity and Metabolic Regulation

Abstract

Purpose of Review

Obesity is a heterogeneous chronic disease involving dysregulated energy intake and expenditure. Dopamine (DA) has traditionally been recognized as a key regulator of reward-driven feeding. However, accumulating evidence indicates that its functions extend beyond hedonic eating. This review examines the central and peripheral actions of DA in obesity. It focuses on neuronal and receptor diversity, DA-related circuits, metabolic interactions, and responses to anti-obesity interventions.

Recent Findings

DA neurons and receptor subtypes exhibit substantial molecular, anatomical, and functional diversity. Obesity-related alterations in DA release, receptor function, and downstream signaling vary across brain regions and metabolic contexts. DA regulates food reward, feeding, physical activity, and thermogenesis through VTA-centered reward circuits, hypothalamus-centered feeding circuits, and central-peripheral metabolic pathways. These circuits interact with neuropeptides, neurotransmitter and neuromodulatory systems, and metabolic hormones. In peripheral tissues, local DA signaling regulates gastrointestinal motility, pancreatic hormone secretion, adipose tissue function, and skeletal muscle glucose utilization. Dietary adjustment, exercise, microbiome interventions, bariatric surgery, glucagon-like peptide-1 receptor (GLP-1R) agonists, and other DA-modulating agents may alter these pathways. However, direct evidence that DA modulation mediates their clinical effects remains limited.

Summary

Current evidence does not support a uniform pattern of dopaminergic (DAergic) dysfunction or a generalized reward-deficiency model in obesity. DA alterations vary across neural circuits, receptor subtypes, tissues, metabolic states, and feeding phases. Most human findings are associative, whereas mechanistic evidence is derived largely from animal models. It remains unclear whether DA alterations precede obesity or result from dietary exposure and metabolic dysfunction. The coordination between central and peripheral DA systems is also poorly defined. Longitudinal and mechanistically informed human studies are needed to identify clinically relevant DAergic biomarkers and therapeutic targets.

Introduction

Obesity arises from a disruption of energy-balance regulation. Its prevalence has increased markedly worldwide, with more than 890 million adults living with obesity in 2022 [1]. Evidence-based obesity management includes behavioral therapy, nutritional intervention, physical activity, pharmacotherapy, and metabolic or bariatric procedures [2]. However, achieving sustained weight loss remains difficult. Impaired neuronal responses to nutritional signals may contribute to excessive energy intake, while resistance to post-ingestive nutrient signals may persist after substantial weight loss and contribute to weight regain [3]. A better understanding of the neural mechanisms linking feeding, energy expenditure, and metabolic state is therefore needed.

The dopamine (DA) system has traditionally been investigated in obesity for its role in food reward and motivation. The mesolimbic pathway regulates reward-related feeding, the mesocortical pathway contributes to cognition and decision-making, and the nigrostriatal pathway supports motor function. Obesity is associated with altered organization of frontal-mesolimbic brain networks, and the magnitude of these alterations correlates with body mass index (BMI) and obesity severity [4]. Genetic and neuroimaging studies have also associated altered DA receptor availability and DA signaling with impaired reward sensitivity and self-regulation [5]. A single photon emission computed tomography study reported lower striatal DA D2/3 receptor (DRD2/3) availability and reduced DA release in obese women [6]. However, available studies have reported divergent patterns of DAergic dysfunction in obesity. Instead, obesity-related alterations appear to differ across neuronal populations, receptor subtypes, brain regions, metabolic conditions, and phases of feeding. These heterogeneous findings cannot be fully explained by a generalized reward-deficiency model.

Despite substantial progress, DAergic involvement in obesity has been studied predominantly in relation to reward-related feeding. Its contributions to other components of energy balance and metabolic regulation have received comparatively less attention. This review therefore examines the diversity and obesity-associated alterations of DA neurons, DA signaling, and receptor function. It then considers DA-related circuits involved in food reward, feeding regulation, physical activity, and thermogenesis; their interactions with neuropeptides, neurotransmitters, and metabolic hormones; and the local actions of DA in the gastrointestinal tract, pancreas, adipose tissue, and skeletal muscle. We further evaluate how dietary, behavioral, microbiome-based, surgical, and pharmacological interventions may modify DA-related pathways. Finally, we discuss whether the observed alterations reflect dietary exposure, adiposity, or metabolic dysfunction; how central and peripheral DA systems may be coordinated; and whether DA modulation contributes to treatment outcomes. By integrating human and animal evidence, this review aims to clarify the context-dependent involvement of DA in obesity and identify the major barriers to its clinical translation.

Central Effects of Dopaminergic (DAergic) Alterations on Food Reward and Energy Homeostasis

Central DA signaling coordinates food reward, feeding behavior, energy expenditure, and metabolic homeostasis. DAergic neuronal populations differ in their molecular profiles, anatomical distributions, and projection targets. DA receptor subtypes also exhibit distinct regional expression patterns and downstream signaling mechanisms. This heterogeneity supports the functional specialization of DAergic circuits. Obesity and metabolic dysfunction can alter DA neurons, DA transmission, and receptor function, thereby disrupting reward and metabolic regulation. These effects are mediated through ventral tegmental area (VTA)-centered reward circuits, hypothalamus-centered feeding circuits, and central-peripheral metabolic pathways. DA signaling is further shaped by interactions with neuropeptides, neurotransmitter and neuromodulatory systems, and metabolic hormones.

Diversity of DA Neurons and DA Receptors

DAergic neurons are predominantly localized in the ventral midbrain, specifically within the VTA and the substantia nigra pars compacta (SNc), as well as in the hypothalamus, with smaller populations distributed across other brain regions. Multiple DA neuronal subtypes have been identified [7, 8]. Anatomically, the primate ventral midbrain contains the A8, A9, and A10 DAergic cell groups [9]. The SNc and VTA contain several molecularly distinct DAergic populations. Neurons expressing aldehyde dehydrogenase 1 family member A1 (Aldh1a1) and sex-determining region Y-box transcription factor 6 (Sox6) are found mainly in the ventral SNc; within the VTA, vesicular gamma-aminobutyric acid transporter (Vgat)-expressing DA neurons are broadly distributed; orthodenticle homeobox 2 (Otx2)/Aldh1a1-expressing neurons are found mainly in the ventromedial VTA; vasoactive intestinal peptide (Vip)-expressing neurons are located caudally; vesicular glutamate transporter 2 (Vglut2)- and calbindin 1 (Calb1)-expressing populations are less clearly defined. Nevertheless, both populations participate in reward responses; Calb1-expressing neurons also contribute to reward-based associative learning [8, 10–12]. Addtionly, hypothalamic DA neurons correspond primarily to the A11, A12, A14, and A15 cell groups [13, 14]. Molecular heterogeneity has also been identified in the hypothalamus. Reported populations include tyrosine hydroxylase (Th)/growth hormone-releasing hormone (Ghrh)-expressing neurons and Th/prolactin receptor (Prlr)-expressing neurons in the arcuate region [15]. One cut homeobox 3 (Onecut3)/neuromedin U receptor 2 (Nmur2)-expressing DA neurons are found in the periventricular nucleus [16]. However, a unified molecular classification has not yet been established.

DA receptors are classified into two major families. The D1-like family comprises DA receptor D1 (DRD1) and DA receptor D5 (DRD5), whereas the D2-like family comprises DA receptor D2 (DRD2), DA receptor D3 (DRD3), and DA receptor D4 (DRD4) [17]. D1-like receptors are primarily located postsynaptically and are associated with Gs/Golf proteins, leading to an elevation in intracellular cyclic adenosine monophosphate (cAMP) levels and subsequent activation of protein kinase A (PKA) signaling pathways, which collectively enhance neuronal excitability. Conversely, postsynaptic D2-like receptors are linked with Gi/o proteins, resulting in the inhibition of adenylyl cyclase activity, a decrease in intracellular cAMP levels, and a general suppression of neuronal excitability.

Alterations in DAergic Neurons, DA Signaling, and Receptor Function in Obesity and Metabolic Dysfunction

Human Evidence

Genetic and epigenetic variation in the DA system may contribute to obesity susceptibility by altering reward processing and executive control. At the polygenic level, a multilocus composite score indicating high DA signaling capacity is associated with increasing BMI over time, possibly through enhanced reward responses to food cues [18]. Individual DA-related polymorphisms also influence prefrontal executive function. These effects vary by age and sex and are most pronounced in individuals with obesity [19]. Among individual variants, the catechol-O-methyltransferase Val/Val genotype has been linked to increased obesity risk, potentially through reward-driven eating [20]. Beyond inherited variation, DA-related methylation patterns may serve as obesity biomarkers, particularly in association with high carbohydrate intake [21]. Functional alterations in DA signaling have also been observed in humans. In people with obesity and prediabetes, striatal DA release fails to increase after a satiating meal but remains responsive to high-calorie food cues, indicating impaired satiety-dependent modulation of DA signaling that may promote excessive energy intake [22]. As the primary mediator of DA reuptake into presynaptic terminals, the DA transporter (DAT) regulates extracellular DA availability and signaling duration. However, striatal DAT availability is generally unrelated to BMI or food craving, whereas impaired DAT function appears to be associated with established obesity [23–26]. This pattern suggests that DAT dysfunction may be a consequence rather than a primary cause of obesity.

Human evidence linking D1-like receptors to obesity and metabolic dysfunction is currently lacking, whereas human studies have primarily focused on associations between D2-like receptors and obesity-related phenotypes. Positron emission tomography studies of DRD2/3 availability have produced heterogeneous findings, including increased availability in some reward-related regions and no detectable alteration in striatal DRD2 binding in other studies [27]. Striatal and midbrain DRD2 binding has also been positively associated with emotional eating [28]. The relationship between DRD2/3 availability and BMI may vary with age: no association has been observed in individuals younger than 30 years, whereas a positive association has been reported in those older than 30 years [29]. Pharmacological evidence further suggests that DRD3 contributes to food-cue processing, as DRD3 antagonism reduces approach preference toward food-related reward cues in individuals with obesity [30]. Genetic findings indicate that DRD2-related Taq1A and mu-opioid receptor A118G variants may interact to increase susceptibility to hedonic eating in individuals with obesity and binge-eating disorder [31]. DRD4-related genetic findings also indicate age- and sex-dependent associations. Young adults with the DRD4 4/4 genotype generally have a lower mean BMI [32]. In girls, lower genotype-predicted prefrontal DRD4 expression is associated with reduced activation of appetite-related circuits in response to high-energy food cues, whereas this association is minimal in boys [33].

Animal Evidence

Aberrant DA neuron function is associated with obesity [34]. Exposure to a high-fat diet (HFD) can induce region-specific changes in DA neuronal function. VTA neurotensin receptor 1 (Ntsr1)-expressing DA neurons are linked to out-of-phase feeding during HFD exposure [35]. In female mice, HFD-induced inflammation and glial cell activation in the VTA impair DA neuron function and cause abnormal eating behaviors accompanied by insulin resistance in the VTA [36]. Molecularly, activation of Toll-like receptor 4 in VTA DA neurons enhances DA release through the PKA/cAMP response element-binding protein (CREB) pathway, increases TH expression, and promotes food-reward behavior [37]. Direct evidence for obesity- or HFD-induced functional alterations in SNc DA neurons are currently lacking. Evidence for altered excitability of hypothalamic DA neurons is also limited. One study reported that paraventricular hypothalamic DA neurons show increased activity and TH expression, and their activation prolongs feeding and promotes obesity progression [38]. Accordingly, it remains unclear whether and how the molecularly defined DA neuronal subtypes described above are differentially affected in obesity.

In mice, high-fat feeding impairs DA terminal function and adaptive plasticity in a time- and dose-dependent manner [39]. Diet-induced inflammation and insulin resistance impair DA function, sensitize stress-related pathways, and promote stress-induced eating [40]. The effects of stress on DAergic reward processing, however, appear to vary with the nature of the stressor. Mild stress reduces motivation for palatable food by attenuating the DA response to food rewards in the nucleus accumbens (NAc) shell [41].

Animal studies have also identified obesity-related alterations in DA receptor expression and function. In diet-induced obese rats, DRD1 expression is increased in the cingulate cortex and caudate-putamen [42]. Within the NAc, DRD1 signaling is associated with overeating in obesity-prone rats and modulates motivation for exercise reward [43, 44]. D1-like receptors also contribute to stress-induced food seeking, with chronic stress reinstating food seeking through D1-like receptor signaling in male but not female animals [45]. Moreover, blocking D1-like receptors during restraint stress prevents stress-induced alterations in DAergic transmission and attenuates the subsequent increase in food-seeking behavior [46]. As has been confirmed, DRD1- and DRD2-expressing neurons in the NAc core exert opposing effects on feeding and physical activity [47]. Obesity- and diet-related changes in DRD2 are shaped by both the brain region examined and the duration and nature of dietary exposure. Even short-term HFD exposure can weaken central insulin receptor signaling and reduce DRD2 availability, disrupting cognitive and reward processes involved in hedonic feeding [48]. In diet-induced obese rats, DRD2 expression is elevated in the caudate-putamen, ventromedial hypothalamus, NAc core, and lateral hypothalamus [42]. Conversely, repeated exposure to high-fat food reduces DRD2 expression and sensitivity, impairs DAergic signaling, and activates the cAMP/PKA/CREB pathway, thereby promoting compulsive eating [49]. DRD2 signaling exerts region-specific effects on feeding behavior. Chronic stress increases DRD2 levels in the NAc and may increase susceptibility to food addiction [50]. In the amygdala, DRD2 activation suppresses food intake and behavioral responses to sucrose in rats [51]. In addition to functioning independently, DRD1 and DRD2 can form D1-D2 receptor heteromers [52]. These heteromers are expressed throughout the striatum, including the caudate nucleus, putamen, and both the core and shell of the NAc [53]. These heteromers also contribute to addiction-related processes [54]. Their activation enhances cyclin-dependent kinase 5-Thr75-DA- and cyclic-AMP-regulated phosphoprotein of 32 kDa signaling while suppressing extracellular signal-regulated kinase activation and ΔFosB accumulation. Functionally, D1-D2 receptor heteromer activation reduces sucrose intake and the motivation to seek and consume palatable food [55]. These obesity-related alterations in DA neurons, signaling, and receptors in animal models are shown in Fig. 1.

Fig. 1.

Obesity-associated alterations in central dopaminergic systems in animal models. The figure was created by Figdraw (ID: YOOYR82554). (A) Dopaminergic neurons. HFD recruits VTA Ntsr1-expressing DA neurons and induces VTA inflammation and glial activation, impairing DA neuronal function and causing abnormal eating accompanied by VTA insulin resistance. TLR4-PKA/CREB signaling increases TH expression and DA release, thereby enhancing food-reward behavior. Increased activity and TH expression in paraventricular hypothalamic DA neurons prolong feeding and promote obesity progression. (B) Dopamine signaling. High-fat feeding impairs DA terminal function and adaptive plasticity, whereas diet-induced inflammation and insulin resistance disrupt DA function and sensitize stress-related pathways. Mild stress attenuates food reward-evoked DA responses in the NAc shell, reducing motivation for palatable food. (C) Dopamine receptors. Obesity, dietary exposure, and stress produce region-, sex-, and exposure-dependent alterations in D1-like receptor and DRD2 expression and function, influencing overeating, food seeking, hedonic and compulsive eating, and susceptibility to food addiction. Activation of striatal D1-D2 receptor heteromers enhances Cdk5-mediated phosphorylation of DARPP-32 at Thr75, suppresses ERK activation and ΔFosB accumulation, and reduces sucrose intake and motivation for palatable food. CREB cAMP response element-binding protein, DA dopamine, DARPP-32 dopamine- and cAMP-regulated phosphoprotein of 32 kDa, DRD1 dopamine receptor D1, DRD2 dopamine receptor D2, ERK extracellular signal-regulated kinase, HFD high-fat diet, NAc nucleus accumbens, Ntsr1 neurotensin receptor 1, PKA protein kinase A, TH tyrosine hydroxylase, TLR4 Toll-like receptor 4, VTA ventral tegmental area

DAergic Circuits Regulating Food Reward and Energy Expenditure

VTA-Centered DAergic Reward Circuits

The VTA-NAc pathway constitutes a core mesolimbic circuit regulating reward valuation, food motivation, and hedonic feeding. Distinct NAc subregions exert opposing effects on VTA DA neurons. Medial NAc shell neurons directly inhibit VTA DA neurons through γ-aminobutyric acid (GABA)-mediated signaling, thereby reducing motivation, whereas lateral NAc shell neurons inhibit VTA GABAergic neurons and consequently disinhibit VTA DA neurons, enhancing reward and motivation [56]. The VTA-NAc circuit is also shaped by local lipid signaling and early nutritional exposure. N-acyl phosphatidylethanolamine-specific phospholipase D maintains N-acylethanolamine homeostasis and restrains DA release within the VTA-NAc circuit, thereby regulating food-reward seeking, feeding behavior, energy expenditure, and susceptibility to HFD-induced obesity [57].

VTA DA neurons also integrate hypothalamic signals linking metabolic state to food reward. The lateral hypothalamus (LH) provides substantial input to VTA DA neurons and participates in the evaluation of food reward [58]. Pituitary adenylate cyclase-activating polypeptide-expressing neurons in the ventromedial hypothalamus synapse onto and inhibit reward-encoding A10 DA neurons in the VTA, suppressing hedonic eating [59]. Stress strengthens glutamatergic synapses from the LH onto VTA DA neurons, thereby increasing reward-related DA signaling and promoting palatable food consumption [60]. In leptin-deficient ob/ob mice, increased orexin-A release from the LH activates orexin receptor-1 on VTA DA neurons and induces 2-arachidonoylglycerol/cannabinoid receptor type 1 (CB1R)-mediated inhibition of GABAergic inputs. The resulting enhancement of VTA-NAc DA signaling is accompanied by DRD2 desensitization in the NAc [61].

Additionly, activation of calcitonin receptors on VTA GABAergic interneurons inhibits VTA-to- medial prefrontal cortex DAergic signaling and reduces food-evoked DA release in the medial prefrontal cortex, thereby suppressing palatable-food intake and food-directed impulsivity [62]. VTA DA neurons further integrate cortical, habenular, and post-ingestive inputs. Activation of the anterior insular cortex-VTA circuit increases reward cue-induced DA release and reinforces reward-associated contextual memories [63]. The habenula regulates VTA DA neuron activity through cholinergic inputs, whereas chronic nicotine exposure disrupts this regulatory pathway and increases motivation for food rewards [64]. Furthermore, VTA DA neurons project to DRD1-expressing GABAergic neurons in the SCN, where increased DA signaling enhances local inhibition, reduces overall SCN excitability, and promotes out-of-phase HFD consumption and obesity [65].

DA-Related Hypothalamus-Centered Feeding Circuits

Beyond VTA-centered reward pathways, DA interacts with hypothalamus-centered circuits and their connections with other brain regions to regulate meal initiation, food motivation, and the temporal organization of feeding. In the arcuate nucleus (ARC), DA activates DRD1-expressing neurons that provide both excitatory and inhibitory inputs to agouti-related peptide (AgRP)/neuropeptide Y neurons. These DRD1-expressing neurons are themselves inhibited by leptin, enabling the circuit to integrate DAergic and satiety signals in the regulation of food intake [66]. DAergic input acting through DRD2 cooperates with local GABAergic inhibition of dorsal raphe nucleus (DRN) 5-hydroxytryptamine neurons, thereby regulating the DRN-to-ARC serotonergic circuit that initiates feeding [67]. At the interface between reward and homeostatic feeding systems, NAc shell Serpinb2-expressing neurons project to leptin receptor-expressing GABAergic neurons in the LH, promoting food motivation and consumption [68].

DA-Related Central-Peripheral Metabolic Circuits

Central DAergic signaling contributes to energy expenditure through the autonomic nervous system. DA released from the posterior hypothalamus activates DRD2 in the rostral raphe pallidus, reducing sympathetic stimulation of brown adipose tissue (BAT) and suppressing thermogenesis [69]. In contrast, activation of DRD2-expressing GABAergic neurons in the LH and adjacent zona incerta enhances orexin and cAMP/PKA signaling, thereby increasing sympathetic activity and BAT thermogenesis [70]. DRD2 activation suppresses LHb-driven sympathetic outflow to BAT, thereby attenuating emotion-induced BAT thermogenesis [71]. Conversely, LHb-mediated inhibition of VTA DA neurons may promote BAT thermogenesis by relieving tonic VTA-mediated inhibition of thermogenic sympathetic output [72].

Experimental manipulation of DAergic neurons further demonstrates their region-specific metabolic effects. Substantia nigra lesions enhance BAT thermogenesis by reducing paraventricular DRD2 expression and increasing brain-derived neurotrophic factor signaling [73]. Forkhead box O1 deletion in substantia nigra and VTA DA neurons increases energy expenditure, BAT thermogenesis, and insulin sensitivity [74]. In male mice, enhanced dorsomedial ARC DAergic activity reduces peripheral sympathetic activity, thermogenic futile cycling, and energy expenditure, ultimately promoting age-related obesity under non-obesogenic conditions [75]. The major VTA-centered, hypothalamus-centered, and central-peripheral DAergic circuits described above are described in Fig. 2.

Fig. 2.

Major Dopaminergic Circuits Involved in Feeding and Energy Expenditure. The figure was created using Figdraw (ID: TOWOId79cb). (A) VTA-centered reward circuits showing connections of the VTA with the NAc shell, LH, VMH, mPFC, and SCN. (B) Hypothalamus-centered feeding circuits involving the DRN–ARC and NAc shell–LH circuits. (C) Central-peripheral metabolic circuits linking the PH, rRPa, PVN, ARC, SN, LHb, VTA, LH, and ZI to sympathetic outflow. ARC arcuate nucleus, DRN dorsal raphe nucleus, LH lateral hypothalamus, LHb lateral habenula, mPFC medial prefrontal cortex, NAc nucleus accumbens, PH posterior hypothalamus, PVN paraventricular nucleus, rRPa rostral raphe pallidus, SCN suprachiasmatic nucleus, SN substantia nigra, VMH ventromedial hypothalamus, VTA ventral tegmental area, ZI zona incerta

Interactions of DA and its Receptors with Other Metabolic Regulatory Networks

Interactions with Neuropeptides

Interactions between DA receptors and hypothalamic melanocortin signaling link homeostatic energy sensing to reward-related feeding. DRD1 signaling in AgRP neurons facilitates foraging and consumption of high-fat food, serving as an integrator of hedonic and homeostatic feeding circuits in response to energy-dense diets [76]. By contrast, Drd2-expressing pro-opiomelanocortin neurons in the ARC suppress feeding and participate in the regulation of core body temperature [77]. Melanocortin signaling from pro-opiomelanocortin neurons activates melanocortin 3 receptor on VTA DA neurons, thereby enhancing DA signaling and motivation for palatable food rewards [78]. In the bed nucleus of the stria terminalis, a hub involved in food-reward processing, melanocortin 4 receptor and DRD2 jointly regulate food motivation and intake [79].

Hypothalamic orexin and pituitary adenylate cyclase-activating polypeptide (PACAP) signaling exert distinct effects on DAergic reward circuits. Hypothalamic orexin neurons integrate stress- and reward-related information and adjust behavioral responses to changing environmental demands [80]. DA, in turn, modulates excitatory input to orexin neurons in a concentration-dependent manner, enhancing it through DRD1 at low concentrations but inhibiting it through DRD2 at high concentrations [81]. Orexin released from the LH further modulates VTA DA neuron activity [82]. In contrast, at the receptor and cellular levels, PACAP activates PACAP type 1 receptors and ATP-sensitive potassium channels in A10 VTA DA neurons, suppressing neuronal firing, reward signaling, and binge-like eating [83, 84].

Interactions with Neurotransmitter and Neuromodulatory Systems

DA function is modulated through interactions with opioid, endocannabinoid, and serotonergic systems. Within the VTA, µ-opioid receptors disinhibit DA neurons by suppressing GABAergic inputs, thereby promoting reward seeking [82, 85]. In contrast, κ-opioid receptors inhibit DA neurons and promote aversive responses [86]. Obesity-associated lipoinflammation disrupts DAergic and opioid signaling within brain reward circuits. These alterations increase motivation and impulsivity toward palatable food while diminishing normal reward sensitivity [87].

The endocannabinoid system modulates DA signaling by regulating synaptic inputs to DA neurons. It also regulates serotonin release and thereby influences reward, mood, and motivation [88]. In the VTA, presynaptic CB1R regulate neurotransmitter release from both excitatory and inhibitory terminals onto DA neurons [89]. CB1R-mediated suppression of GABAergic transmission disinhibits VTA DA neurons and enhances mesolimbic DA signaling [61].

DA also interacts bidirectionally with the serotonergic system to regulate food intake. Low-frequency firing of VTA DA neurons suppresses DRN 5-hydroxytryptamine neurons through DRD2 and promotes hyperphagia. In contrast, high-frequency firing activates these neurons through DRD1 and suppresses food intake [90].

Interactions with Metabolic Hormones

Insulin interacts with central DAergic pathways to regulate DA release, food motivation, and reward-related feeding. Insulin enhances striatal DA release by activating cholinergic interneurons, which subsequently stimulate nicotinic acetylcholine receptors on DA axons [91]. Central insulin signaling also modulates striatal DAergic tone and mesocorticolimbic activity, linking metabolic status to reward regulation and whole-body metabolism [92]. Its behavioral effects depend on the site of action. Insulin delivery into the VTA reduces hedonic eating and preference for food-reward cues without decreasing the effort exerted to obtain food; in contrast, delivery into the NAc core reduces food intake by diminishing food motivation [93]. Disruption of brain insulin signaling broadly impairs DAergic function [94].

Ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous antagonist of the ghrelin receptor growth hormone secretagogue receptor 1a, exert opposing effects on DAergic reward signaling. Ghrelin activates the mesolimbic DA system by increasing nitric oxide production in the VTA, thereby stimulating DA release in the NAc and supporting reward-related behavior [95]. It also recruits endocannabinoid signaling to enhance VTA DA neuron activity, food motivation, and consumption [96]. Conversely, LEAP2 antagonizes GHSR1a and counteracts ghrelin signaling. Central administration of LEAP2 reduces reward-driven food intake and palatable-food-associated memory by decreasing DA release in the NAc and weakening the reward response to palatable food [97].

Leptin and amylin modulate DAergic circuits involved in food reward, locomotor activity, and energy balance. Leptin activates leptin receptor-expressing SNc DA neurons and increases DA signaling to the striatum. This response indirectly activates SNr GABAergic neurons through DRD1 and transient receptor potential canonical 3 channels and promotes locomotor activity, providing a mechanism through which metabolic signals can coordinate energy status with motor output [98]. During food restriction, leptin reduces the motivational value of reward-predictive cues and inhibits the associated firing of midbrain DA neurons, although it does not alter feeding behavior [99]. Amylin also modulates reward-related DAergic signaling. Amylin receptor activation in the VTA inhibits DA signaling to the NAc core and reduces DRD1 and DRD2 activation. These effects decrease palatable-food intake and promote weight loss [100]. The interactions of DA signaling with neuropeptides, neurotransmitter and neuromodulatory systems, and metabolic hormones are depicted in Fig. 3.

Fig. 3.

Interactions of dopamine with metabolic regulatory networks. The figure was created by Figdraw (ID: UTTWUdd5a0). (A) Neuropeptide interactions. DRD1 signaling in AgRP neurons and melanocortin signaling through MC3R on VTA DA neurons enhance motivation for palatable food. DA bidirectionally regulates orexin neurons in a concentration- and receptor-dependent manner, whereas orexin and PACAP exert opposing effects on VTA DA neuronal activity and reward-related feeding. (B) Neurotransmitter and neuromodulatory interactions. µ-opioid receptors and CB1R disinhibit VTA DA neurons by suppressing GABAergic inputs, thereby enhancing DA signaling and reward seeking, whereas κ-opioid receptors inhibit DA neurons and promote aversive responses. Low-frequency VTA DA neuronal firing inhibits DRN 5-HT neurons through DRD2 and promotes hyperphagia, whereas high-frequency firing activates these neurons through DRD1 and suppresses food intake. (C) Metabolic hormone interactions. Insulin, ghrelin, LEAP2, leptin, and amylin convey metabolic-state information to DA circuits. Their region-specific actions regulate DA neuronal activity and DA release in the striatum and NAc, thereby influencing food motivation, hedonic and reward-driven eating, locomotor activity, and energy balance. AgRP agouti-related peptide, CB1R cannabinoid receptor type 1, DA dopamine, DRD1 dopamine receptor D1, DRD2 dopamine receptor D2, GABA γ-aminobutyric acid, 5-HT 5-hydroxytryptamine, LEAP2 liver-expressed antimicrobial peptide 2, MC3R melanocortin 3 receptor, NAc nucleus accumbens, PACAP pituitary adenylate cyclase-activating polypeptide, VTA ventral tegmental area

Effects of DA on Peripheral Metabolic Tissues

Peripheral DA exerts tissue-specific and, in some cases, opposing metabolic effects. Its availability and effects are shaped by local DA sources, receptor distribution, target-cell identity, and the metabolic state of each tissue. Consequently, the same transmitter may exert distinct or even opposing effects across peripheral organs. This heterogeneity is particularly relevant to obesity, because an alteration observed in one tissue cannot be assumed to represent the direction or metabolic consequence of DA signaling in another. The following sections examine these organ-specific mechanisms in the gastrointestinal tract, pancreas, adipose tissue, and skeletal muscle, as summarized in Fig. 4.

Fig. 4.

Peripheral metabolic actions of dopamine. The Figure was created by Figdraw (ID: IAYUR6b9e4). (A) Gastrointestinal tract. DA derived from gastrointestinal cells, enteric neurons, immune cells, and the gut microbiota regulates smooth-muscle activity, mucosal permeability, mucus and bicarbonate secretion, enteric neurotrophic signaling, and intestinal motility through D1- and D2-like receptors. Nutrient sensing also engages vagal gut-brain pathways that promote DA release and reward-driven overeating. (B) Pancreas. Locally produced DA provides autocrine feedback that limits glucose-stimulated insulin secretion through DRD2, D1-D2 receptor heteromers, and adrenergic receptors. DA also regulates glucagon secretion through α2A- and β-adrenergic receptor pathways. (C) Adipose tissue. DRD1 and DRD5 promote lipolysis, adipose browning, mitochondrial activity, and thermogenesis, whereas DRD4 suppresses UCP1-dependent thermogenesis. DRD2-mediated effects vary across receptor context and adipose depot. (D) Skeletal muscle. DA generated from circulating L-DOPA regulates glucose uptake through DRD1 and AMPK signaling through DRD2. DRD4 inhibition enhances heat production. Central DA availability is also associated with skeletal-muscle mitochondrial ATP-production capacity. AMPK AMP-activated protein kinase, DA dopamine, DRD1 dopamine receptor D1, DRD2 dopamine receptor D2, DRD4 dopamine receptor D4, DRD5 dopamine receptor D5, L-DOPA L-3,4-dihydroxyphenylalanine, UCP1 uncoupling protein 1

Gastrointestinal Tract

Gastrointestinal DA is primarily derived from specific gastrointestinal cells, the enteric nervous system, immune cells, and the gut microbiota [101, 102]. Locally available L-DOPA can be converted into DA by aromatic L-amino acid decarboxylase expressed in gastrointestinal cells, thereby providing an important source of locally synthesized DA. DA modulates gastrointestinal motility by activating D1-like receptors, which promote relaxation, and D2-like receptors, which inhibit motility, through effects on smooth-muscle contractility along the gastrointestinal tract [103]. However, the direction and mechanism of these effects vary across species, intestinal regions, and smooth-muscle layers. In the human colon, DA induces contraction of the circular muscle layer through non-neural D1-like receptors coupled to the phospholipase C/inositol 1,4,5-trisphosphate pathway, whereas it promotes relaxation of the longitudinal muscle layer through D2-like receptor-mediated enhancement of K+ conductance [104]. In mice, DA inhibits colonic peristalsis by directly suppressing the spontaneous activity of circular smooth muscle through D2-like receptors and by reducing cholinergic transmission via intestinal nitrergic and purinergic pathways through D1-like receptor activation [105].

DA contributes to gastrointestinal barrier-related physiology with divergent segment-specific effects. It increases duodenal epithelial permeability via DRD5 signaling, whereas it promotes distal colonic mucus secretion through DRD5-dependent pathways to sustain colonic mucosal integrity [106, 107]. DA derived from gastric parietal cells promotes bicarbonate secretion in the duodenum through apical DRD2 activation, protecting the intestinal mucosa from acid-related injury [108]. DA also differentially regulates enteric neurotrophic signaling. Low concentrations promote glial cell line-derived neurotrophic factor secretion through DRD1 activation on cholinergic neurons, whereas high concentrations suppress glial cell line-derived neurotrophic factor secretion through DRD2-dependent mechanisms [109].

Altered DA metabolism can further disrupt intestinal neural regulation. Reduced DAT function increases extracellular DA availability and enhances DRD1-mediated responses while simultaneously weakening cholinergic transmission and altering tachykininergic and glutamatergic pathways, ultimately affecting intestinal motility [110]. In addition, nutrient-derived signals from dietary fats and sugars are sensed through vagus nerve-mediated gut-brain circuits, promoting DA release and potentially reinforcing reward-driven overeating [111].

Pancreas

In addition to DA produced by peripheral sympathetic neurons, pancreatic α cells possess the molecular machinery required for catecholamine biosynthesis and can locally produce DA within the pancreas [112]. β cells secrete and bind DA in situ in response to glucose stimulation [113]. DA stored and released with insulin granules subsequently binds to DRD2 on β cells and inhibits glucose-stimulated insulin secretion, forming an autocrine negative-feedback mechanism [114]. Consistent with this inhibitory function, β-cell-specific DRD2 ablation in mice disrupts the regulation of insulin secretion and results in postprandial hyperinsulinemia in vivo [115]. DA can also transiently suppress insulin secretion by activating D1-D2 receptor heteromers, which reduce glucose-stimulated Ca²⁺ influx and insulin granule exocytosis [116].

Pancreatic DA also regulates endocrine secretion through several DAergic and adrenergic receptor mechanisms. This DRD2-mediated inhibition involves suppression of voltage-dependent calcium channels and activation of potassium channels, which reduce Ca²⁺ influx and insulin secretion [117]. Bromocriptine, a DRD2 agonist, suppresses cAMP production through DRD2 and α2A-adrenergic receptor activation, thereby reducing insulin secretion and glucagon release [118]. In addition, DA inhibits insulin secretion through α2A-adrenergic receptors while promoting glucagon secretion from α cells through β-adrenergic receptor pathways [112]. Together, these findings indicate that pancreatic DA acts through DAergic and adrenergic receptors to regulate insulin and glucagon secretion.

Adipose Tissue

DA may reach adipose tissue through the circulation or be released locally from sympathetic nerve endings and infiltrating immune cells, including lymphocytes and macrophages [119, 120]. Within adipose tissue, DA regulates thermogenesis, browning, lipid metabolism, insulin sensitivity, and inflammatory signaling through distinct receptor subtypes. D1-like and D2-like receptor signaling also modulates the release of pro-inflammatory cytokines [121].

D1-like receptors generally promote catabolic and thermogenic processes in adipose tissue. In brown adipocytes, D1-like receptor activation stimulates p38 mitogen-activated protein kinase signaling, increases mitochondrial mass, and upregulates thermogenic markers, including uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, thereby increasing oxygen consumption and energy expenditure [122]. However, repeated peripheral administration of the D1-like receptor agonist SKF38393 produces only transient BAT activation, indicating that its thermogenic effect diminishes with repeated administration [123]. DRD1 is also highly expressed in white adipose tissue, where it promotes catabolic activity, reduces lipotoxicity, and improves insulin sensitivity [124]. Mechanistically, DRD1 activation promotes lipolysis through the cAMP/PKA/hormone-sensitive lipase pathway and induces browning through the cAMP/PKA/p38 mitogen-activated protein kinase/ peroxisome proliferator-activated receptor gamma coactivator 1-alpha /UCP1 axis [125]. DRD1 additionally cooperates with β3-adrenergic signaling to promote adipocyte browning and UCP1-independent thermogenesis [126]. Another D1-like receptor, DRD5, shows time-dependent changes in mouse adipose tissue, with increased expression detected only after prolonged obesity [127]. DRD5 promotes adipose browning through cAMP/PKA/p38 mitogen-activated protein kinase signaling and induces futile Ca²⁺ cycling through the cAMP/sarco/endoplasmic reticulum Ca²⁺-ATPase /ryanodine receptor pathway, whereas DRD5 deficiency favors adipogenesis [128].

D2-like receptor effects differ across receptor subtypes and adipose depots. DRD2 activation enhances insulin-mediated glucose uptake in mesenteric adipose tissue, whereas DRD2 inhibition activates AMP-activated protein kinase signaling and promotes lipid catabolism in epididymal adipose tissue [129]. Increased adipose DRD2 expression has also been associated with hyperglycemia and type 2 diabetes [130]. Another D2-like receptor, DRD4, negatively regulates UCP1-dependent thermogenesis, whereas DRD4 inhibition promotes adipose browning [131].

Skeletal Muscle

Skeletal muscle lacks dedicated DAergic innervation, and local DA is generated from circulating L-3,4-dihydroxyphenylalanine through aromatic L-amino acid decarboxylase-mediated conversion [120, 132]. Non-shivering thermogenesis in skeletal muscle has emerged as a potential mechanism for increasing energy expenditure and relies largely on sarco/endoplasmic reticulum Ca²⁺-ATPase -mediated futile Ca²⁺ cycling for heat production [133]. Blocking DRD4 increases ATP-consuming heat production, indicating that endogenous DRD4 signaling restrains muscle thermogenesis [131]. Peripheral DA also influences skeletal muscle metabolism by activating AMP-activated protein kinase signaling through DRD2 and promoting glucose uptake through DRD1 [129]. Central DA signaling may additionally be related to peripheral muscle metabolism. In older adults, higher DA levels in limbic striatal regions are associated with greater mitochondrial ATP-production capacity in skeletal muscle following repeated contractions, suggesting a relationship between central DAergic activity and peripheral metabolic adaptation [134].

Modulation of DA System by Anti-Obesity Interventions

The involvement of DA in reward processing, motivation, energy use, and metabolism makes it an attractive target for obesity management. However, obesity-related DA changes are complex, involving multiple circuits, receptors, and tissues. Current strategies aim to restore DA balance through diet, exercise, microbiome, bariatric surgery and pharmacotherapy.

Dietary Adjustment

Dietary composition can modify mesolimbic DA signaling independently of total caloric intake. Compared with diets rich in saturated fat, a diet enriched in unsaturated fat preserves DA release and uptake in the NAc [135]. An olive oil-based diet activates brain proliferator-activated receptor alpha signaling and modifies the gut microbiota, suppressing VTA DA reward pathways and reducing food intake and weight gain during high-fat feeding [136]. The rice-derived compound γ-oryzanol inhibits DNA methyltransferase activity and restores striatal DRD2 expression, thereby reducing preference for a HFD [137]. These findings suggest that dietary fat quality and specific bioactive components can influence DA-related reward processing.

Caloric and food restriction also alter DAergic responses to food. Caloric restriction increases the responsiveness of mesolimbic DA neurons to rewarding foods [138]. Switching from a high-fat to a low-fat diet increases κ-opioid receptor sensitivity in the NAc, suppressing DA release and potentially heightening cravings for high-calorie foods [139]. Chronic food restriction increases TH protein expression but reduces TH activity, potentially limiting DA synthesis despite increased enzyme abundance [140]. It also enhances striatal DAergic responsiveness by increasing DRD1-mediated c-Fos expression and D2/Gi coupling efficiency, resulting in behavioral and transcriptional hypersensitivity [141].

The effects of dietary restriction further depend on the nutrient being restricted. Chronic protein restriction lowers sucrose-reward motivation by reducing DA release and neuronal activation, thereby decreasing incentive and consumption [142]. Conversely, fat restriction raises DA levels, reduces receptor binding, and attenuates neural responses to food cues, accompanied by greater cravings for foods high in fat and carbohydrates and reduced adherence to a low-fat diet [143]. Thus, the DAergic response to dietary intervention is determined by diet composition, the specific nutrient restricted, and the duration and severity of restriction. An overview of these dietary interventions is provided in Table 1.

Table 1.

Effects of dietary composition and restriction on DAergic signaling and food-related behavior

Subjects	Diet	Methods	Results	References
Male C57BL/6 mice	Diet high in unsaturated fats	Mice were fed a diet high in unsaturated fat from flaxseed oil (3:7 ratio of saturated fats to n3 polyunsaturated fats) and kept on this diet for 6 weeks.	Maintained DA release and uptake with reduced weight gain	[135]
Male C57BL/6J mice	HFD containing olive oil	Mice were placed on isocaloric HFD containing 17% olive oil, 14.7% lard, and 3.3% soybean oil for 7 weeks. The HFD provided 60% of total calories from fat.	Blocked VTA DA reward pathways, reduced food intake and decreased weight gain	[136]
Male C57BL/6J mice	HFD with γ-oryzanol	Over 12 weeks, mice were fed a HFD supplemented with 0.4% γ-oryzanol, corresponding to an estimated intake of approximately 320 µg/g body weight.	Suppressed DNA methyltransferase function, reestablished striatal DRD2 levels and attenuated HFD preference	[137]
Male C57BL/6 mice	Dietary switch from HFD to standard diet	Mice were switched from a HFD to a standard laboratory diet at 10 weeks of age and maintained on the standard laboratory diet for 4 weeks before testing at 14 weeks of age.	Sensitized DA neurons and increased HFD preference	[138]
C57BL/6 mice	HFD followed by low-fat control diet	Mice were fed a HFD containing 60% kcal from fat (5.24 kcal/g) for 6 weeks. The HFD was then replaced with a control diet containing 10% kcal from fat (3.85 kcal/g) for 1 day or 1 week.	Inhibited DA release and reduced intake of non-preferred foods	[139]
Male Sprague-Dawley rats	Chronic food restriction	Rats received daily 10 g of Purina rat chow. After body weight fell by 20–25%, daily rations were titrated to maintain this reduced weight for an additional 7–14 days prior to sacrifice.	Elevated TH levels, reduced TH activity and decreased DA synthesis	[140]
Male Sprague–Dawley rats	Chronic food restriction	Each day, 10 g of Purina rat chow was given to the rats until their body weight decreased by 20%.	Enhanced DAergic responses	[141]
Male C57Bl/6J mice	Dietary protein restriction	Mice maintained on low-protein high-carbohydrate diet (4 kcal% protein, 74 kcal% carbohydrate) for approximately 5 weeks.	Reduced DA release and neuronal activation, diminished sucrose palatability, removal of the conditioned place preference for sucrose and reduced sucrose intake	[142]
Participants	Dietary fat restriction	Participants received a standard diet consisting of 50% carbohydrates, 35% fat, and 15% protein for 5 days to maintain body weight. They were then switched to a fat-reduced diet for 6 days with 30% of baseline calories removed.	Enhanced tonic DA levels and increased preference for high-fat and high-carbohydrate foods	[143]

DA dopamine, DAergic dopaminergic, DRD2 dopamine receptor D2, HFD high-fat diet, TH tyrosine hydroxylase, VTA ventral tegmental area

Exercise

Exercise modifies DA-related reward processing in a manner that depends on exercise modality and intensity. Moderate-intensity treadmill exercise enhances DAergic plasticity in the VTA-NAc pathway, shifts food preference, and improves insulin sensitivity [144]. Treadmill running also attenuates susceptibility to obesity and metabolic complications associated with DRD2 deficiency [145]. Aerobic exercise enhances insulin signaling through the protein kinase B/glycogen synthase kinase 3 beta pathway and increases DA levels in the NAc, thereby modifying food-reward processing [146]. In female mice, moderate-intensity aerobic exercise similarly improves NAc DA signaling and reward sensitivity, although these changes do not necessarily prevent weight gain [147]. Passive swinging exercise increases DA production in rats and may limit weight gain through DA receptor-dependent metabolic signaling [148]. High-intensity interval training also alters DAergic signaling, accompanied by increased DRD2 expression [149].

Exercise additionally engages peripheral metabolic and neuroimmune pathways involving DA. It improves skeletal muscle insulin sensitivity by restoring DRD1 signaling through oxidative stress-dependent regulation of G protein-coupled receptor kinase 4 [150]. Moderate-intensity swimming suppresses tumor necrosis factor-mediated inflammation through subdiaphragmatic vagus nerve-dependent DA release and subsequent activation of splenic DRD1 [151]. These findings suggest that exercise-related DA signaling extends beyond reward circuits to peripheral metabolic and immune regulation.

DA signaling may also influence exercise capacity and individual responses to training. Central DRD1 regulates exercise endurance by selectively modifying neuronal activation in the median preoptic nucleus, paraventricular nucleus, and supraoptic nucleus without affecting thermoregulation [152]. In healthy sedentary individuals, lower baseline DAergic tone was associated with greater fat loss and muscle gain following exercise [153]. Therefore, improvements in DA signaling after exercise do not necessarily translate into weight loss, while baseline DAergic tone may partly explain individual differences in training outcomes. The exercise-related findings are presented in Table 2.

Table 2.

Effects of exercise on DAergic signaling and food-related behavior

Subjects	Exercise	Methods	Results	References
Male C57BL/6J mice	Moderate-intensity treadmill running	Obese mice underwent moderate-intensity treadmill running with 0° incline for 8 consecutive weeks, 5 days per week. Training was conducted once daily and each daily session began with 10 min of running at 8 m/min, followed by 30 min at 12 m/min, and ended with a final 10 min at 13 m/min.	Boosted DAergic plasticity, reduced preference for HFD and increased preference for sucrose and milk	[144]
C57BL/6J mice	Treadmill running	Mice underwent treadmill training 5 days per week for 10 weeks. Each session consisted of 5 min at 8 m/min, followed by 40 min at 12 m/min and 5 min at 8 m/min.	Reduced HFD-induced weight gain, alleviated HFD-induced metabolic complications and increased locomotor activity	[145]
Male Sprague-Dawley rats	Aerobic exercise	Obese rats were subjected to moderate-intensity aerobic treadmill running with 0° incline. Each daily 40-min session consisted of 10 min running at 5 m/min followed by 25 min at 15 m/min and the final 10 min at 18 m/min with an intensity of approximately 50 − 0% maximal oxygen uptake. The intervention was performed 5 days per week for consecutive 8 weeks.	Increased DA levels in the NAc, reduced weight gain, lowered energy efficiency, improved body composition and decreased preference for fat food	[146]
C57BL/6J mice	Moderate-intensity aerobic exercise	Mice were required to begin with a warm-up at 10 m/min for 5 min and then progressively increase to 15 m/min. Starting from the first week, the mice ran for 30 min per day, 5 days per week. The duration of each session was increased by 10 min per day each week until reaching a maximum of 60 min per day.	No significant attenuation of body-weight gain	[147]
Male Sprague-Dawley rats	Swinging exercise	Rats were housed in suspended cages swinging at 34–36 cycles per minute through a 40-degree angle. Each daily exercise session lasted 30 min. The whole intervention lasted for 9 consecutive weeks.	Elevated serum DA levels and reduced weight gain	[148]
Lewis rats	High-intensity interval training	Rats were subjected to treadmill-based high-intensity interval training 7 days per week for 6 weeks after a 7-day acclimation period. Each daily 30-min session contained ten repeated 3-min cycles (2 min running followed by 1 min rest), running speed progressively increased from initial 10 m/min by 2.87 m/min every day after 5 days until reaching the maximal speed of 21.46 m/min.	Increased D2-like receptor binding in Nac shell	[149]
C57BL/6n mice	Moderate-intensity treadmill running	Mice participated in treadmill running at 10 m/min for 60 min each day. The exercise intervention was performed 5 days per week for 4 weeks.	Improved skeletal muscle insulin sensitivity	[150]
Male C57BL/6J mice	Moderate-intensity aerobic exercise	Mice were subjected to moderate-intensity aerobic swimming in 30–32 °C water and the intervention lasted for 1–2 h for 7 days.	Elevated DA serum level and reduced systemic inflammation	[151]
Male Wistar rats	Treadmill running	All animals were allowed to rest for 5 min before running at a low speed (10 m/min). The training was conducted for 5 min per session on 4 consecutive days, with a treadmill slope of 5%. Following familiarization, the rats immediately underwent incremental exercise testing. The incremental exercise began at 10 m/min and increased by 1 m/min every 3 min until the rats could no longer maintain the treadmill speed, at which point the test was terminated after 10 s of continuous, uniform movement.	Activation of neurons in the median preoptic nucleus, paraventricular nucleus, and supraoptic nucleus, along with reduced exercise endurance in rats with DRD1 blockade	[152]
Male participants	Aerobic treadmill activity and circuit-type resistance training	The subjects underwent an 8-week supervised exercise intervention, with 4 sessions per week, each lasting 60 min. The single training program consisted of 5–10 min of full-body warm-up, 20 min of aerobic exercise, 20 min of resistance training, and the remaining time was spent on full-body stretching and relaxation.	Increased fat reduction and muscle growth	[153]

DA dopamine, DAergic dopaminergic, DRD1 dopamine receptor D1, HFD high-fat diet, NAc nucleus accumbens

Microbiome Interventions

Microbial metabolism may influence DA metabolism and availability. Gut bacteria such as Eubacterium limosum and Blautia producta can regenerate DA from 3-methoxytyramine [154]. The microbiota-associated metabolite rhamnose also activates DRD1 in white adipose tissue, increasing cAMP/PKA signaling and UCP1 expression and thereby promoting thermogenesis and energy expenditure [155].

Prebiotic interventions can modify both gut microbial composition and DAergic signaling. Supplementation with 1-kestose increases striatal DA levels and locomotor activity, accompanied by enrichment of Bifidobacterium and Akkermansia [156]. Similarly, switching from a long-term high-fat, high-sugar diet to a standard diet supplemented with fructo-oligosaccharides restores mesocorticolimbic DA signaling and reduces preference for and intake of palatable food [157].

Interventions involving specific bacterial strains or probiotic mixtures may exert broader behavioral and metabolic effects. Administration of Bacteroides uniformis CECT 7771 reduces binge-eating and anxiety-like behaviors, accompanied by changes in DA signaling and gut microbial composition [158]. Probiotic supplementation also modifies glycolysis, pyruvate metabolism, and bacterial pathways associated with DA metabolism, thereby improving energy metabolism [159]. Collectively, these findings suggest that microbiome-targeted interventions can modify central and peripheral DA-related pathways through several mechanisms. However, the causal microbial mediators and the relevance of these predominantly preclinical findings to human obesity remain to be established. Further details of these microbiome interventions are provided in Table 3.

Table 3.

Effects of microbiome interventions on DAergic signaling and food-related behavior

Subjects	Microbiome	Methods	Results	References
Participants	Eubacterium limosum and Blautia producta	Faecal samples were resuspended in pre-reduced PBS (pH 7.4, 0.1 g/ml), vortexed for 5 min, settled for 5 min, and diluted 1:100 in Gifu anaerobic media, then anaerobically cultured at 37 °C for 72 h.	Realized 3-methoxytyramine to DA	[154]
Male BALB/c mice	Gut microbiota	Mice from the first through third generations received an isocaloric diet supplemented with 5% 1-Kestose starting at 5 weeks of age or immediately after weaning. The 1-Kestose diet was formulated by replacing an equivalent quantity of sucrose in the AIN-93G-based control diet with 1-Kestose.	Increased striatal DA levels, elevated locomotor activity and increased abundance of Bifidobacteria and Akkermansia	[156]
Male C57Bl/6J mice	Cecal gut microbiota	Mice received corrective fructo-oligosaccharides supplementation in control diet for 2 months after 2-month high-fat, high-sugar diet exposure.	Modulation of cecal abundance of Bifidobacterium spp., Akkermansia muciniphila as well as Lactobacillus spp. and reduced palatable-food preference	[157]
Male Wistar-Kyoto rats	Bacteroides uniformis CECT 7771	Rats received a daily dose of Bacteroides uniformis CECT 7771 (1 × 10⁸ CFU).	Reduced caloric intake, alleviated anxiety-like behavior and elevated extracellular DA levels	[158]
Beagle dogs	Enterococcus faecium IDCC 2102 and Bifidobacterium lactis IDCC 4301	Obese beagle dogs were orally administered 1 × 1010 CFU/day of Enterococcus faecium IDCC 2102 or Bifidobacterium lactis IDCC 4301 mixed into HFD for 9 consecutive weeks.	Reduced weight gain and lipid accumulation, alleviated systemic inflammation and reshaped gut microbiota composition	[159]

DA dopamine, DAergic dopaminergic, HFD high-fat diet

Bariatric Surgery

Bariatric surgery alters striatal DRD2/3 availability and VTA-striatal responses to high-fat and high-sugar food cues, accompanied by reductions in appetite, food cravings, and compulsive eating [160–162]. Reduced striatal D2-like receptor availability has been reported in individuals with obesity, and some evidence suggests that these alterations are partially reversible following bariatric surgery [163]. Surgery also modifies opioid-DA interactions in the ventral striatum, providing another potential mechanism for altered reward processing after surgery [164]. In individuals with type 2 diabetes, improvements in glucose homeostasis following bariatric surgery have additionally been linked to the bypass of gastrointestinal DA-producing regions and enhanced incretin-mediated insulin secretion [165].

Experimental studies have identified several gut-derived pathways that may contribute to these DAergic effects. Roux-en-Y gastric bypass increases intestinal oleoylethanolamide synthesis and activates peroxisome proliferator-activated receptor alpha signaling. This intestinal signal is transmitted through the vagus nerve to the brain, increasing dorsal striatal DA release and DRD1 expression and thereby reducing fat preference and high-fat food intake [166]. Changes in intestinal fat metabolism may further contribute to the sustained regulation of feeding after surgery [167]. Bariatric surgery-induced remodeling of the gut microbiota has also been associated with altered DA signaling in the VTA and NAc and with reduced reward-driven food seeking [168]. Moreover, fecal microbiota transfer from donors who had undergone Roux-en-Y gastric bypass altered brain DAT binding in individuals with obesity and metabolic syndrome, supporting a potential microbiota-DA link along the gut-brain axis [169]. Collectively, these findings suggest that bariatric surgery may modify DAergic function through multiple neural, hormonal, lipid-derived, and microbial pathways. However, whether these DA alterations directly mediate postoperative changes in eating behavior, body weight, or glucose metabolism remains uncertain. The evidence on bariatric surgery is outlined in Table 4.

Table 4.

Effects of bariatric surgery on DAergic signaling and food-related behavior

Subjects	Bariatric Surgery	Results	References
Female participants	RYGB and vertical sleeve gastrectomy (VSG)	Reduced weight, diminished feelings of hunger and RYGB-specific decreased liking for taste mixtures with added sugar and fat	[160]
Female participants	RYGB and sleeve gastrectomy	Reversed striatal DAergic dysfunction	[161]
Female participants	RYGB and VSG	Greater total weight loss percentage in RYGB group at one-year follow-up, larger weight-loss variability and partial weight-regain events within VSG group, disappearance of preoperative taste-preference at 1-year time-point and decreased self-reported food-craving and dietary disinhibition after surgery	[162]
Participants	RYGB and VSG	Restored striatal D2-like receptor availability	[163]
Female participants	RYGB and VSG	Restored mesolimbic opioid-DA interaction	[164]
Male Wistar rats	RYGB	Enhanced DA release, increased expression of DRD1, sustained weight reduction and decreased HFD preference	[166]
Participants	Fecal transplantation from donors who have undergone RYGB	Increased striatal DAT binding	[169]

DA dopamine, DAergic dopaminergic, DAT dopamine transporter, DRD1 dopamine receptor D1, HFD high-fat diet, RYGB Roux-en-Y gastric bypass, VSG vertical sleeve gastrectomy

Pharmacotherapy

Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists

Clinical studies suggest that GLP-1R agonists may influence both homeostatic appetite regulation and DAergic mechanisms underlying food motivation. Liraglutide modulates hunger-driven motivation according to insulin sensitivity. It may also help normalize dysregulated midbrain DAergic function in individuals with insulin resistance [170]. The investigational oral small-molecule GLP-1R agonist DA-302,168 S was well tolerated in a first-in-human Phase I trial involving adults with overweight or obesity. It produced dose-dependent weight loss and metabolic improvements [171]. However, whether these effects were mediated by altered DAergic signaling was not examined directly.

Animal studies provide more direct evidence of interactions between incretin signaling and DA circuits. Semaglutide transiently suppresses VTA DA neuron activity by activating satiety pathways. This limits the continued consumption of palatable food without preventing meal initiation [172]. Tirzepatide acts through GLP-1R/glucose-dependent insulinotropic polypeptide receptor co-expressing lateral septal neurons that also express DRD2. It reduces evoked DA release and attenuates cocaine-induced increases in DA [173]. Although these findings demonstrate incretin-DA interactions, their relevance to food reward and obesity requires further investigation.

DA Receptor Agonists and Antagonists

Clinical evidence supporting the use of DA receptor agonists or antagonists for obesity treatment remains limited. No clinical trials have established that selective activation or blockade of individual DA receptor subtypes produces sustained weight loss by modifying food reward or energy expenditure. The efficacy and safety of these receptor-directed strategies therefore remain uncertain in humans.

Available evidence is derived primarily from animal studies. A DRD4 antagonist combined with a cannabinoid type 2 receptor agonist suppresses binge eating through synergistic regulation of reward pathways [174]. A DRD2 agonist combined with a κ-opioid receptor antagonist promotes weight loss by enhancing thermogenesis and energy expenditure. This treatment selectively reduces fat mass while preserving lean mass [175]. These findings support the potential of receptor-directed combination therapies, but their translational relevance requires clinical evaluation.

Other DA-Modulating Agents

Among other DA-modulating therapies, extended-release naltrexone-bupropion provides the strongest clinical evidence. Bupropion inhibits DA and norepinephrine reuptake and activates hypothalamic proopiomelanocortin neurons. Naltrexone blocks µ-opioid receptor-mediated autoinhibition and thereby sustains anorexigenic signaling. Clinical studies have shown that naltrexone-bupropion improves binge-eating disorder [176]. It also promotes weight loss accompanied by improvements in hepatic steatosis and fibrosis risk [177]. Moreover, it reduces body weight primarily through fat loss while improving the lean-to-fat mass ratio [178].

Animal studies provide mechanistic evidence for several DA-modulating agents. In HFD-fed rats, naltrexone-bupropion reduces food intake and body weight. It also increases mesolimbic TH and DRD2 expression without affecting DRD1 expression [179]. Methylphenidate strengthens the circuit connecting caudal VTA DA neurons with DRD1-expressing neurons in the lateral parabrachial nucleus. This enhances satiety responses to an HFD and reduces food intake and body weight [180]. Methylamine produces dose-dependent effects on feeding through Kv1.6 potassium channels. Nitric oxide release induces hyperphagia at low doses, whereas DA release induces hypophagia at high doses [181]. These experimental mechanisms require further validation before clinical translation. The pharmacological evidence is compiled in Table 5.

Table 5.

Effects of pharmacotherapy on DAergic signaling and food-related behavior

Subjects	Drugs	Methods	Results	References
Participants	Liraglutide (GLP-1R agonist)	Subjects received subcutaneous injection of 0.6 mg liraglutide or equal-volume saline placebo on the evening before each test day. Two test sessions were separated by at least one-week wash-out period.	Removed motivational disparities between groups with high and low insulin sensitivity	[170]
Participants	DA-302,168 S (GLP-1R agonist)	The drug was administered orally as a tablet under fasting conditions. Single-dose groups received single oral doses (2.5, 7.5, 15, 30, and 50 mg). Multiple-dose groups received once-daily oral dosing for 28 days with weekly dose escalation to target doses of 7.5 mg, 15 mg, 20 mg or 30 mg.	Improved weight loss and metabolic enhancements that depend on the dose	[171]
C57BL/6J mice	Semaglutide (GLP-1R agonist)	The mice were given daily intraperitoneal doses of semaglutide, starting at 0.05 mg/kg on the first day, 0.1 mg/kg on the second day, and 0.15 mg/kg from the third to the fifth day.	Short-term inhibition of VTA DA neuron activity and intake of palatable foods	[172]
Male C57BL/6J mice	Semaglutide (GLP-1R agonist) and [D-Ala²] GIP₁-₄₂ (Glucose-dependent insulino tropic polypeptide receptor agonist)	Semaglutide (10 nmol/kg), [D-Ala²] GIP₁-₄₂ (10 nmol/kg) or the combination of both (10 nmol/kg each) was administered by subcutaneous injection.	Inhibited DA release and decreased DA levels	[173]
Male C57BL6/J mice	L-745,870 (DRD4 antagonist) and HU308 (Cannabinoid type 2 receptor agonist)	Mice were administered an intraperitoneal injection of 5 mg/kg L-745870 30 minutes before binge-eating test sessions and 5 mg/kg HU308 immediately before binge-eating test sessions. Mice received combined-drug treatment regimens.	Reduced binge eating of tasty foods	[174]
Male Sprague Dawley rats	Bromocriptine mesylate (DRD2 agonist) and PF-04455242 (selective κ-opioid receptor antagonist)	Rats received intraperitoneal bromocriptine mesylate at 1.25 mg/kg, PF-04455242 at 0.625 mg/kg, or DMSO vehicle. Treatments were administered in combination for either an acute 24-h intervention or once-daily treatment for 10 days.	Enhanced BAT thermogenesis, increased energy expenditure, reduced weight and improved obesity status	[175]
Participants	Naltrexone-bupropion combination	The participants took two tablets of naltrexone-bupropion orally twice a day, with each tablet containing 8 milligrams of naltrexone and 90 milligrams of bupropion. The dosage started at one quarter of the full dose, and was increased weekly. By the fourth week, the maximum dose was reached. The drug intervention lasted for 16 weeks.	Reduced binge eating	[176]
Participants	Naltrexone-bupropion combination	Dosing started from one tablet per day and was titrated up to two tablets twice daily by week four, and drug intervention lasted for total 56 weeks. Each tablet contained 8 milligrams of naltrexone and 90 milligrams of bupropion.	Improved liver steatosis and reduced fibrosis	[177]
Participants	Naltrexone-bupropion combination	Dosing was started at one-quarter of target dose and titrated weekly to full target dose by week four, and drug intervention lasted for total 52 weeks.	Lowered body weight and better lean-to-fat mass proportion	[178]
Wistar rats	Naltrexone-bupropion combination	Rats received once-daily subcutaneous injections for a total 14-day treatment period. The active-treatment groups were administered naltrexone 1 mg/kg combined with bupropion 20 mg/kg.	Reduced calorie intake, decreased weight, reduction in visceral fat volume, and increased expression of TH and DRD2	[179]
C57Bl/6 background mice	Methylphenidate	Mice received methylphenidate via intraperitoneal injection (1.25 mg/kg) or bilateral intracerebral microinjection (2 µg per side).	Enhanced firing activity of DRD1-expressing neurons in the lateral parabrachial nucleus, reduced food intake and decreased weight gain	[180]
Male Wistar rats	Methylamine	Conscious rats that had undergone 12-hour fasting received single intracerebroventricular injections of methylamine at graded doses from 15 µg up to 80 µg.	Hyperphagia at low doses and anorexia at high doses	[181]

BAT brown adipose tissue, DA dopamine, DAergic dopaminergic, DRD1 dopamine receptor D1, DRD2 dopamine receptor D2, DRD4 dopamine receptor D4, GLP-1R glucagon like peptide-1 receptor, TH tyrosine hydroxylase, VTA ventral tegmental area

Discussion and Future Directions

The apparently conflicting DAergic findings in obesity likely reflect biological and methodological heterogeneity. The direction and functional consequences of these alterations depend on the neuronal population, receptor subtype, physiological state, behavioral phase, and measurement approach. Receptor availability, receptor expression, and functional signaling should therefore be interpreted as distinct outcomes. DA should also be considered as one component of broader neural and metabolic networks. Although central and peripheral DA systems both participate in metabolic regulation, current evidence does not establish direct functional communication between them.

Several limitations prevent firm causal conclusions. In animal models, dietary exposure, adiposity, inflammation, insulin resistance, and behavioral adaptation often develop concurrently. It is therefore difficult to determine whether a DAergic alteration precedes obesity, results from metabolic dysfunction, or represents a compensatory response. Experimental manipulations can establish the functional capacity of a pathway but may not reproduce the gradual and distributed adaptations associated with obesity. Generalization is also limited by differences in dietary paradigms, exposure duration, sex, and age. Human studies provide limited cellular resolution and remain predominantly associative. Consequently, intervention-related changes in DA measures do not establish that DA mediates changes in body weight or metabolic health.

Future studies should separate the effects of nutrient exposure, adiposity, and metabolic dysfunction using pair-fed and weight-matched controls, time-resolved measurements, and reversal experiments. DA release, neuronal activity, receptor signaling, behavior, autonomic output, and peripheral metabolism should be assessed within integrated experimental frameworks. Cell-type- and projection-specific methods should be combined with single-cell and spatial analyses. Findings should also be replicated across sexes, ages, and obesity phenotypes. Longitudinal human studies should determine whether DA-related measures predict or mediate responses to dietary, pharmacological, surgical, or microbiome-based interventions. Participant stratification should extend beyond BMI to include eating phenotype, insulin sensitivity, sex, age, and obesity duration. A DA-related measure should be considered a clinically meaningful biomarker or therapeutic target only when it is reproducible across cohorts, linked to a defined metabolic outcome, and consistently responsive to effective intervention.

Conclusion

DA contributes to processes relevant to obesity through heterogeneous neuronal populations, receptor subtypes, central circuits, and peripheral tissue-specific mechanisms. Obesity alters DA release, receptor function, and downstream signaling in a region-, cell-, and context-dependent manner. These alterations affect food reward, feeding, physical activity and thermogenesis. DA also interacts with neuropeptides, neurotransmitter and neuromodulatory systems, and metabolic hormones to integrate homeostatic and reward-related signals. Collectively, these findings support a context-dependent model of DAergic involvement in obesity rather than a single overarching pattern of dysfunction. Although incretin-based and DA-modulating therapies show clinical or preclinical benefits, the contribution of DAergic mechanisms to these effects remains incompletely established. Future studies should identify circuit-, receptor-, and tissue-specific DA alterations and determine whether they are causal, compensatory, or secondary to metabolic dysfunction, as well as establish their reproducibility and clinical relevance.

Key References

• van Galen KA, Schrantee A, Ter Horst KW, la Fleur SE, Booij J, Constable RT, et al. Brain responses to nutrients are severely impaired and not reversed by weight loss in humans with obesity: a randomized crossover study. Nat Metab. 2023;5:1059-72. https://doi.org/10.1038/s42255-023-00816-9.

  • ○ Impaired brain responses to nutrient signals in humans with obesity highlight disrupted central regulation of food reward and energy homeostasis as important features of obesity pathophysiology.
• Zhu Z, Gong R, Rodriguez V, Quach KT, Chen X, Sternson SM. Hedonic eating is controlled by dopamine neurons that oppose GLP-1R satiety. Science. New York, N.Y.; 2025;387:eadt0773. https://doi.org/10.1126/science.adt0773.

  • ○ Dopamine neurons coordinate hedonic eating through interactions with glucagon-like peptide-1 receptor-mediated satiety pathways, revealing neural mechanisms linking reward and metabolic control.
• Walle R, Petitbon A, Fois GR, Varin C, Montalban E, Hardt L, et al. Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure. Nat Commun. 2024;15:2543. https://doi.org/10.1038/s41467-024-46874-9.

  • ○ Distinct D1- and D2-expressing dopamine neurons in the nucleus accumbens regulate feeding behavior and activity-related energy expenditure, extending dopamine functions beyond reward processing.
• Liu Y, Wang Y, Zhao Z-D, Xie G, Zhang C, Chen R, et al. A subset of dopamine receptor-expressing neurons in the nucleus accumbens controls feeding and energy homeostasis. Nat Metab. 2024;6:1616-31. https://doi.org/10.1038/s42255-024-01100-0.

  • ○ Dopamine receptor-defined neuronal populations in the nucleus accumbens contribute to feeding regulation and energy homeostasis, emphasizing cellular heterogeneity in dopaminergic control.
• Ferrero E, Masini M, Carli M, Moscato S, Beffy P, Vaglini F, et al. Dopamine-mediated autocrine inhibition of insulin secretion. Mol Cell Endocrinol. 2024;592:112294. https://doi.org/10.1016/j.mce.2024.112294.

  • ○ Peripheral dopamine signaling regulates pancreatic insulin secretion, supporting a broader role of dopamine in metabolic regulation beyond central neural circuits.
• Lapo Pais M, Crisóstomo J, Abrunhosa A, Castelo-Branco M. PET/fMRI demonstrates that bariatric surgery may reverse striatal dopaminergic dysfunction in women with obesity. Commun Med (Lond). 2025;5:375. https://doi.org/10.1038/s43856-025-01079-z.

  • ○ Reversal of striatal dopaminergic dysfunction after bariatric surgery highlights dopamine pathways as potential mediators of metabolic improvement and therapeutic response.

Author Contributions

S.Y., Z.H., and W.L. contributed equally and are listed as co-first authors. S.Y., Z.H., and W.L.: conceptualization. W.W., S.W., Y.W., and L.H.: data curation. S.Y., Z.H., W.L., W.W., S.W., Y.W., and L.H.: writing—original draft. L.C., R.C., and F.L.: writing—review and editing. All authors read and approved the submitted version of the manuscript and agreed to its publication.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82274634) and the Key Project of the Innovation and Development Joint Fund of the Natural Science Foundation of Hubei Province (No. 2024AFD238).

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.