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

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.

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. 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.