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. 2026 May 7;32(4):320–337. doi: 10.1177/10738584261440907

Figure 3.

Two diagrams show VTA→NAc pathways in lean vs obese individuals. Leptin enhances VTA DA signaling in lean, inhibits it in obese. Obesity's reduced DA signaling leads to inactivity.

Leptin–dopamine (DA) interactions within the ventral tegmental area–nucleus accumbens (VTA–NAc) pathway and their role in physical activity regulation in lean vs obese states. Illustration adapted from Ruegsegger et al (2017), depicting the dopaminergic VTA → NAc pathway and the impact of leptin resistance on physical inactivity in obesity. Licensed under CC BY 4.0. (Top panel LEAN) In lean individuals, medium spiny neurons (MSNs) of the NAc express DA receptors, especially D2, at normal levels, allowing effective dopaminergic signaling. DA is released from neurons in the VTA, where functional leptin receptors (LEPRs) respond to circulating leptin. This supports motivation and regular physical activity. (Bottom panel OBESE) In obesity, medium spiny neurons in the NAc show reduced expression of D2 receptors, weakening the motivational response to DA. At the same time, high leptin levels lead to central leptin resistance, impairing LEPR signaling in VTA DA neurons and reducing DA release. This blunted reward signaling contributes to decreased movement and reinforces a cycle of physical inactivity and further obesity. DxR, dopamine receptor(s).