In a groundbreaking study published in Nature Metabolism, researchers led by Casanueva Reimon and colleagues have illuminated how early life exposure to fat-related sensory cues exerts a profound influence on the brain’s response to food and susceptibility to obesity. Their work reveals that not only does a maternal high-fat diet reshape offspring metabolism through structural brain changes, but also that olfactory cues associated with fat during developmental periods program the central nervous system in ways that alter dopamine signaling and feeding behaviors in adulthood.
It is well-established that developmental exposure to a high-fat diet (HFD) alters the brain’s architecture, particularly rewiring hypothalamic circuits responsible for energy homeostasis as well as mesolimbic pathways governing reward processing. Prior work identified that such nutritionally driven neuroplasticity predisposes offspring to maladaptive metabolic responses and hyperphagia. Building on this foundation, the current investigation probed whether sensory cues—specifically odorants linked to dietary fat—similarly sculpt neuronal activity patterns, thereby gating later-life food preferences and energy expenditure.
Using a sophisticated fluorodeoxyglucose (^18FDG) positron emission tomography (PET) protocol to measure regional glucose uptake as a proxy for neuronal activation, adult mice who had been exposed developmentally to either a normal chow diet (NCD_dev) or a broader fat-rich diet (BFD_dev) were challenged with the acute odor of lard-based HFD (HFD_lard). Intriguingly, BFD_dev mice exhibited a pronounced increase in activation across multiple brain regions upon odor exposure. Among these, olfactory processing centers—the olfactory bulb, olfactory tubercle, and piriform cortex—showed markedly amplified responses in BFD_dev relative to NCD_dev controls, confirming that early diet alters sensitivity to fat-related sensory stimuli.
Critically, and of particular interest to the field of reward neuroscience, BFD_dev mice demonstrated significant elevation of glucose metabolism in dopaminergic nuclei tied to the mesolimbic reward circuit: namely, the lateral nucleus accumbens shell (LAcbSh) and ventral tegmental area (VTA). These regions did not show comparable increases in the NCD_dev cohort, highlighting a key role for developmental sensory programming in modulating dopamine-related reward circuits that are known to control feeding behavior and fat preference.
To dissect the functional implications of these PET findings, the team implemented fibre photometry leveraging the cutting-edge dLight1.1 optical dopamine sensor to monitor real-time dopamine release in the LAcbSh during presentation of different diets. This approach revealed that BFD_dev mice, despite their heightened basal dopaminergic responsiveness to fat odor, exhibited a blunted dopamine response specifically to normal chow diet (NCD) pellets compared with NCD_dev mice. However, dopamine release evoked by the broader fat diet (BFD) or HFD_lard pellets was relatively preserved, suggesting a sensory-specific devaluation of dopamine signaling for lower-fat foods.
This dopaminergic skewing has important behavioral correlates. In two-choice feeding assays, adult BFD_dev mice preferentially consumed a greater percentage of calories from HFD_lard over a less palatable low-fat control diet during initial exposure, demonstrating that the primed neural alterations translate into a stronger hedonic bias favoring fatty foods. Notably, this shift was not linked to altered expression of canonical fat taste receptors (Cd36, Gpr120/Ffar4) or intracellular signaling components (Plcb2), indicating that the mechanism largely involves central processing alterations rather than peripheral sensory changes.
Further scrutiny of feeding behavior under exclusive HFD_lard conditions disclosed no significant differences in total food intake between NCD_dev and BFD_dev mice both before and after diet introduction, nor after prolonged feeding up to 10 weeks. This uncouples the observed early preference gate from overall caloric consumption, implying the sensory exposure programs initial approach and choice behavior rather than absolute intake.
Energy expenditure analyses deepen the mechanistic insights. Male and female BFD_dev mice exhibited reduced total energy expenditure post-HFD_lard feeding compared to NCD_dev counterparts, accompanied by lower interscapular brown adipose tissue (iBAT) temperature and diminished expression of thermogenesis-linked genes such as Cidea and Pparg in iBAT. These findings suggest a developmental sensory imprinting effects systemic metabolic regulation by dampening thermogenic activity, thereby compounding energy imbalance.
Interestingly, when adult mice were exposed to BFD or NCD diets without developmental programming (BFD_adult vs. NCD_adult), no significant differences in energy expenditure were observed, underscoring the importance of the developmental window for sensory-mediated metabolic programming. Such a developmental critical period is essential for revealing the lasting impact of early fat cue exposure on the brain and systemic metabolism.
Together, this suite of neurometabolic and behavioral data compellingly establishes that early life sensory experience with dietary fat primes the brain’s reward circuitry, gating preference for fatty foods and modulating energy homeostasis through dopaminergic and thermogenic pathways. The work emphasizes that the programming seen with maternal HFD exposure encompasses not only structural brain effects but also finely tunes sensory-driven neural responses, altering dopamine-mediated reward valuation and influencing long-term obesity risk.
These findings have broad translational implications. In an obesogenic environment saturated with fat cues, early-life exposure may set the stage for lifelong shifts in food preference and metabolic efficiency. Understanding the precise neurological mechanisms by which sensory experience during critical developmental windows calibrates neural circuits opens exciting avenues for intervention. Targeting these sensory-reward pathways could enable novel strategies to prevent or reverse obesity predisposition by reprogramming maladaptive sensory biases.
Moreover, the application of advanced tools like ^18FDG-PET imaging and fibre photometry with genetically encoded dopamine sensors exemplifies how integrative neuroimaging and neurophysiology can elucidate complex brain–body interactions in metabolic disease. Future investigations might explore whether similar sensory programming occurs with sugar or salt cues and if these pathways intersect with other neuroendocrine systems.
This pioneering research highlights that the sensory environment encountered during early life, particularly fat-related olfactory cues, is a critical determinant of the brain’s reward landscape and metabolic trajectory. As dietary patterns continue to shift globally, unraveling the sensory circuits that underpin food preference and energy balance offers a promising frontier for tackling obesity at its roots.
Subject of Research:
Developmental programming of brain dopamine circuits by fat-related sensory cues and its impact on food preference and energy expenditure.
Article Title:
Fat sensory cues in early life program central response to food and obesity.
Article References:
Casanueva Reimon, L., Gouveia, A., Carvalho, A. et al. Fat sensory cues in early life program central response to food and obesity. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01405-8
Image Credits:
AI Generated
DOI:
https://doi.org/10.1038/s42255-025-01405-8
Tags: brain structure and obesitydevelopmental diet impact on braindopamine signaling and feeding behaviorearly life fat exposurefluorodeoxyglucose PET imaging in researchhypothalamic circuits and energy homeostasismaternal high-fat diet effectsmetabolic responses to high-fat dietneuronal activity and energy expenditureneuroplasticity and metabolismolfactory cues and food preferencessensory cues in obesity risk
