­­­Fat sensory cues in early life program central response to food and obesity

Maternal obesity predisposes offspring to metabolic diseases. Here, we show that non-nutritive sensory components of high-fat diet (HFD), beyond its hypercaloric, obesogenic effects, are sufficient to alter metabolic health in the offspring. To dissociate the caloric and sensory components of HFD, we feed dams a bacon-flavored diet isonutritional to a normal chow diet but enriched with fat-related odors. Offspring exposed to these fat-related odors during development display metabolic inflexibility and increased adiposity when fed HFD in adulthood independently of maternal metabolic health. Developmental exposure to fat-related odors shifts mesolimbic dopaminergic circuits and Agouti-related peptide (AgRP) hunger neurons' responses to phenocopy those of obese mice, including a desensitization of AgRP neurons to dietary fat. While neither neonatal optogenetic activation of sensory circuits nor passive exposure to fat-related odors is sufficient to alter metabolic responses to HFD, coupling optogenetic stimulation of sensory circuits with caloric intake exacerbates obesity. Collectively, we report that fat-related sensory cues during development act as signals that can prime central responses to food cues and whole-body metabolism regulation.