Pro-opiomelanocortin (POMC) neuron translatome signatures underlying obesogenic gestational malprogramming in mice

Summary Objective Maternal unbalanced nutritional habits during embryonic development and perinatal stages perturb hypothalamic neuronal programming of the offspring, thus increasing obesity-associated diabetes risk. However, the underlying molecular mechanisms remain largely unknown. In this study we sought to determine the translatomic signatures associated with POMC neuron malprogramming in maternal obesogenic conditions. Methods We used the Ribotag mouse model to specifically profile the translatome of POMC neurons during neonatal (P0) and perinatal (P21) life and its neuroanatomical, functional and physiological consequences. Results Maternal HFD exposure did not interfere with offspring’s hypothalamic POMC neuron specification, but significantly impaired their spatial distribution and axonal extension to target areas. Importantly, we established POMC neuron-specific translatome signatures accounting for aberrant neuronal development and axonal growth. These anatomical and molecular alterations caused metabolic dysfunction in early-life and adulthood. Conclusions Our study provides fundamental insights on the molecular mechanisms underlying POMC neuron malprogramming in obesogenic contexts.