AbstractEarly life nutrition can reprogram development and exert long‐term consequences on body weight regulation. In mice, maternal high‐fat diet (HFD) during lactation predisposed male but not female offspring to diet‐induced obesity when adult. Molecular and cellular changes in the hypothalamus at important time points are examined in the early postnatal life in relation to maternal diet and demonstrated sex‐differential hypothalamic reprogramming. Maternal HFD in lactation decreased the neurotropic development of neurons formed at the embryo stage (e12.5) and impaired early postnatal neurogenesis in the hypothalamic regions of both males and females. Males show a larger increased ratio of Neuropeptide Y (NPY) to Pro‐opiomelanocortin (POMC) neurons in early postnatal neurogenesis, in response to maternal HFD, setting an obese tone for male offspring. These data provide insights into the mechanisms by which hypothalamic reprograming by early life overnutrition contributes to the sex‐dependent susceptibility to obesity in adult life in mice.