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There are sex differences in metabolic disease risk, and early-life stress (ES) increases the risk to develop such diseases, potentially in a sex-specific manner. It remains to be understood, however, how sex and ES affect such metabolic vulnerability. The hypothalamus regulates food intake and energy expenditure by sensing the organism’s energy state via metabolic hormones (leptin, insulin, ghrelin) and nutrients (glucose, fatty acids). Here, we investigated if and how sex and ES alter hypothalamic nutrient sensing short and long-term. ES was induced in mice by limiting the bedding and nesting material from postnatal day (P)2-P9, and the expression of genes critical for hypothalamic nutrient sensing were studied in male and female offspring, both at P9 and in adulthood (P180). At P9, we observed a sex difference in both Ppargc1a and Lepr expression, while the latter was also increased in ES-exposed animals relative to controls. In adulthood, we found sex differences in Acacb, Agrp, and Npy expression, whereas ES did not affect the expression of genes involved in hypothalamic nutrient sensing. Thus, we observe a pervasive sex difference in nutrient sensing pathways and a targeted modulation of this pathway by ES early in life. Future research is needed to address if the modulation of these pathways by sex and ES is involved in the differential vulnerability to metabolic diseases.

A certain degree of age-related cognitive decline is normal; however, some people retain more cognitive function than others. Cognitive impairment is associated with an increased risk of dementia. Thus, understanding the factors that contribute to cognitive reserve is crucial, so effective strategies for the prevention of dementia can be developed. Engaging in physical activity can delay cognitive decline and reduce the risk of dementia and a number of early life conditions have been shown to have long-lasting effects on cognition. This mini-review combines these two observations to evaluate the evidence from both animal models and epidemiological studies for physical activity in early life (≤30 years) delaying cognitive decline in later life (cognition tested ≥60 years). Three epidemiological studies were found; two showed a positive association and one found none. The latter was deemed to have an unreliable method. A review of animal studies found none that analyzed the effect of physical activity in early life on cognition in later life. However, in rodent models that analyzed mid-life cognition, runners showed improved cognition and enhanced adult hippocampal neurogenesis, changes which were preserved across the life span. Currently, there is insufficient evidence to conclude whether physical activity in early life may delay cognitive decline in later life, but these results indicate that further studies are warranted. Future human research should be in the form of longitudinal studies that begin below ≤15 years and assess sex differences. Crucially, the physical activity data must define type, quantity and intensity of exercise.