Childhood obesity and associated comorbidities in adulthood are of great concern worldwide. Evidence highlights the importance of lactation in later disease development. In this sense, obese children Show more
Childhood obesity and associated comorbidities in adulthood are of great concern worldwide. Evidence highlights the importance of lactation in later disease development. In this sense, obese children are at great risk of developing adult obesity, insulin resistance, type 2 diabetes, and cardiovascular disease at adulthood. PPARα activation during lactation promotes the expression of key enzymes involved in lipid oxidation, and it was associated with reduced adiposity in children. Therefore, we hypothesized that an animal model of childhood obesity, small litter (SL), would lead to the development of obesity and metabolic dysfunction in adulthood, which could be prevented by postnatal PPARα agonism. Wistar dams had their litter reduced, leading to postnatal overfeeding and obesity early in life. SL male pups were treated with fenofibrate, an PPARα agonist, during lactation, from postnatal day (PND) 1 until weaning (PND21), to verify whether PPARα activation prevents the developmental programming at adulthood (PND120). Childhood obesity induced by postnatal overfeeding leads to decreased markers for oxidative metabolism during infancy, leading to increased visceral adiposity and oxidative stress, insulin resistance, hepatic microvesicular steatosis, and increased fibroblast growth factor 21 (Fgf21) expression, followed by decreased brown adipose tissue (BAT) sympathetic nerve activity and decreased Fgfr1 hypothalamic expression in adulthood. Agonist-induced PPARα activation during lactation mitigated the development of aforementioned alterations in adulthood. Postnatal fenofibrate treatment prevents the developmental programming of visceral obesity, liver-associated metabolic dysfunction and BAT autonomic sympathetic hypoactivity in an animal model of childhood obesity. Show less
Obesity and type 2 diabetes have a heritable component that is not attributable to genetic factors. Instead, epigenetic mechanisms may play a role. We have developed a mouse model of intrauterine grow Show more
Obesity and type 2 diabetes have a heritable component that is not attributable to genetic factors. Instead, epigenetic mechanisms may play a role. We have developed a mouse model of intrauterine growth restriction (IUGR) by in utero malnutrition. IUGR mice developed obesity and glucose intolerance with aging. Strikingly, offspring of IUGR male mice also developed glucose intolerance. Here, we show that in utero malnutrition of F1 males influenced the expression of lipogenic genes in livers of F2 mice, partly due to altered expression of Lxra. In turn, Lxra expression is attributed to altered DNA methylation of its 5' UTR region. We found the same epigenetic signature in the sperm of their progenitors, F1 males. Our data indicate that in utero malnutrition results in epigenetic modifications in germ cells (F1) that are subsequently transmitted and maintained in somatic cells of the F2, thereby influencing health and disease risk of the offspring. Show less