Abstract
Maternal high-fat (HF) is associated with offspring hyperphagia and obesity. We hypothesized that maternal HF alters fetal neuroprogenitor cell (NPC) and hypothalamic arcuate nucleus (ARC) development with preferential differentiation of neurons towards orexigenic (NPY/AgRP) versus anorexigenic (POMC) neurons, leading to offspring hyperphagia and obesity. Furthermore, these changes may involve hypothalamic bHLH neuroregulatory factors (Hes1, Mash1, Ngn3) and energy sensor AMPK. Female mice were fed either a control or a high fat (HF) diet prior to mating, and during pregnancy and lactation. HF male newborns were heavier at birth and exhibited decreased protein expression of hypothalamic bHLH factors, pAMPK/AMPK and POMC with increased AgRP. As adults, these changes persisted though with increased ARC pAMPK/AMPK. Importantly, the total NPY neurons were increased, which was consistent with the increased food intake and adult fat mass. Further, NPCs from HF newborn hypothalamic tissue showed similar changes with preferential NPC neuronal differentiation towards NPY. Lastly, the role of AMPK was further confirmed with in vitro treatment of Control NPCs with pharmacologic AMPK modulators. Thus, the altered ARC development of HF offspring results in excess appetite and reduced satiety leading to obesity. The underlying mechanism may involve AMPK/bHLH pathways.
Highlights
Obesity and its related diseases are the leading cause of death in Western society
We studied the changes both in vivo and in vitro (NPCs) of basic helix-loop-helix (bHLH) factors, neuropeptide and AMPK expression, including neuronal sub-type in offspring exposed to maternal obesity and high fat (HF) diet
Studies on strain-specific effects would provide a better understanding of the genetic influence on developmental programmed obesity. These findings suggest that maternal obesity and high fat diet programs offspring obesity, in part via altered neurogenesis and programmed hyperphagia
Summary
Obesity and its related diseases are the leading cause of death in Western society. Currently, more than two-thirds of adults in the United States are overweight and over one-third are obese [1].Increased energy intake, not reduced energy expenditure, likely explains population weight gain in US children and adults [2,3]. Obesity and its related diseases are the leading cause of death in Western society. More than two-thirds of adults in the United States are overweight and over one-third are obese [1]. Not reduced energy expenditure, likely explains population weight gain in US children and adults [2,3]. Despite this understanding, surprisingly little is known as to why the energy intake is increased in select individuals. There is a marked risk for programmed adult metabolic syndrome in relation to birthweight [4,5], Nutrients 2020, 12, 3326; doi:10.3390/nu12113326 www.mdpi.com/journal/nutrients
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