Bernadette Grayson

Neuroscience/ONPRC

B.E. Grayson, P.R. LeVasseur, S.M. Williams, M.S. Smith, D.L. Marks, and K.L. Grove

Changes in melanocortin expression and inflammatory pathways in fetal offspring of nonhuman primates fed a high-fat diet 

Childhood obesity significantly increases the risk of metabolic

diseases later in life. Maternal nutrition and metabolic health during

pregnancy may have a profound influence on the development of

metabolic systems in children, including the hypothalamic circuits

that control appetite and energy expenditure. The hypothalamic

melanocortin system, including pro-opiomelanocortin (POMC) and agouti

related peptide (AgRP) are key regulators of body-weight homeostasis.

This system develops during the 3rd trimester in nonhuman primates

(NHP); therefore, their development may be impacted by maternal diet

and health. The purpose of these studies was to use the NHP model to

investigate the contribution of chronic maternal high-fat diet on

fetal nutrient sensing systems in the hypothalamus. Japanese macaques

were placed on one of two diets for 4 years: 1) control diet or 2)

high fat/calorie diet. During each year of the diet, fetuses were

obtained at the beginning of the 3rd trimester, a critical period of

hypothalamic development. Fetuses from mothers on the high fat diet

for 2-4 years exhibited shifts in hypothalamic melanocortin gene

expression indicating a response to this high-fat environment. These

fetuses showed increases in POMC and melanocortin 4 receptor mRNA,

while AgRP mRNA and protein levels were decreased. Cortisol levels

were increased. Proinflammatory cytokines, including IL1β and

IL1R1, were elevated in the hypothalamus and may be responsible for

fetal shifts in melanocortin expression. Thus, during the prenatal

period, maternal consumption of a diet high in calories and fat leads

to an altered metabolic response in the fetal melanocortin system.

These results raise the concern that widespread activation of

proinflammatory cytokines may alter the development of the

melanocortin system and blood-brain barrier. These abnormalities could

impair long-term nutrient sensing and lead to early-onset obesity.