Maternal Dietary Fat Determines Metabolic Profile and the Magnitude of Endocannabinoid Inhibition of the Stress Response in Neonatal Rat Offspring

Endocannabinoids (eCBs) are products of phospholipid (PL)-derived arachidonic acid (AA) that regulate hypothalamus-pituitary-adrenal axis activity. We hypothesized that differences in the quality and quantity of maternal dietary fat would modulate the PL AA content in the neonatal brain affecting stress responsiveness via differences in eCB production and activity in stress-activated brain areas. Pregnant rats were fed a 5% [control (C)] or 30% fat [high fat (HF)] diet rich in either n-6 (HF-n-6) or n-3 (HF-n-3) fat during the last week of gestation and lactation. Postnatal d 10 offspring were tested for metabolic hormones, AA (n-6) and eCB brain content, and hormonal effects of eCB receptor antagonism (AM251, 1 or 3 mg/kgip) on stress responses. Like maternal diet, milk from HF-n-3 mothers had a reduced n-6/n-3 fat ratio compared with that of C and HF-n-6 mothers. Hypothalamic and hippocampal levels of PL AA were diet specific, reflecting the maternal milk and dietary n-6/n-3 ratio, with HF-n-3 offspring displaying reduced AA content relative to C and HF-n-6 offspring. Plasma corticosterone and insulin were elevated in HF-fed pups, whereas leptin was increased only in HF-n-6 pups. Basal eCB concentrations were also diet and brain region specific. In C pups, eCB receptor antagonist pretreatment increased stress-induced ACTH secretion, but not in the HF groups. Stress-induced corticosterone secretion was not sensitive to AM251 treatment in HF-n-3 pups. Thus, the nature of preweaning dietary fat differentially influences neonatal metabolic hormones, brain PL AA levels, and eCB, with functional consequences on hypothalamus-pituitary-adrenal axis modulation in developing rat pups. (Endocrinology 151: 1685-1694, 2010)