Maternal high-fat diet impairs leptin signaling and up-regulates type-1 cannabinoid receptor with sex-specific epigenetic changes in the hypothalamus of newborn rats

Maternal high fat (HF) diet down-regulated the transcriptional factor STAT3 in the hypothalamus of male and female offspring, but induced hypoleptinemia only in males and decreased pSTAT3 only in female offspring. Because leptin acts through STAT3 pathway to inhibit central ECS, our results suggest that leptin pathway impairment might contribute to increased levels of Crn1 mRNA in hypothalamus of both sex offspring. Besides, maternal HF diet increased the histone acetylation percentage of Cnr1 promoter only in male offspring and increased the AR binding to the Cnr1 promoter, which can contribute to higher expression of Cnr1 in newborn HF offspring. Maternal HF diet increased hypothalamic AR protein content only in newborn male offspring. Maternal HF diet increased plasma n6 to n3 fatty acid ratio in male offspring, which is an important risk factor to metabolic diseases and might indicate an over activation of endocannabinoid signaling. Thus, although maternal HF diet programs a similar phenotype in adult offspring of both sexes (obesity, hyperphagia and higher preference for fat), here we showed that molecular mechanisms were modified prior to obesity development and can differ between male and female offspring at birth. Red arrow: maternal HF diet effect from two-away ANOVA test; Black arrow: statistical differences between control vs HF offspring; Equal symbol: There were no statistical differences between control vs HF offspring; STAT3: Signal transducer and activator of transcription 3; pSTAT3: phosphorylation of STAT3. Cnr1 mRNA (messenger RNA of Cnr1 gene codes type-1 cannabinoid receptor (CB1)); Ac: percentage of histone acetylation in Cnr1 promoter; AR: Androgen Receptor. [Display omitted] •Maternal high-fat (HF) diet induced sex-specific changes on hypothalamic leptin signaling in the offspring at birth.•Maternal HF diet increased plasma n6 to n3 fatty acid ratio in male offspring.•Maternal HF diet increased mRNA levels of the type-1 cannabinoid receptor (Cnr1) in hypothalamus of offspring.•Maternal HF diet increased histone acetylation and androgen receptor binding to Cnr1 promoter in hypothalamus of male pups.•Maternal HF diet induced sex-specific epigenetic and metabolic changes prior to obesity development in the offspring. Maternal nutritional imbalances trigger developmental adaptations involving early epigenetic mechanisms associated with adult chronic disease. Maternal high-fat (HF) diet promotes obesity and hypothalamic leptin resistance