172-OR: Perinatal Exposure to a Western Diet Alters Hypothalamic Gene Expression and Predisposes to Diabetes in Adult Male Mice

• Published in: Diabetes (New York, N.Y.) Vol. 70; no. Supplement_1
• Main Authors: ELGAZZAZ, MONA, LAZARTIGUES, ERIC D., MAUVAIS-JARVIS, FRANCK
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.06.2021
• Subjects: Appetite; Diabetes; Diabetes mellitus (non-insulin dependent); Epigenetics; Exocytosis; Gene expression; Genomic imprinting; Glucose tolerance; Heart rate; High fat diet; Hyperglycemia; Hypothalamus; Insulin; Insulin secretion; Intolerance; Males; Neural coding; Neurotransmitters; Offspring; Perinatal exposure; SNAP-25 protein; Synaptic plasticity; Weaning
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db21-172-OR

Cardiometabolic diseases are among the most prevalent diseases worldwide. Maternal epigenetic imprinting affects gene expression in offspring, leading to increased disease susceptibility later in life. We showed previously that perinatal exposure to high fat diet (HFD) leads to obesity, fasting hyperglycemia, glucose intolerance, elevated heart rate and hypertension, exclusively in male mice. Here, we hypothesize that epigenetic maternal programming alters gene expression in the hypothalamus to promote the cardiometabolic disturbances seen in male offspring. To investigate this, C57BL6/J dams were fed a HFD or regular diet (RD) for 1 month and mated with RD-fed males. All offspring were maintained on RD after weaning. At 3 months of age, hypothalami from programmed (HFD-RD) and control (RD-RD) offspring were harvested for mRNA sequencing (Illumina NextSeq). Results show 11 differentially expressed genes (DEG) in HFD-RD males in comparison to RD-RD males. Using iPathway analysis, some of the DEGs were involved in insulin secretion and synaptic vesicle cycle pathways. Among the DEG, Snap25, coding a protein of the exocytosis machinery important for neurotransmitters, and insulin release was upregulated (p= 2.31E-06). Additionally, Nnat gene, involved in appetite suppression and regulation of synaptic plasticity in the hypothalamus, as well as insulin secretion was downregulated (p= 0.04955). MiRNA6236 (p= 2.28E-09) and Rn45s (p= 0.002), whose deficiency in islets is known to be associated with prediabetes in mice, were both downregulated in programmed males. Interestingly, with exception of Nnat gene downregulation (p= 0.001), all the male DEGs were unaltered in HFD-RD females compared to RD-RD females. In conclusion, perinatal exposure to HFD programs sex-specific alterations in gene expression in the hypothalamus, possibly impairing the central metabolic regulation and predisposing to type 2 diabetes. Disclosure M. Elgazzaz: None. E. D. Lazartigues: None. F. Mauvais-jarvis: None. Funding American Diabetes Association (1-19-IBS-291 to E.D.L.); U.S. Department of Veterans Affairs (BX004294)