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Epigenetic Programming Induces Changes in Metabolic and Gene Expression and Reverses the Effects of Ang‐II Infusion in Male Mice
Author(s) -
Elgazzaz Mona,
Lazartigues Eric
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01788
Subject(s) - offspring , endocrinology , medicine , angiotensin ii , weaning , adipose tissue , gene expression , blood pressure , homeostasis , biology , gene , pregnancy , biochemistry , genetics
Cardiometabolic diseases are highly prevalent chronic illnesses associated with high risk morbidities. Maternal epigenetic programming modulates gene expression in offspring thus affecting their disease susceptibility later in life. The renin‐angiotensin system (RAS) contributes to cardiometabolic homeostasis however, its over‐activation is associated with cardiometabolic dysfunctions. Previously, we showed that perinatal exposure to high fat diet (HFD) leads to elevated BP, heart rate, fasting blood glucose (FBG) and weight gain in addition to elevated brain AT1R and ADAM17 gene expression exclusively in males. We hypothesize that perinatal HFD exposure leads to changes in RAS gene expression in peripheral tissues and these changes could be accentuated by low dose Angiotensin‐II (Ang‐II) revealing a stronger cardiometabolic dysfunction. C57BL6/J dams were fed a HFD or regular diet (RD) for 1 month and mated with RD‐fed males. After weaning, offspring were put on RD resulting in two groups; HFD‐RD (programmed) and RD‐RD (control). At 3 months, offspring underwent 24 h BP recording (telemetry) and glucose tolerance test (GTT). Half of the mice in each group were then implanted with an osmotic pump filled with Ang‐II (200 ng/kg/min/2 weeks) resulting in 4 groups; HFD‐RD, RD‐RD, HFD‐RD+Ang‐II, RD‐RD+Ang‐II. BP (24 h) was recorded weekly and GTT was repeated after the 2 nd week for the Ang‐II‐treated mice. For all groups, Liver, muscle and adipose tissues were harvested and selected genes expression was quantified using qPCR. HFD‐RD males exhibited higher FBG than RD‐RD males (172.7 ±6 vs . 145.2 ±5 mg/dL, p=0.01) and higher blood glucose at 15 min (387.8 ±17 vs. 303.4 ±30 mg/dL, p=0.04). Surprisingly, only HFD‐RD+Ang‐II males showed lowered FBG level compared to HFD‐RD males (139.7 ±8 mg/dL vs. 172.7 ±6, p=0.007) and at 15 min (279.8 ±19 mg/dL vs. 387.8 ±17, p=0.006). Interestingly, no metabolic changes were seen in females in any of the groups. In addition, Ang‐II infusion had no effect on hemodynamic parameters in treated groups. Regarding gene expression, HFD‐RD showed upregulation of insulin receptor (p=0.0019), ACE2 (p=0.008), and ADAM17 (p=0.04) in the liver compared to RD‐RD. Conversely, in HFD‐RD+Ang‐II, insulin receptor and ACE2 were downregulated in the liver (p<0.0001) relative to HFD‐RD. In muscle tissue, while ADAM17 was upregulated in RD‐RD+Ang‐II (p=0.039), there was no change in ADAM17 expression in HFD‐RD+Ang‐II. Additionally, AT1 receptor was strongly upregulated in RD‐RD+Ang‐II (p<0.0001) with a slight upregulation in HFD‐RD+Ang‐II (p=0.03). We conclude that perinatal exposure to HFD leads to a pre‐diabetic state evident by elevated FBG, disturbed first phase insulin secretion, changes in insulin receptor and RAS gene expression exclusively in male mice. This programming reverses the effects of Ang‐II, possibly switching signaling towards another angiotensin receptor involved in a protective mechanism.