Metformin attenuates cardiac deficiencies and repairs hepatic insulin signaling in a rat model of acute food insecurity followed by recovery

• Published in: Physiology (Bethesda, Md.) Md.), 2023-05, Vol.38 (S1)
• Main Authors: Sweidan, Raneem, de Souza, Aline, Ji, Hong, Stanic, Branka, Korolowicz, Kyle, Sandberg, Kathryn, Ecelbarger, Carolyn
• Format: Article
• Language: English
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2023.38.S1.5733203

Abstract only States of acute severe food restriction (sFR) can result voluntarily, e.g., anorexia nervosa (~1-4% of women in their lifetime) or involuntarily, e.g., very low food insecurity (~3.8% of U.S. households). This is often followed by periods of normal food intake, i.e., refeeding. We’ve shown increased propensity toward the development of metabolic syndrome (MetS) and cardiac injury in our sFR-Refed rat model. Rats receive 40% of their normal ad libitum grams of rat chow for 2-weeks followed by 3-months of recovery (ad libitum feeding). We hypothesized that treatment with metformin, a type 2 diabetic therapeutic, would attenuate features of MetS and potentially reverse or attenuate cardiac damage. Female Fischer rats (3-months old) were randomly assigned to one of four treatments: 1) Control (CT); 2) Metformin (MF); 3) sFR-Refed (FR); or 4) FR-MF (n = 9/group). MF (0.5% incorporated into the chow) was fed for 5-weeks (from week 8-12) of the study before euthanizing at week 14. Ultrasound was conducted to assess heart function just after food restriction ended (week 4, prior to beginning MF) and near the end of the study (week 13 after completion of MF). Cardiac output (CO) and heart rate (HR) were decreased (38 and 15%, respectively, p < 0.05) in the FR groups (week 4), relative to CT. In week 13, CO in the FR rats was still 11% lower than CT rats (p = 0.04); however, not in the FR-MF group (2% higher than CT). MF alone did not significantly alter CO or HR. There were no significant differences in final body weight; however, liver weight was increased by MF (p = 0.008, 2-way ANOVA). Fat pads were weighed and parametrial fat (visceral) was increased in the FR group and this rise attenuated by MF (g/185 g·bw): 5.7 ± 0.2 (CT); 5.5 ± 0.3 (MF); 7.0 ± 0.3 (FR); 6.1 ± 0.3 (FR-MT), (p < 0.0003 between CT and FR, unpaired t-test). To analyze the effects of MF on insulin signaling pathways in liver, hepatic cell suspensions were incubated ex vivo with insulin. Isolated proteins were biotinylated and incubated with antibody arrays (Phospho-antibody array, PIG-219, Full Moon Biosystems). Antibody spot densities were quantitated and normalized between chips. MF treatment altered the expression or phosphorylation of 24 distinct proteins (by 2-way ANOVA). FR in the presence or absence of MF altered 8. In addition, MF prevented the sFR-induced up-regulation of several proteins including the activating phosphorylation of ATP citrate lyase (ACLY), an enzyme invol