(886.6) 17α-Estradiol Mitigates the Negative Effects of High-Fat Feeding in Both Male and Female Mice

Poster Board Number: E315

Matthew Bubak (The Oklahoma Medical Research Foundation), Shivani Mann (University of Arizona, University of Arizona), Matle Broomfield (The Oklahoma Medical Research Foundation), Michael Stout (The Oklahoma Medical Research Foundation), Benjamin Miller (The Oklahoma Medical Research Foundation)

17α-estradiol (17α-E2) is an endogenous, non-feminizing enantiomer of 17β-estradiol. 17α-E2 supplementation improves the lifespan of male, but not female, mice through metabolic mechanisms. Although the effects of 17α-E2 on liver and adipose tissue are well described, potential benefits in skeletal muscle are unknown. The objective of this study was to determine if 17α-E2 can mitigate the negative effects of a high-fat diet (HFD) on skeletal muscle metabolism. In addition, we sought to determine if there were sex differences in these responses. We hypothesized that 17α-E2 supplementation would ameliorate the negative effects of a HFD in skeletal muscle of male, but not female mice. To test this hypothesis, wild type male (n=19) and female (n=15) mice began a HFD (45% fat) at 3 months of age. At 9 months of age, half of the males (n=10) and females (n=8) received diets supplemented with 17α-E2 (14.4ppm) for 3.5 months. Mice underwent weekly assessment of body composition by QMR throughout the 17α-E2 supplementation, while glucose and insulin tolerance tests were completed 8 weeks into treatment. Leg muscles were harvested and analyzed for inflammatory cytokines via RT-qPCR, fat infiltration via Oil Red O (ORO) staining, and triglyceride content. 17α-E2 reduced whole-body fat mass (p = 0.001, 11.6% ± 0.4%) and whole-body lean mass (p = 0.003, 3.5% ± 0.2) in males. In females, 17α-E2 reduced fat mass (p = 0.0001, 33.1% ± 1.1%), but did not alter lean mass (p = 0.99, 0.9% ± 0.2%). There were no changes in the mass of the quadriceps, gastrocnemius, soleus, tibialis anterior or extensor digitorum longus muscles in males or females (p gt; 0.05). 17α-E2 improved glucose tolerance in females (p = 0.03, 22301 ± 573 AUC and 33022 ± 1663 AUC) but not in males (p = 0.11, 24856 ± 159 AUC and 29968 ± 466 AUC). 17α-E2 reduced insulin resistance in males (p = 0.001, 14784 ± 326 AUC and 19220 ± 246 AUC) and females (p = 0.05, 10992 ± 315 AUC and 14644 ± 540 AUC). 17α-E2 reduced the expression of IL-6 (p = 0.005), IL-1α (p = 0.002), and TNFα (p lt; 0.001) in males, but 17α-E2 did not change cytokine expression in females (p gt; 0.05). There was no difference in gastrocnemius ORO staining in the males (p = 0.59) or females (p = 0.68). 17α-E2 supplementation did not change quadricep triglycerides in males (p = 0.98, 25.6 ± 1.6 mg/g and 27.3 ± 1.7 mg/g). However, females on 17α-E2 had significantly lower quadricep triglycerides compared to HFD (p = 0.03, 13.6 ± 1.1 mg/g and 26.6 ± 0.7 mg/g). These results suggest that long term 17α-E2 supplementation ameliorates the effects of a HFD on skeletal muscle in both males and females but in a sex dimorphic manner. Further research is needed to determine how 17α-E2 supplementation alters skeletal muscle metabolism in both sexes. 

Support or Funding Information

This project was supported by the NIA grant R01AG070035 and the NIH Gerontology T32 Grant 5T32AG052363-04.