Ke Sui, Ali Yasrebi, Natasha Malonza, Zehra H Jaffri, Samuel E Fisher, Isaac Seelenfreund, Brandon D McGuire, Savannah A Martinez, Avery T MacDonell, Kevin M Tveter, Candace R Longoria, Sue A Shapses, Sara C Campbell, Diana E Roopchand, Troy A Roepke

In menopausal and postmenopausal women, obesity, cardiovascular disease, osteoporosis and gut dysbiosis are induced by loss of ovarian 17β-estradiol (E2). Dietary fatty acid profile high in omega-6 polyunsaturated fatty acids (PUFAs), specifically linoleic acid (LA), and low in coconut oil saturated fatty acids (SFAs) and omega-3 PUFAs may worsen symptoms of estrogen deficiency. To investigate this hypothesis, vehicle (Veh)- or estradiol benzoate (EB)-treated ovariectomized C57BL/6J and transgenic fat-1 mice were fed high-fat diet (HFD, 45% kcal fat) with a high LA:SFA ratio (22.5%:8%; 22.5% LA diet) or a HFD with a low LA:SFA ratio (1%:31%; 1% LA) diet for a period of 14-15 weeks. EB treatment rescued obesity, glucose intolerance, and bone loss in OVX mice. fat-1 mice fed 1% LA diet mitigated weight gain and adiposity in Veh-treated OVX mice. fat-1 mice fed 22.5% LA diet had increased EE and activity as wheel running in EB-treated OVX mice. Except for EB treatment, coconut oil SFAs and omega-3 FAs can protect against glucose intolerance. Apparent improvement of insulin sensitivity was achieved by EB treatment in both WT and fat-1 mice fed 1% LA diet, while fat-1 mice fed 22.5% LA diet was protected against insulin resistance without EB treatment. Increase of relative abundance of gut microbial taxa as SCFA producers were associated with omega-3 FAs production and improved energy homeostasis. These data suggest that a balanced dietary FA profile containing coconut oil SFAs, and a lower ratio of omega-6/omega-3 FAs is a safer strategy for alleviating metabolic disorders during E2 deficiency.