The Nelson Memorandum: How two HELIOS members are responding

UT Librarie

Ovariectomy results in differential shifts in gut microbiota in low versus high aerobic capacity rats

The increased risk for cardiometabolic disease with the onset of menopause is widely studied and likely precipitated by the decline in endogenous estradiol (E2), yet the precise mechanisms are unknown. The gut microbiome is involved in estrogen metabolism and has been linked to metabolic disease, suggesting its potential involvement in the postmenopausal phenotype. Furthermore, menopause‐associated risk factors, as well as gut ecology, are altered with exercise. Therefore, we studied microbial changes in an ovariectomized (OVX vs. Sham) rat model of high (HCR) and low (LCR) intrinsic aerobic capacity (n = 8–10/group) in relation to changes in body weight/composition, glucose tolerance, and liver triglycerides (TG). Nine weeks after OVX, HCR rats were moderately protected against regional adipose tissue gain and liver TG accumulation (P < 0.05 for both). Microbial diversity and number of the Bacteroidetes phylum were significantly increased in LCR with OVX, but unchanged in HCR OVX relative to Sham. Plasma short‐chain fatty acids (SCFA), produced by bacteria in the gut and recognized as metabolic signaling molecules, were significantly greater in HCR Sham relative to LCR Sham rats (P = 0.05) and were decreased with OVX in both groups. These results suggest that increased aerobic capacity may be protective against menopause‐associated cardiometabolic risk and that gut ecology, and production of signaling molecules such as SCFA, may contribute to the mediation.We have demonstrated modest protection from the metabolic effects of surgical menopause (ovariectomy, OVX) in rats with increased aerobic capacity (high running capacity, HCR) relative to those with low aerobic capacity (low running capacity, LCR). These results are associated with significant differences in gut microbiota and their products (short chain fatty acids) between the two groups.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113123/1/phy212488.pd

The Effect of Hops (Humulus lupulus L.) Extract Supplementation on Weight Gain, Adiposity and Intestinal Function in Ovariectomized Mice

Estrogen decline during menopause is associated with altered metabolism, weight gain and increased risk of cardiometabolic diseases. The gut microbiota also plays a role in the development of cardiometabolic dysfunction and is also subject to changes associated with age-related hormone changes. Phytoestrogens are plant-based estrogen mimics that have gained popularity as dietary supplements for the treatment or prevention of menopause-related symptoms. These compounds have the potential to both modulate and be metabolized by the gut microbiota. Hops (Humulus lupulus L.) contain potent phytoestrogen precursors, which rely on microbial biotransformation in the gut to estrogenic forms. We supplemented ovariectomized (OVX) or sham-operated (SHAM) C57BL/6 mice, with oral estradiol (E2), a flavonoid-rich extract from hops, or a placebo carrier oil, to observe effects on adiposity, inflammation, and gut bacteria composition. Hops extract (HE) and E2 protected against increased visceral adiposity and liver triglyceride accumulation in OVX animals. Surprisingly, we found no evidence of OVX having a significant impact on the overall gut bacterial community structure. We did find differences in the abundance of Akkermansia muciniphila, which was lower with HE treatment in the SHAM group relative to OVX E2 treatment and to placebo in the SHAM group

Monounsaturated fatty acids protect against palmitate-induced lipoapoptosis in human umbilical vein endothelial cells.

Diets high in saturated fatty acids are linked to increased cardiovascular disease risk, whereas monounsaturated fatty acids have been associated with improved cardiovascular outcomes. Accordingly, cell culture studies have demonstrated that saturated fatty acids, particularly long chain saturated fatty acids such as palmitate, induce dysfunction and cell death in a variety of cell types, and monounsaturated fatty acids may confer protection against palmitate-mediated damage. The aim of the present study was to examine whether monounsaturated fatty acids could protect against palmitate-mediated cell death in endothelial cells, to determine if AMPK inactivation and activation (via compound C and AICAR, respectively) underlies both palmitate-induced damage and monounsaturated fatty acid-mediated protection, and to explore the role of ER stress in this context. Human umbilical vein endothelial cells were examined for cell viability and apoptosis following treatment for 24 hours with palmitate (0.25 and 0.5mM) alone or in combination with the monounsaturated fatty acids oleate or palmitoleate (0.25 and 0.5mM), AICAR, compound C, 4μ8C, or TUDCA. Compared to control cells, palmitate significantly decreased cell viability and increased apoptosis in a dose-dependent manner. The monounsaturated fatty acids oleate and palmitoleate completely prevented the cytotoxic effects of palmitate. Although palmitate induced markers of ER stress, chemical inhibition of ER stress did not prevent palmitate-induced lipoapoptosis. Conversely, the AMPK activator AICAR (0.1 and 0.5mM) conferred protection from palmitate mediated-alterations in viability, apoptosis and ER stress, whereas the AMPK inhibitor compound C (20 and 40μM) significantly exacerbated palmitate-mediated damage. Lastly, co-incubation with palmitate, monounsaturated fatty acids, and compound C significantly mitigated the protective effects of both oleate and palmitoleate. In conclusion, monounsaturated fatty acids confer protection against the cytotoxic effects of palmitate in vascular endothelial cells; and palmitate-mediated damage, as well as monounsaturated-mediated protection, are due in part to inactivation and activation, respectively, of the metabolic regulator AMPK. These results may have implications for understanding the deleterious effects of high saturated fat diets on cardiovascular dysfunction and disease risk

Data from: Estradiol-mediated improvements in adipose tissue insulin sensitivity are related to the balance of adipose tissue estrogen receptor α and β in postmenopausal women

We recently demonstrated that short-term estradiol (E2) treatment improved insulin-mediated suppression of lipolysis in postmenopausal women, but to a greater extent in those who were late compared to early postmenopausal. In this follow-up study we tested whether subcutaneous adipose tissue (SAT) expression of estrogen receptors (ER) α and β differs between early and late postmenopausal women. We further tested whether the balance of ERα to ERβ in SAT determined the effect of E2 on SAT insulin sensitivity. The present study included 35 women who were ≤6 years past menopause (EPM; n = 16) or ≥10 years past menopause (LPM; n = 19). Fasted SAT samples were taken following 1-week transdermal E2 treatment or placebo (PL) in a random cross-over design. Samples were analyzed for nuclear/cytosolic protein content and mRNA expression using Western blot and qPCR, respectively. While ESR1 increased slightly (~1.4-fold) following E2 treatment in both groups, ERα and ERβ protein expression did not differ between groups at baseline or in response to E2. However, the balance of ERα/ERβ protein in the SAT nuclear fraction increased 10% in EPM compared to a 25% decrease in LPM women (group x treatment interaction, p<0.05). A greater proportion of ERα/ERβ protein in the nuclear fraction of SAT at baseline (placebo day) was associated with greater reduction in SAT insulin resistance (i.e., better suppression of lipolysis, EC50) in response to E2 (r = -0.431, p<0.05). In conclusion, there do not appear to be differences in the proportion of adipose tissue ERα/ERβ protein in late, compared to early, postmenopausal women. However, the balance of ERα/ERβ may be important for E2-mediated improvement in adipose tissue insulin sensitivity

Estradiol-mediated improvements in adipose tissue insulin sensitivity are related to the balance of adipose tissue estrogen receptor α and β in postmenopausal women

<div><p>We recently demonstrated that short-term estradiol (E₂) treatment improved insulin-mediated suppression of lipolysis in postmenopausal women, but to a greater extent in those who were late compared to early postmenopausal. In this follow-up study we tested whether subcutaneous adipose tissue (SAT) expression of estrogen receptors (ER) α and β differs between early and late postmenopausal women. We further tested whether the balance of ERα to ERβ in SAT determined the effect of E₂ on SAT insulin sensitivity. The present study included 35 women who were ≤6 years past menopause (EPM; n = 16) or ≥10 years past menopause (LPM; n = 19). Fasted SAT samples were taken following 1-week transdermal E₂ treatment or placebo (PL) in a random cross-over design. Samples were analyzed for nuclear/cytosolic protein content and mRNA expression using Western blot and qPCR, respectively. While ESR1 increased slightly (~1.4-fold) following E₂ treatment in both groups, ERα and ERβ protein expression did not differ between groups at baseline or in response to E₂. However, the balance of ERα/ERβ protein in the SAT nuclear fraction increased 10% in EPM compared to a 25% decrease in LPM women (group x treatment interaction, <i>p</i><0.05). A greater proportion of ERα/ERβ protein in the nuclear fraction of SAT at baseline (placebo day) was associated with greater reduction in SAT insulin resistance (i.e., better suppression of lipolysis, EC₅₀) in response to E₂ (r = -0.431, <i>p</i><0.05). In conclusion, there do not appear to be differences in the proportion of adipose tissue ERα/ERβ protein in late, compared to early, postmenopausal women. However, the balance of ERα/ERβ may be important for E₂-mediated improvement in adipose tissue insulin sensitivity.</p><p><b>Trial Registration: Clinical Trials#:</b><a href="https://clinicaltrials.gov/ct2/show/NCT01605071" target="_blank">NCT01605071</a></p></div