Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques

Abstract

The beneficial effects of bioidentical ovarian steroid hormone therapy (HT) during the perimenopause are gaining recognition. However, the positive effects of estrogen (E) plus or minus progesterone (P) administration to ovariectomized (Ovx) lab animals were recognized in multiple systems for years before clinical trials could adequately duplicate the results. Moreover, very large numbers of women are often needed to find statistically significant results in clinical trials of HT; and there are still opposing results being published, especially in neural and cardiovascular systems. One of the obvious differences between human and animal studies is diet. Laboratory animals are fed a diet that is low in fat and refined sugar, but high in micronutrients. In the US, a large portion of the population eats what is known as a “western style diet” or WSD that provides calories from 36% fat, 44% carbohydrates (includes 18.5% sugars) and 18% protein. Unfortunately, obesity and diabetes have reached epidemic proportions and the percentage of obese women in clinical trials may be overlooked. We questioned whether WSD and obesity could decrease the positive neural effects of estradiol (E) in the serotonin system of old macaques that were surgically menopausal. Old ovo-hysterectomized female monkeys were fed WSD for 2.5 years, and treated with placebo, Immediate E (ImE) or Delayed E (DE). Compared to old Ovx macaques on primate chow and treated with placebo or E, the WSD-fed monkeys exhibited greater individual variance and blunted responses to E-treatment in the expression of genes related to serotonin neurotransmission, CRH components in the midbrain, synapse assembly, DNA repair, protein folding, ubiquitylation, transport and neurodegeneration. For many of the genes examined, transcript abundance was lower in WSD-fed than chow-fed monkeys. In summary, an obesogenic diet for 2.5 years in old surgically menopausal macaques blunted or increased variability in E-induced gene expression in the dorsal raphe. These results suggest that with regard to function and viability in the dorsal raphe, HT may not be as beneficial for obese women as normal weight women.

Aging Reduces Estradiol Protection Against Neural but Not Metabolic Effects of Obesity in Female 3xTg-AD Mice

“…Together, these findings suggest that neuroprotective effects of E2 are retained in early-MA even in the presence of a preexisting obese state. In apparent contrast to our observations, recent work in aged female macaques showed that positive effects of E2 on object recognition memory were blunted by obesogenic diet (Bethea et al, 2017). This lack of concordance suggests the possibility of a complex relationship between obesity and E2 neural efficacy during aging that may be affected by several parameters, including specific aspects of diet, aging, and neural measure.…”

Effects of Immediate or Delayed Estradiol on Behavior in Old Menopausal Macaques on Obesogenic Diet

“…When serum E levels declined below 50 pg/ml, the implants were replaced. There is a surge of E immediately after implantation that gradually declines and stabilizes; so, monitoring every 2 months enabled us to maintain the goal on average [ 16 ].…”

“…The behavioral observations were obtained as part of a larger study involving these animals ([ 16 ]).…”

“…In addition, we sought to model single hormone therapy administered during the perimenopause with E replacement immediately upon OvH (ImE) versus E administered long after menopause (as in the WHI) with E replacement 2 years after OvH (DE; 2 monkey years = 6–8 human years). We have reported that WSD blunted or abolished the positive effects of immediate E replacement (ImE) on gene expression in the serotonin neural system [ 16 ], in circadian activity [ 17 ], and in a large number of metabolic parameters [ 18 – 20 ]. All of the monkeys gained weight, although ImE delayed the increase; by the end of the study, all monkeys reached the same average higher weight.…”

Obesogens in Foods

“…There are a number of examples in medicine that synthetically produced chemicals (drugs) may influence the development of adiposity. This usually adverse effect of pharmaceuticals is evidenced in glucocorticoids, estrogens, some antidiabetics (such as insulin, sulphonylureas, thiazolidinediones, glitazones), thyreostatics, dopaminergic blockers, beta sympathetic blockers, and, in some drugs, from the groups of tricyclic antidepressants, selective serotonin re-uptake inhibitors, atypical antipsychotic medicines, antiepileptics, Biomolecules 2022, 12, 680 2 of 18 neuropeptides, and eutonics of the gastrointestinal tract [2][3][4][5][6][7][8]. However, not only medicines, but many compounds introduced in mega doses to the environment over the last decades by human production, were recognized to be able to act as obesogens.…”