Kathleen V. Axen

Biological sex and menstrual cycle phase modulation of cortisol levels and psychiatric symptoms in a non-clinical sample of young adults.

Prior research examined the complex, bidirectional interplay of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal axes and their roles in (clinical) cognitive/behavioral functions. Less well understood are contemporaneous relationships in non-clinical samples. This pilot study explored cortisol in relation to psychiatric symptoms/personality as a function of self-reported menstrual cycle phase and sex differences in a non-clinical, young adult sample. Consistent with literature and hypotheses, cortisol levels were lowest during early-follicular, intermediary during late-follicular, and highest during mid-luteal phases (not significant), and greater among males than early-follicular females. An acute stressor uniformly affected cortisol across phases and sex, though magnitude and time course differed. Psychiatric symptoms were greater among early-follicular/late-follicular females versus males, and early-follicular and/or late-follicular versus mid-luteal. Contrary to hypotheses, positive psychotic-like symptoms were greater among males than (mid-luteal) females. Cortisol inversely related to early-follicular symptoms, and directly related to late-follicular/mid-luteal symptoms. Results suggest menstrual cycle phase modulates non-clinical psychiatric symptomatology and HPA activity. Findings tentatively bolster a dimensional/continuum model of psychopathology with implications for understanding neurobiological underpinnings and risk/protective factors for mental/physical health conditions, particularly those marked by sex differences and neuroendocrine dysfunction (depression/schizophrenia/Alzheimers/multiple sclerosis). We speculate a dose-response cortisol effect on symptoms, modulated by endogenous gonadal hormones via gene expression.

Very low-carbohydrate versus isocaloric high-carbohydrate diet in dietary obese rats.

Objective: The effects of a very low‐carbohydrate (VLC), high‐fat (HF) dietary regimen on metabolic syndrome were compared with those of an isocaloric high‐carbohydrate (HC), low‐fat (LF) regimen in dietary obese rats.

Longitudinal Adaptations to Very Low–carbohydrate Weight‐reduction Diet in Obese Rats: Body Composition and Glucose Tolerance

Longitudinal effects of a very low–carbohydrate (VLC) and a calorie‐matched high‐carbohydrate (HC) weight reduction diet were compared in dietary obese Sprague–Dawley rats exhibiting impaired glucose tolerance and insulin resistance. Obese rats were divided into weight‐matched groups: (i) VLC rats consumed an energy‐restricted 5% carbohydrate, 60% fat diet for 8 weeks, (ii) HC rats consumed an isocaloric 60% carbohydrate, 15% fat diet, and (iii) HF rats consumed a high‐fat diet ad libitum. HC and VLC rats showed similar reductions in body fat and hepatic lipid at the midpoint of the weight‐reduction program, indicating effects due to energy deficit. At the end point, however, HC rats showed greater reductions in total and percent body fat, hepatic lipid and intramuscular lipid than did VLC rats, suggesting that diet composition induced changes in the relative efficiencies of the HC and VLC diets over time. HC rats showed marked improvement in glucose tolerance at the midpoint and end point, whereas VLC rats showed no improvement. Impaired glucose tolerance in VLC rats at the end point was due to insulin resistance and an attenuated insulin secretory response. Glucose tolerance in energy‐restricted rats correlated negatively with hepatic and intramuscular lipid levels, but not visceral or total fat mass. These findings demonstrate that adaptations to diet composition eventually enabled HC rats to lose more body fat than VLC rats even though energy intakes were equal, and suggest that the elevated levels of hepatic and intramuscular lipid associated with VLC diets might predispose to insulin resistance and impaired glucose tolerance despite weight loss.

Choline prevents fetal overgrowth and normalizes placental fatty acid and glucose metabolism in a mouse model of maternal obesity

Maternal obesity increases placental transport of macronutrients, resulting in fetal overgrowth and obesity later in life. Choline participates in fatty acid metabolism, serves as a methyl donor and influences growth signaling, which may modify placental macronutrient homeostasis and affect fetal growth. Using a mouse model of maternal obesity, we assessed the effect of maternal choline supplementation on preventing fetal overgrowth and restoring placental macronutrient homeostasis. C57BL/6J mice were fed either a high-fat (HF, 60% kcal from fat) diet or a normal (NF, 10% kcal from fat) diet with a drinking supply of either 25 mM choline chloride or control purified water, respectively, beginning 4 weeks prior to mating until gestational day 12.5. Fetal and placental weight, metabolites and gene expression were measured. HF feeding significantly (P<.05) increased placental and fetal weight in the HF-control (HFCO) versus NF-control (NFCO) animals, whereas the HF choline-supplemented (HFCS) group effectively normalized placental and fetal weight to the levels of the NFCO group. Compared to HFCO, the HFCS group had lower (P<.05) glucose transporter 1 and fatty acid transport protein 1 expression as well as lower accumulation of glycogen in the placenta. The HFCS group also had lower (P<.05) placental 4E-binding protein 1 and ribosomal protein s6 phosphorylation, which are indicators of mechanistic target of rapamycin complex 1 activation favoring macronutrient anabolism. In summary, our results suggest that maternal choline supplementation prevented fetal overgrowth in obese mice at midgestation and improved biomarkers of placental macronutrient homeostasis.

Choline Supplementation Normalizes Fetal Adiposity and Reduces Lipogenic Gene Expression in a Mouse Model of Maternal Obesity

Maternal obesity increases fetal adiposity which may adversely affect metabolic health of the offspring. Choline regulates lipid metabolism and thus may influence adiposity. This study investigates the effect of maternal choline supplementation on fetal adiposity in a mouse model of maternal obesity. C57BL/6J mice were fed either a high-fat (HF) diet or a control (NF) diet and received either 25 mM choline supplemented (CS) or control untreated (CO) drinking water for 6 weeks before timed-mating and throughout gestation. At embryonic day 17.5, HF feeding led to higher (p < 0.05) percent total body fat in fetuses from the HFCO group, while the choline supplemented HFCS group did not show significant difference versus the NFCO group. Similarly, HF feeding led to higher (p < 0.05) hepatic triglyceride accumulation in the HFCO but not the HFCS fetuses. mRNA levels of lipogenic genes such as Acc1, Fads1, and Elovl5, as well as the transcription factor Srebp1c that favors lipogenesis were downregulated (p < 0.05) by maternal choline supplementation in the HFCS group, which may serve as a mechanism to reduce fat accumulation in the fetal liver during maternal HF feeding. In summary, maternal choline supplementation improves indices of fetal adiposity in obese dams at late gestation.

Maternal Choline and Betaine Supplementation Modifies the Placental Response to Hyperglycemia in Mice and Human Trophoblasts

Gestational diabetes mellitus (GDM) is characterized by excessive placental fat and glucose transport, resulting in fetal overgrowth. Earlier we demonstrated that maternal choline supplementation normalizes fetal growth in GDM mice at mid-gestation. In this study, we further assess how choline and its oxidation product betaine influence determinants of placental nutrient transport in GDM mice and human trophoblasts. C57BL/6J mice were fed a high-fat (HF) diet 4 weeks prior to and during pregnancy to induce GDM or fed a control normal fat (NF) diet. The HF mice also received 25 mM choline, 85 mM betaine, or control drinking water. We observed that GDM mice had an expanded placental junctional zone with an increased area of glycogen cells, while the thickness of the placental labyrinth zone was decreased at E17.5 compared to NF control mice (p < 0.05). Choline and betaine supplementation alleviated these morphological changes in GDM placentas. In parallel, both choline and betaine supplementation significantly reduced glucose accretion (p < 0.05) in in vitro assays where the human choriocarcinoma BeWo cells were cultured in high (35.5 mM) or normal (5.5 mM) glucose conditions. Expression of angiogenic genes was minimally altered by choline or betaine supplementation in either model. In conclusion, both choline and betaine modified some but not all determinants of placental transport in response to hyperglycemia in mouse and in vitro human cell line models.