Effect of high-dose glucocorticoid treatment on human brown adipose tissue activity: a randomised, double-blinded, placebo-controlled cross-over trial in healthy men.

BACKGROUND: Glucocorticoids (GCs) are widely applied anti-inflammatory drugs that are associated with adverse metabolic effects including insulin resistance and weight gain. Previous research indicates that GCs may negatively impact brown adipose tissue (BAT) activity in rodents and humans. METHODS: We performed a randomised, double-blinded cross-over trial in 16 healthy men (clinicaltrials.govNCT03269747). Participants received 40 mg of prednisone per day for one week or placebo. After a washout period of four weeks, participants crossed-over to the other treatment arm. Primary endpoint was the increase in resting energy expenditure (EE) in response to a mild-cold stimulus (cold-induced thermogenesis, CIT). Secondary outcomes comprised mean 18F-FDG uptake into supraclavicular BAT (SUVmean) as determined by FDG-PET/CT, volume of the BAT depot as well as fat content determined by MRI. The plasma metabolome and the transcriptome of supraclavicular BAT and of skeletal muscle biopsies after each treatment period were analysed. FINDINGS: Sixteen participants were recruited to the trial and completed it successfully per protocol. After prednisone treatment resting EE was higher both during warm and cold conditions. However, CIT was similar, 153 kcal/24 h (95% CI 40-266 kcal/24 h) after placebo and 186 kcal/24 h (95% CI 94-277 kcal/24 h, p = 0.38) after prednisone. SUVmean of BAT after cold exposure was not significantly affected by prednisone (3.36 g/ml, 95% CI 2.69-4.02 g/ml, vs 3.07 g/ml, 95% CI 2.52-3.62 g/ml, p = 0.28). Results of plasma metabolomics and BAT transcriptomics corroborated these findings. RNA sequencing of muscle biopsies revealed higher expression of genes involved in calcium cycling. No serious adverse events were reported and adverse events were evenly distributed between the two treatments. INTERPRETATION: Prednisone increased EE in healthy men possibly by altering skeletal muscle calcium cycling. Cold-induced BAT activity was not affected by GC treatment, which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes. FUNDING: Grants from Swiss National Science Foundation (PZ00P3_167823), Bangerter-Rhyner Foundation and from Nora van der Meeuwen-Häfliger Foundation to MJB. A fellowship-grant from the Swiss National Science Foundation (SNF211053) to WS. Grants from German Research Foundation (project number: 314061271-TRR 205) and Else Kröner-Fresenius (grant support 2012_A103 and 2015_A228) to MR.

DIETARY RATIOS OF N-6/N-3 POLYUNSATURATED FATTY ACIDS DURING MATERNAL PREGNANCY AFFECT HIPPOCAMPAL NEUROGENESIS AND APOPTOSIS IN MOUSE OFFSPRING.

OBJECTIVE: although n-3 polyunsaturated fatty acids (PUFAs) play crucial roles in brain development and function, neither the optimal level of n-3 PUFAs nor the optimal ratio of n-6/n-3 PUFAs in the maternal diet are well defined. In this study, we investigated the effects of dietary n-6/n-3 PUFA ratios during pregnancy on neurogenesis and apoptosis in the brains of mouse offspring. Metods: female C57BL/6J mice were fed one of three diets with high, medium and low ratios of n-6/n-3 PUFAs (15.7:1, 6.3:1, 1.6:1), as well as a high fish oil diet with a n-6/n-3 ratio of 1:5.7; an n-3 PUFA-deficient diet served as control. The feeding regimens began two months before mouse conception and continued for the duration of the pregnancy. The neurogenesis and apoptosis of hippocampal CA3 area in the offspring were detected. RESULTS: compared to the n-3 PUFA-deficient diet, n-3 PUFA-containing diets, particularly those with n-6/n-3 PUFA ratios of 6.3:1 and 1.6:1, significantly increased both phosphorylation of histone H3 at ser 10 (p-H3ser10) and calretinin-positive cells in hippocampus CA3 of the offspring. Furthermore, increased expression of Bcl2 protein, decreased expression of Bax protein, and reduced caspase 3 activity and numbers of TUNEL apoptotic cells were found in the three diets with high, medium and low n-6/n-3 PUFA ratios. However, there were no differences in any of these parameters between the high fish oil diet group and the n-3 PUFA-deficient diet group. CONCLUSIONS: these data suggest that a higher intake of n-3 PUFAs with a lower ratio of n-6/n-3 PUFAs of between about 6:1 to 1:1, supplied to mothers during pregnancy, may benefit brain neurogenesis and apoptosis in offspring. However, excessive maternal intake of n-3 PUFAs may exert a negative influence on brain development in the offspring.

Objetivo: a pesar de que los ácidos grasos poliinsaturados n-3 (PUFAs por sus siglas en inglés) desempeñan un papel fundamental en el desarrollo y en las funciones cerebrales, aún no está bien definido el nivel óptimo de PUFAs n-3 ni la ratio óptima de PUFA n-6/n-3 en la dieta materna. En este estudio hemos investigado los efectos de las ratios nutricionales de PUFA n-6/n-3 durante la gestación sobre la neurogénesis y la apoptosis en el cerebro de crías de ratón. Métodos: se alimentó a hembras de ratón C57BL/6J con una de las tres dietas de estudio: ratio alta, media y baja de PUFA n-6/n-3 (15,7:1, 6,3:1, 1,6:1). También se añadió una dieta rica en aceite de pescado con una ratio n-6/n-3 de 1:5,7; como control se empleó una dieta deficitaria en PUFA n-3. Los regímenes alimenticios se iniciaron dos meses antes de la concepción de los ratones y continuó durante todo el embarazo. Se detectó la neurogénesis y apoptosis del área hipocampal CA3 en las crías. Resultados: en comparación con la dieta deficitaria en PUFA n-3, las dietas con PUFA que contienen n-3, particularmente aquellas con ratios PUFA n-6/n-3 de 6,3:1 y 1,6:1, aumentaron significativamente la fosforilación de histona H3 en la Ser10 (p-H3ser10) y las células calretinina positivas en el área hipocampal CA3 de las crías. Además, se detectó un aumento de la expresión de proteína Bcl2, una reducción de la expresión de proteína Bax, y una reducción de la actividad de caspasa 3, así como de las cifras de células apoptósicas TUNEL en las tres dietas, con ratios altas, medias y bajas de PUFA n-6/n-3. Sin embargo, no se observó diferencias en ninguno de estos parámetros entre el grupo de dieta rica en aceite de pescado y el grupo de dieta deficitaria en PUFA n-3. Conclusiones: estos datos sugieren que una ingesta más elevada de PUFA n-3 con una ratio más baja de PUFAs n-6/n-3 entre 6:1 y 1:1 aproximadamente, administrada a las madres durante la gestación, podría ser beneficiosa para la neurogénesis cerebral y la apoptosis de las crías. Sin embargo, una ingesta excesiva de PUFA n-3 puede ejercer una influencia negativa sobre el desarrollo de las crías.