Men and women differ in their diurnal expression of monocyte peroxisome proliferator‐activated receptor‐α in the fed but not in the fasted state

Abstract

Peroxisome proliferator-activated receptor-a (PPARa) plays a pivotal role in regulating metabolic response to fasting and is an inhibitor of inflammatory pathways in immune cells. It represents a therapeutic target for treatment of several diseases, mainly hyperlipidemia. To shed light on PPARa expression changes in response to fasting, young healthy male and female volunteers were fed or fasted for 24 hours. Monocytes were analyzed every 2 hours to compile both profiles of mRNA and protein expression of PPARa and its interactive partner, the circadian pacemaker brain and muscle aryl hydrocarbon receptor nuclear translocator like-1 (BMAL1). We found that women change their diurnal expression profiles of PPARa and BMAL1 when switching from the fed to the fasted state, whereas men do not. Interestingly, the PPARa and BMAL1 profiles of men and women in the fed state are different, whereas the profiles in the fasted state are virtually identical. The finding of diametrically opposite responses of male and female PPARa expression in the fed state might have practical implication in human medicine as PPARa activators like fibrates are used for the therapy of chronic lymphocytic leukemia, microvascular complications in diabetes, and kidney diseases.-Wege, N., Schutkowski, A., Boenn, M., Bialek, J., Schlitt, A., Noack, F., Grosse, I., Stangl, G. I. Men and women differ in their diurnal expression of monocyte peroxisome proliferator-activated receptor-a in the fed but not in the fasted state. FASEB J. 29, 2905-2911 (2015). www.fasebj.org Key Words: caloric intake • nuclear receptor • circadian pacemaker FOOD SHORTAGE IS A FREQUENT phenomenon in nature. Hence, organisms have evolved a metabolic program to survive periods of food shortage. During fasting, organisms suspend growth and reproduction, induce defense molecules, and shift whole-body fuel utilization from both carbohydrates and fat to almost exclusively fat (1). This metabolic flexibility is vital to survival. Adaptations to fasting are mediated by peroxisome proliferator-activated receptor-a (PPARa), a nuclear hormone receptor, which plays a pivotal role as a nutritional state sensor and key regulator in the mediation of metabolic responses to fasting (2, 3). Besides its pivotal role in fasting adaptation, there is emerging evidence that PPARa exerts antiinflammatory effects in cells and animals (4-6) and that it mediates the delay of aging and the extension of lifespan in response to caloric restriction (7). It further serves as receptor for therapeutic PPARa agonists such as fibrates that have been widely used as drugs to reduce high lipid levels in plasma (8). Human PPARa is expressed among various tissues with high expression levels in immune cells (4). Its expression is, among other factors, regulated by brain and muscle aryl hydrocarbon receptor nuclear translocator like-1 (BMAL1), a basic helix-loop-helix protein that functions as circadian pacemaker (9, 10) and that is involved in regulation of energy homeostasis (11).Despite the significant phys...

A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

“…The data in Figure suggest that sex differences in PPARα are involved in sex differences in hypertrophy. This hypothesis would be consistent with data showing sex differences in the regulation of PPARα . Of note in PPARα‐knockout mice, inhibition of carnitine palmitoyltransferase I resulted in death of 100% of the male mice but only 25% of the female mice, suggesting sex differences in the response to changes in PPARα .…”

“…This hypothesis would be consistent with data showing sex differences in the regulation of PPARa. [61][62][63] Of note in PPARa-knockout mice, inhibition of carnitine palmitoyltransferase I resulted in death of 100% of the male mice but only 25% of the female mice, suggesting sex differences in the response to changes in PPARa. 64 We reasoned that if PPARa mediates the sex difference in hypertrophy, elimination of sex differences in PPARa using an acute 3-week treatment with an inhibitor should block the sex differences in the development of hypertrophy.…”

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