Abstract
Estrogens are important for maintaining metabolic health in males. However, the key sources of local estrogen production for regulating energy metabolism have not been fully defined. Immune cells exhibit aromatase activity and are resident in metabolic tissues. To determine the relative contribution of immune cell-derived estrogens for metabolic health in males, C57BL6/J mice underwent bone marrow transplant with marrow from either wild-type (WT(WT)) or aromatase-deficient (WT(ArKO)) donors. Body weight, body composition, and glucose and insulin tolerance were assessed over 24 weeks with mice maintained on a regular chow diet. No differences were found in insulin sensitivity between groups, but WT(ArKO) mice were more glucose tolerant than WT(WT) mice 20 weeks after transplant, suggestive of enhanced glucose disposal (AUCglucose 6061±3349 in WT(WT) mice versus 3406±1367 in WT(ArKO) mice, p = 0.01). Consistent with this, skeletal muscle from WT(ArKO) mice showed higher expression of the mitochondrial genes Ppargc1a (p = 0.03) and Nrf1 (p = 0.01), as well as glucose transporter type 4 (GLUT4, Scl2a4; p = 0.02). Skeletal muscle from WT(ArKO) mice had a lower concentration of 17β-estradiol (5489±2189 pg/gm in WT(WT) mice versus 3836±2160 pg/gm in WT(ArKO) mice, p = 0.08) but higher expression of estrogen receptor-α (ERα, Esr1), raising the possibility that aromatase deficiency in immune cells led to a compensatory increase in ERα signaling. No differences between groups were found with regard to body weight, adiposity, or gene expression within adipose tissue or liver. Immune cells are a key source of local 17β-estradiol production and contribute to metabolic regulation in males, particularly within skeletal muscle. The respective intracrine and paracrine roles of immune cell-derived estrogens require further delineation, as do the pathways that regulate aromatase activity in immune cells specifically within metabolic tissues.
Highlights
Estrogens are recognized to play important metabolic roles in men
Adipocyte size did not differ between groups in either inguinal or epididymal adipose tissue (Fig 8C and 8D). These findings demonstrate novel evidence that immune cells contribute to total estrogen generation in metabolic tissues and support the importance of immune cell-derived estrogens for regulating metabolic health in males
This enhanced glucose tolerance occurred in the absence of differences in body weight, lean body mass, or adiposity between WT(WT) and WT(ArKO) mice
Summary
Estrogens are recognized to play important metabolic roles in men. Initial evidence that men require adequate estrogen exposure for metabolic health derived from men with rare genetic syndromes of estrogen deficiency. Clinical intervention studies have shown that short-term estrogen deprivation in men results in increased adiposity [3, 4] and reduced insulin sensitivity [5]. In parallel with these clinical observations, genetic mouse models have demonstrated the importance of estrogens for regulating energy balance, body composition, insulin sensitivity, and skeletal health in males [6,7,8]. Similar to men with estrogen insufficiency, male mice with global aromatase deficiency exhibit increased adiposity, insulin resistance, and lower bone mass [9, 10]. The mechanisms underlying estrogen-mediated metabolic regulation in males remain incompletely understood, and the key tissue-specific sites of estrogen action, as well as local sources of estrogen production, have to yet be clearly defined
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