Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice

Abstract

Leptin, critical in regulation of energy metabolism, is also important for normal bone growth, maturation and turnover. Compared to wild type (WT) mice, bone mass is lower in leptin-deficient ob/ob mice; osteopenia in growing ob/ob mice is due to decreased bone accrual, and is associated with reduced longitudinal bone growth, impaired cancellous bone maturation and increased marrow adipose tissue (MAT). However, leptin deficiency also results in gonadal dysfunction, disrupting production of gonadal hormones which regulate bone growth and turnover. The present study evaluated the role of increased oestrogen in mediating the effects of leptin on bone in ob/ob mice. Three-month-old female ob/ob mice were randomized into one of 3 groups: (1) ob/ob+vehicle (veh), (2) ob/ob+leptin (leptin), or (3) ob/ob+leptin and the potent oestrogen receptor antagonist ICI 182,780 (leptin+ICI). Age-matched WT mice received vehicle. Leptin (40 μg/mouse, daily) and ICI (10 μg/mouse, 2x/w) were administered by sc injection for 1 month and bone analyzed by x-ray absorptiometry, microcomputed tomography, and static and dynamic histomorphometry. Uterine weight did not differ between ob/ob mice and ob/ob mice receiving leptin+ICI, indicating that ICI successfully blocked the uterine response to leptin-induced increases in oestrogen levels. Compared to leptin-treated ob/ob mice, ob/ob mice receiving leptin+ICI had lower uterine weight, did not differ in weight loss, MAT, or bone formation rate, and had higher longitudinal bone growth rate and cancellous bone volume fraction. We conclude that increased oestrogen signaling following leptin treatment is dispensable for the positive actions of leptin on bone and may attenuate leptin-induced bone growth.

Leptin stimulates aromatase in the growth plate: limiting catch-up growth efficiency

“…The increase in aromatase expression enhanced the aromatization process of testosterone to estrogen, increased locally produced estrogen then bound to its receptors (also increased), enhancing the senescent decline in the GP chondrocyte proliferation rate, reducing GP height and leading to incomplete CUG. Our results are also supported by a recent study showing a significant higher longitudinal growth rate in animals treated with leptin + estrogen receptor inhibitor compared to leptintreated group, indicating that the concurrent increase in estrogen levels during leptin treatment antagonizes the growth-promoting actions of leptin (Turner 2017).…”

Effect of Leptin Deficiency on the Skeletal Response to Hindlimb Unloading in Adult Male Mice

“…Lower testosterone levels potentially contribute to elevated bone resorption and cancellous bone loss 43 . However, in spite of gonadal insufficiency, leptin deficiency typically results in a low turnover skeletal phenotype in ob/ob mice of both sexes 44 . The precise role of androgens in mediating the action of leptin on bone is unknown but antagonism of estrogen receptor signaling was largely dispensable for leptin’s actions in female ob/ob mice 44 .…”

“…However, in spite of gonadal insufficiency, leptin deficiency typically results in a low turnover skeletal phenotype in ob/ob mice of both sexes 44 . The precise role of androgens in mediating the action of leptin on bone is unknown but antagonism of estrogen receptor signaling was largely dispensable for leptin’s actions in female ob/ob mice 44 . The present results, identifying similar bone loss in HU WT and HU ob/ob mice, suggest that preexisting hypogonadism in male ob/ob mice did not have a major influence on the magnitude of bone loss following HU.…”

Leptin action in normal and pathological pregnancies

“…Mutations in the leptin gene, in human and/or mouse models, result in infertility or significant reproductive dysfunction . Leptin is required for the release of gonadotrophin‐releasing hormone (GnRH) from the pituitary, and as a consequence, female ob/ob mice (deficient in leptin) have reduced oestrogen levels and exhibit low uterine weight . Male ob/ob mice also show reduced GnRH levels and diminished production of luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) as well as testosterone, an essential hormone for the maintenance of male fertility and testicular function .…”