Proc Natl Acad Sci USA. 2020, Nov; 117(46): 28971–28979https://bit.ly/2RQiZlz
The authors report the generation, structure and function of a fully humanized, humanized antibody that profoundly inhibits follicle-stimulating hormone (FSH) actions in cell-based assays. Administration of the antibody to ovariectomized mice prevented bone loss and also accumulation of adipose tissue when fed a high-fat diet (HFD).
In women, serum levels of FSH increase markedly starting from the 2–3 years before menopause and remain high for many years, due to the lack of ovarian sex hormone feedback inhibition. There are increasing suggestions that, instead of being a passive marker of oocyte depletion, high FSH levels may contribute to the bone loss and visceral fat gains that coincide with these reproductive ageing changes.
To explore this question, the authors targeted a 13-amino-acid sequence in the β-subunit of FSH to produce an antibody with Kd (dissociation constant) 7 nM. Protein thermal shift, molecular dynamics and fine mapping of the FSH–FSH receptor interface confirmed stable binding of the Fab domain to 2 of 5 receptor-interacting residues of the FSH β subunit, which is sufficient to block the interaction of FSH with the FSH receptor. After 2 weeks of administration of the FSH antibody to mice, they observed mitochondrial biogenesis (activation) in brown adipose tissue, and beiging or visceral and subcutaneous white adipose tissue. To build on these findings, they fed male and female mice HFD or normal chow.
These findings show that humanized blocking antibodies to FSH have the potential to prevent and treat obesity, osteoporosis and hypercholesterolemia, particularly when these changes occur at around the menopause. This paradigm-shifting discovery provides the framework for preclinical studies in humans and subsequent clinical trials.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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