Pituitary crosstalk with bone, adipose tissue and brain

Abstract

Traditional textbook physiology has ascribed unitary functions to hormones from the anterior and posterior pituitary gland, mainly in the regulation of effector hormone secretion from endocrine organs. However, the evolutionary biology of pituitary hormones and their receptors provides evidence for a broad range of functions in vertebrate physiology. Over the past decade, we and others have discovered that thyroid-stimulating hormone, follicle-stimulating hormone, adrenocorticotropic hormone, prolactin, oxytocin and arginine vasopressin act directly on somatic organs, including bone, adipose tissue and liver. New evidence also indicates that pituitary hormone receptors are expressed in brain regions, nuclei and subnuclei. These studies have prompted us to attribute the pathophysiology of certain human diseases, including osteoporosis, obesity and neurodegeneration, at least in part, to changes in pituitary hormone levels. This new information has identified actionable therapeutic targets for drug discovery.

Fig. 1. Diversity of pituitary hormone action beyond the traditional effector functions.

Follicle-stimulating hormone (FSH) acts on ovaries to stimulate secretion of oestrogen, which negatively regulates FSH secretion. However, FSH might also act directly on somatic and central organs to stimulate bone resorption, enhance adipose tissue accrual and promote neurodegeneration; in all cases to oppose the known actions of oestrogen on these tissues. Similarly, in addition to stimulating the production of thyroid hormones (tri-iodothyronine (T3) and tetraiodothyronine (T4)) from the thyroid gland, studies show that thyroid-stimulating hormone (TSH) modulates bone and adipose tissue remodelling directly. In addition, adrenocorticotropic hormone (ACTH), oxytocin and arginine vasopressin (AVP) modulate bone mass and have established roles in cortisol secretion (ACTH), parturition (oxytocin), lactation (oxytocin) and sodium homeostasis (AVP). CRH, corticotropin-releasing hormone; GHRH, growth-hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; IGF1, insulin-like growth factor 1; TNF, tumour necrosis factor; TRH, thyrotropin-releasing hormone; TSHβv, TSHβ splice variant.

Fig. 2. Pituitary hormone directly regulates bone cells.

Both osteoclasts and osteoblasts express high levels of G protein-coupled receptors for all pituitary hormones, as well as receptors for the effector hormones that they release from target organs. It has been shown that follicle-stimulating hormone (FSH) acts on FSH receptors (FSHRs) on the osteoclast, and indirectly through FSHRs on macrophages, to release tumour necrosis factor (TNF), which stimulates bone resorption. By contrast, FSHRs on osteoblast precursors (mesenchymal stem cells) suppress osteoblastogenesis. Thyroid-stimulating hormone receptors (TSHRs) on osteoclasts inhibit osteoclastic bone resorption and increase osteoblastic bone formation. The adrenocorticotropic hormone receptor, melanocortin 2 receptor (MC2R), seems to stimulate bone formation, as does the oxytocin receptor (OXTR), whereas AVPR1 activation is anti-anabolic. Although the effects of growth hormone on bone growth and modelling are exerted largely via insulin-like growth factor 1 released from the liver, growth hormone might also have direct actions on both bone cells. In addition, certain pituitary hormones are themselves produced by bone cells and bone marrow cells, including oxytocin and a variant of TSHβ, namely, TSHβ splice variant (TSHβv). Key intracellular signalling cascades downstream of receptor activation, namely, the nuclear factor-kappa B (NF-κB) and MAPK, are shown. The dashed arrow indicates differentiation of mesenchymal stem cells to osteoblasts and the stop arrows indicate inhibition. GHR, growth hormone receptor.

Fig. 3. Pituitary hormones regulate adipose tissue mass accrual and body composition.

Follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH) and oxytocin might regulate adipose tissue mass through different mechanisms. The FSH receptor (FSHR), which is coupled to Gαi, opposes sympathetic tone exerted via the β3-adrenergic receptor on adipocytes, which prevents beiging and thermogenesis. FSH blockade thus causes weight loss by promoting beiging and thermogenesis. Studies also implicate TSH receptor (TSHR) in causing adipogenesis, beiging and lipolysis, but the effect of TSH signalling deficiency on body composition is controversial. Oxytocin receptors (OXTRs) are present on white adipocytes, and their stimulation causes weight loss and reduced adipose tissue accrual; there is also a direct anorexigenic action of oxytocin exerted at the ventromedial hypothalamus. The ventromedial hypothalamus is also the target for leptin released from adipocytes. The dashed arrow indicates activation of the sympathetic nervous system.