Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat

Abstract

The hypothalamus regulates the skeleton and adipose tissue via endocrine mechanisms. Changes in sex steroid levels in menopause and aging are central to the associated changes in bone mass and adiposity. Whereas many of these effects occur via direct actions on osteoblasts or adipocytes, sex hormones can also mediate effects on bone and adipose tissue via interaction with neuronal pathways. A key hypothalamic regulator of bone and adipose tissue is neuropeptide Y (NPY), which coordinately influences these tissues via effects on neuroendocrine and sympathetic nervous output. Better understanding of the interaction between NPY and sex steroids in regulating skeletal and energy homeostasis could lead to more effective treatments for osteoporosis and obesity. Neuroendocrine control of bone and fatOsteoporosis and excess central adiposity, increasingly prevalent in ageing populations, increase the risk of fractures and diseases such as type-2 diabetes mellitus, and adversely affect both quality of life and survival. The regulation of bone and adipose tissue mass has traditionally been studied independently, but osteoblasts and adipocytes are derived from the same mesenchymal precursor cells, and recent findings that the bone-or fat-derived hormones, osteocalcin and leptin, have significant effects on energy homeostasis and bone [1], respectively, now suggest that bone and adipose tissue share common regulatory pathways. The hypothalamus acts as a pivotal regulator of homeostasis in bone and adipose tissue via regulation of hypothalamopituitary axes. For instance, activation of the hypothalamo-pituitary-adrenal axis, or inhibition of the hypothalamo-pituitary-somatotropic or -gonadotropic axes (as in stress or negative energy balance), can affect circulating concentrations of cortisol, insulin like growth factor-1 (IGF-1) and sex steroids that inhibit bone formation while promoting conservation of fat mass, particularly central adiposity 2, 3 and 4. Sex hormones -a major focus of this review -influence bone and fat via direct actions on osteoblasts or adipocytes 2, 3, 5, 6, 7 and 8. Recently, however, it has been recognized that sex hormones can influence these tissues via the neuropeptide Y (NPY) system (Box 1) 9, 10, 11 and 12, that also regulates bone and adipocyte homeostasis via actions in the hypothalamus and peripheral tissues 9, 13 and 14. In this review we examine the role of sex hormones in skeletal and energy homeostasis, with particular focus on their interaction with NPY. Whereas research into the isolated effects of sex hormones or the NPY system on bone and adipose tissue homeostasis has led to identification of potential novel drug targets for the treatment of osteoporosis or central obesity, emerging research into the interaction of these systems could pave the way for even better treatments for these conditions, particularly in the context of reduced circulating concentrations of sex hormones, as in menopause or ageing in women and in men. Zenging et al.: Trends in Endocrinology & Metabolism, 2(7): 4...

Increased PTHrP and Decreased Estrogens Alter Bone Turnover but Do Not Reproduce the Full Effects of Lactation on the Skeleton

“…Thus, hyperprolactinemia may be an additional factor required for bone loss during lactation. Finally, it has become increasingly clear that bone cell behavior can be regulated by direct neural input from the hypothalamus (61)(62)(63). In this regard, it is interesting to note that suckling stimulates the production of neuropeptide Y (NPY) in the hypothalamus and that NPY contributes to alterations in feeding behavior and GnRH secretion during lactation (15,64,65).…”

Corticosterone Regulates the Expression of Neuropeptide Y and Reelin in MLO-Y4 Cells

“…NPY is a potential modulator of bone remodeling. It exerts hypothalamic actions on the bone and adipose tissues and locally affects osteoblasts and adipocytes (Karsenty, 2000;Zengin et al, 2010). Recent studies have demonstrated NPY expression in osteocytes and an inhibitory effect of NPY on the osteoblast activity Paic et al, 2009).…”

Rodent Models of Aging Bone: An Update

“…A direct role has been described in the recent years for cannabinoid receptors (G-protein-coupled receptor superfamily) in the prevention of age-related osteoporosis using a knockout mouse for the cannabinoid receptor (CB1 −/− mice) [45]. Interactions between the neuromodulator, neuropeptide Y, and sex hormones in the regulation of bone and fat have also now been suggested based on a body of work with genetically modified mouse models for neuromodulatory agents and estrogen receptors [46]. It will be interesting to see how this translates into the "switch" between bone and fat cells in the aging marrow [46].…”

“…Interactions between the neuromodulator, neuropeptide Y, and sex hormones in the regulation of bone and fat have also now been suggested based on a body of work with genetically modified mouse models for neuromodulatory agents and estrogen receptors [46]. It will be interesting to see how this translates into the "switch" between bone and fat cells in the aging marrow [46]. Recently, a hitherto unrecognized protein known to be involved in neuronal cell migration and development has also been shown to display bone effects [47•].…”