A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms

Abstract

Thanks to integrative physiology, new relationships between organs and homeostatic functions have emerged. This approach to physiology based on a whole organism approach has allowed the bone field to make fundamental progress. In the last decade, clinical observations and scientific evidences in vivo have uncovered that fat with leptin controls bone mass through brain including a hypothalamic relay and sympathetic nervous system. The finding that energy metabolism affects bone remodelling suggested that in an endocrine perspective, a feedback loop should exist. Beside its classical functions, bone can now be considered as a true endocrine organ secreting osteocalcin, a hormone pharmacologically active on glucose and fat metabolism. Indeed osteocalcin stimulates insulin secretion and β-cell proliferation. Simultaneously, osteocalcin acts on adipocytes to induce Adiponectin which secondarily reduce insulin resistance. This cross regulation between bone and energy metabolism offers novel therapeutic targets in type 2 diabetes and osteoporosis.

Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice

“…(reviewed in refs (24) and (25) ). Leptin interacts directly or indirectly with these systems, thereby accounting for some of the differential effects reported for leptin in different bone compartments.…”

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

“…Leptin is a gut and adipose tissue-derived hormone that regulates a range of biological functions and processes, including energy intake and expenditure, body fat, neuroendocrine systems, autonomic function, and insulin and glucose balance (12). Leptin receptors, LepRb, are located on neurons throughout the central nervous system as well as on VAN and other peripheral tissue.…”

The white adipose tissue connection with calcium and bone homeostasis

“…The contribution of the central role of leptin on neuroendocrine signaling in the hypothalamic region and its ultimately negative effects on (trabecular) bone formation, resorption, and bone mass by activating the sympathetic nerve signaling pathway has been amply demonstrated by a series of studies in at least 10 transgenic mouse models (mostly females) and has been confirmed by several intervention studies in other mouse models by the Karsenty group. (3,4) Several other groups, however, found leptin to have a positive effect on (mostly male) bone. Indeed, several studies did not confirm the increased bone mass in ob/ob mice (8,27) and found that, in contrast to the Karsenty data, peripheral leptin administration increased femoral length and bone mass in ob/ob mice.…”

“…(1) Leptin then crosses the blood-brain barrier to activate its receptor in the hypothalamic regions, thereby starting a complex feedback on energy intake and expenditure but also regulating other systems such as sexual maturation and reproduction (2) and bone homeostasis. (3) Indeed, a series of elegant studies of the Karsenty group clearly demonstrated that central activation of leptin signaling activates the sympathetic postganglionic neuronal system that ultimately decreases bone formation and increases bone resorption. (3,4) Leptin receptors are also found outside the hypothalamus in insulin-producing b cells, bone marrow stromal cells, osteoblasts and chondrocytes, and kidney cells.…”

“…(3) Indeed, a series of elegant studies of the Karsenty group clearly demonstrated that central activation of leptin signaling activates the sympathetic postganglionic neuronal system that ultimately decreases bone formation and increases bone resorption. (3,4) Leptin receptors are also found outside the hypothalamus in insulin-producing b cells, bone marrow stromal cells, osteoblasts and chondrocytes, and kidney cells. (5) This suggests a much wider spectrum of activities for this fat cell signal, not mediated by a central neuroendocrine system.…”