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Leptin's balancing act between bone and fat

For decades, investigators from multiple disciplines have pondered the complex relationship governing the distinction between bone and fat within the marrow microenvironment. Pioneering work led by Friedenstein, Owen, and others defined what is now referred to as the bone marrow mesenchymal stromal/stem cell (BMSC) as the common progenitor for both marrow adipocytes and osteoblasts. The relative proportion of these populations changes as a function of advancing age and disease states, such as osteoporosis and aplastic anemia. In their seminal 1992 work, Beresford, Owen, and their colleagues at Oxford University introduced data supporting the hypothesis that an inverse relationship exists between BMSC adipogenesis and osteogenesis, namely, that factors promoting BMSC adipogenic differentiation did so at the expense of osteogenesis and vice versa. This study has set the paradigm that has since been the subject of multiple in vitro and in vivo analyses. Lineage determination by BMSCs has been compared with a seesaw or teeter-totter governed by the relative strength of the adipogenic versus osteogenic factors present within the microenvironment. Almost simultaneous with the publication of Beresford and colleagues, the gene encoding leptin, the first modern adipokine, was mapped and cloned in the ob/ob murine strain. These mice, identified in the 1950 s, were remarkable for their display of hyperphagia and obesity. The discovery of leptin revolutionized our narrow view of adipose tissue as simply a passive energy-storage reservoir. Since then, thousands of articles on leptin alone have documented that adipose tissue is a dynamic endocrine organ contributing to systemic feedback loops integrating multiple peripheral organs with the central nervous system (CNS) as well as adipose tissue metabolism itself. Leptin’s actions are mediated in part through multiple isoforms of its surface receptor which interact with the Janus Kinase (JAK) and STAT transcription factors. Both short and long forms of the leptin receptor exist on undifferentiated BMSCs, on hematopoietic cells, within the hypothalamus of the CNS, on adipocytes, on osteoblasts, and elsewhere. While the ob/ob murine strain displays an inactivating mutation of the leptin gene, the db/db murine strain and the rat fa/fa counterpart reflect an inactivating mutation in the long (but not short) isoform of the leptin receptor. While rodents with all three mutations exhibit hyperphagia and obesity, only the ob/ob strain can be treated effectively by parabiosis to a wild-type control mouse with normal circulating levels of leptin or by treatment with recombinant leptin. A number of studies had reported the impact of leptin or leptin receptor mutations on bone biology in rodent models. Furthermore, leptin expression was detected in bone marrow adipocytes in vivo and found to promote osteogenesis in BMSCs in vitro, implicating leptin as an autocrine and/or paracrine factor locally. However, Ducy and colleagues’ publication in 2000 has remained a landmark study in the field. Using histologic analyses of femoral and vertebral bones, Ducy and colleagues reported that ob/ob mice exhibited increased bone mass relative to wild-type controls. Following chronic intracerebroventricular (ICV) leptin administration, bone mass and strength were reduced in ob/ob and wild-type C57BL6 mice based on X-ray analysis, three-point bending, and histology. Leptin actions were linked to the CNS via feedback loops mediated by the sympathetic nervous system (SNS) and the b-adrenergic receptor pathway. This set the stage for subsequent publications documenting leptin as a bone catabolic agent. This conclusion conforms to the hypothesis that adipose and bone tissue are inversely related because an abundance of adipose tissue and the secretion of leptin downregulate the formation of bone. If only it was this simple! A growing body of evidence complicates the story by suggesting that leptin plays an anabolic role in bone formation. Independent studies reported that ob/ob mice display reduced femoral bone mineral content and density and trabecular bone volume relative to wild-type controls. Furthermore, leptin administration subcutaneously increased bone mineral content while reducing marrow adipocyte numbers in ob/ob mice. Likewise, in rat models, leptin administration reduced bone loss owing to ovariectomy and reduced marrow adipogenesis resulting from tail suspension. COMMENTARY JBMR