Obesity and osteoporosis are endemic in our society yet their relationship is perplexing. While obesity has long been considered beneficial for skeletal health, recent studies suggest bone mass is diminished in a substantial subset of obese individuals. Thus, despite its demographic importance, the influence of fat on bone remains enigmatic. Although controversial, studies of the effect of fat-produced molecules, such as leptin and adiponectin, indicate these selected adipokines impact bone. Adipose tissue is, however, a complex organ and there is little mechanistic insight as to how fat, per se, and which variety of fat, regulates the skeleton. Such information is clinically relevant as individuals with a predominance of visceral fat are osteopenic whereas subcutaneous and brown fat may positively influence bone mass. Determination of how fat, in its various forms, targets bone cells will provide the framework for ameliorating the skeletal complications of obesity. Resolution of this issue, in patients, is limited, however, by the absence of an animal model in which manipulation of fat abundance eventuates in a robust skeletal phenotype. To this end, we generated mice completely lacking visceral, subcutaneous and brown fat. Despite the hypogonadal state of these fat free (FF) mice, trabecular bone volume is strikingly increased (400-500%) due to enhanced osteoblast activity. Unexpectedly in face of its marked increase in bone mass, osteoclastogenesis in FF mice is also markedly enhanced. This observation raises the possibility that visceral fat diminishes bone mass by arresting osteoclast-induced remodeling. Our observations establish that, by mechanisms to be determined, fat signals to bone and decreased adiposity may greatly increase bone mass, challenging the concept that obesity generally improves skeletal health. Most importantly, the skeletal phenotype of FF mice is completely rescued by adipocyte precursor transplantation. This transplantation-mediated normalization of FF bone provides the opportunity to directly explore the impact of deleting various adipocyte products on bone accrual and how visceral, subcutaneous and/or brown adipose tissue targets the skeleton. Hence, we hypothesize that fat diminishes bone accrual in an osteoblast- and osteoclast-dependent manner.
. For reasons unknown, many obese people have a decreased amount of bone and are predisposed to fracture. This project will study a mouse that completely lacks fat yet has a 4-5 fold increase in bone proving that fat decreases skeletal mass. The results will determine how fat regulates bone and as such provide potential therapeutic strategies to diminish osteoporosis and fractures in obese patients.
| Rohatgi, Nidhi; Zou, Wei; Collins, Patrick L et al. (2018) ASXL1 impairs osteoclast formation by epigenetic regulation of NFATc1. Blood Adv 2:2467-2477 |
| Zhang, Yan; Rohatgi, Nidhi; Veis, Deborah J et al. (2018) PGC1? Organizes the Osteoclast Cytoskeleton by Mitochondrial Biogenesis and Activation. J Bone Miner Res 33:1114-1125 |
