Congenital lipodystrophy induces severe osteosclerosis

Abstract

Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated "fat-free" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals. FF mice, like Berardinelli-Seip patients, are diabetic but normalization of glucose tolerance and significant reduction in circulating insulin fails to alter their skeletal phenotype. Importantly, the skeletal phenotype of FF mice is completely rescued by transplantation of adipocyte precursors or white or brown fat depots, indicating that adipocyte derived products regulate bone mass. Confirming such is the case, transplantation of fat derived from adiponectin and leptin double knockout mice, unlike that obtained from their WT counterparts, fails to normalize FF bone. These observations suggest a paucity of leptin and adiponectin may contribute to the increased bone mass of Berardinelli-Seip patients.

Increased marrow adipogenesis does not contribute to age‐dependent appendicular bone loss in female mice

“…The modest skeletal effects of marrow adipocyte ablation in the present study contrasts with the high bone mass seen in mouse models of lipodystrophy (Sun et al, 2013; Zou et al, 2019). Nevertheless, when peripheral, but not marrow adipocytes, are ablated, bone mass is still increased (Zou et al, 2019), arguing against a role of bone marrow adipocytes in this lipodystrophy model.…”

Adipose Tissue is a Critical Regulator of Osteoarthritis

“…The timeline for these studies is depicted in Supplementary Figure 1. In the transplantation studies, male and female LD mice received either a mouse embryonic fibroblast transplant (MEF-rescue, (17) between 3-5 weeks of age, or wildtype fat transplant containing visceral and subcutaneous fat (WT fat-rescue (14,15)) between 6-8 weeks of age. At 16-weeks, surgical animals underwent surgery for destabilization of the medial meniscus (DMM) in their left knee joints, and the right limb served as a non-surgical contralateral control (6,9,10,41).…”

“…Mature fat depots were implanted in accordance with previously described methods (14,15). Donor WT mice (6-8 weeks old) were euthanized and subcutaneous and visceral fat pads were harvested and cut into 100-150 mg pieces, in PBS on ice.…”

“…To directly investigate the mechanisms by which fat affects OA, we used a transgenic mouse with lipodystrophy (LD) that completely lacks adipose tissue and therefore, adipokine signaling. The LD model system affords the unique opportunity to directly examine the effects of adipose tissue and its secretory factors on musculoskeletal pathology without the confounding effect of diet (14,15). LD mice completely lack adipose tissue depots, demonstrate similar body mass to WT controls on a chow diet, but exhibit metabolic dysfunction similar to mice with obesity (12,(14)(15)(16)(17).…”

Hepatic lipids promote liver metastasis

“…The skeleton is the primary target of metastatic breast cancer, but the relationship between bone mass and metastatic predisposition is unknown. To address this issue, we turned to DTA-Stop-flox-Adipoq Cre “fat-free” (FF) mice, which lack brown adipose tissue (BAT) and white adipose tissue (WAT) via germline depletion ( 7 ) and are substantially osteosclerotic. However, we found no effect of enhanced bone mass on breast cancer metastasis to the skeleton.…”