Abstract
Epididymal white adipose tissue (eWAT) secretes an array of cytokines to regulate the metabolism of organs and tissues in high-fat diet (HFD)-induced obesity, but its effects on bone metabolism are not well understood. Here, we report that macrophages in eWAT are a main source of osteopontin, which selectively circulates to the bone marrow and promotes the degradation of the bone matrix by activating osteoclasts, as well as modulating bone marrow-derived macrophages (BMDMs) to engulf the lipid droplets released from adipocytes in the bone marrow of mice. However, the lactate accumulation induced by osteopontin regulation blocks both lipolysis and osteoclastogenesis in BMDMs by limiting the energy regeneration by ATP6V0d2 in lysosomes. Both surgical removal of eWAT and local injection of either clodronate liposomes (for depleting macrophages) or osteopontin-neutralizing antibody show comparable amelioration of HFD-induced bone loss in mice. These results provide an avenue for developing therapeutic strategies to mitigate obesity-related bone disorders.
Highlights
Epididymal white adipose tissue secretes an array of cytokines to regulate the metabolism of organs and tissues in high-fat diet (HFD)-induced obesity, but its effects on bone metabolism are not well understood
(rBMAT). constitutive BMAT (cBMAT) is a contiguous group of adipocytes that predominate at distal skeletal sites, whereas regulated BMAT (rBMAT) is interspersed with the haematopoietic bone marrow in the proximal tibia21,22. rBMAT adipocytes are more closely situated in areas of high bone turnover and are better positioned to actively influence bone remodelling[23]
The body weight began to diverge at week 2 when the HFD-fed group showed a significantly greater body weight than the normal-fat diet (NFD)-fed group (Fig. 1a). epididymal white adipose tissue (WAT) (eWAT) showed a significantly greater mass at week 4 in the HFD-fed group than in the NFD-fed group, and its mass peaked at week 12 (Fig. 1b)
Summary
Epididymal white adipose tissue (eWAT) secretes an array of cytokines to regulate the metabolism of organs and tissues in high-fat diet (HFD)-induced obesity, but its effects on bone metabolism are not well understood. The lactate accumulation induced by osteopontin regulation blocks both lipolysis and osteoclastogenesis in BMDMs by limiting the energy regeneration by ATP6V0d2 in lysosomes Both surgical removal of eWAT and local injection of either clodronate liposomes (for depleting macrophages) or osteopontin-neutralizing antibody show comparable amelioration of HFD-induced bone loss in mice. Growing epidemiological evidence offers an explanation that the metabolic syndrome of visceral obesity is responsible for bone loss through the secretion of proinflammatory cytokines and hormones, such as tumour necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β)[3,4] These released cytokines can metabolically regulate other organs and tissues, such as the liver, skeletal muscle, and cardiovascular system[4,5], while their regulations on bone metabolism is far from clear. RBMAT is a dynamic compartment that performs lipolysis and lipogenesis related to ageing, inflammation, obesity, and type 2 diabetes, as well as being relevant in therapeutic contexts such as radiotherapy or glucocorticoid treatment[23]
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