Increased Circulating Adiponectin in Response to Thiazolidinediones: Investigating the Role of Bone Marrow Adipose Tissue

Abstract

BackgroundBone marrow adipose tissue (MAT) contributes to increased circulating adiponectin, an insulin-sensitizing hormone, during caloric restriction (CR), but whether this occurs in other contexts remains unknown. The antidiabetic thiazolidinediones (TZDs) also promote MAT expansion and hyperadiponectinemia, even without increasing adiponectin expression in white adipose tissue (WAT).ObjectivesTo test the hypothesis that MAT expansion contributes to TZD-associated hyperadiponectinemia, we investigated the effects of rosiglitazone, a prototypical TZD, in wild-type (WT) or Ocn-Wnt10b mice. The latter resist MAT expansion during CR, leading us to postulate that they would also resist this effect of rosiglitazone.DesignMale and female WT or Ocn-Wnt10b mice (C57BL/6J) were treated with or without rosiglitazone for 2, 4, or 8 weeks, up to 30 weeks of age. MAT content was assessed by osmium tetroxide staining and adipocyte marker expression. Circulating adiponectin was determined by ELISA.ResultsIn WT mice, rosiglitazone caused hyperadiponectinemia and MAT expansion. Compared to WT mice, Ocn-Wnt10b mice had significantly less MAT in distal tibiae and sometimes in proximal tibiae; however, interpretation was complicated by the leakage of osmium tetroxide from ruptures in some tibiae, highlighting an important technical consideration for osmium-based MAT analysis. Despite decreased MAT in Ocn-Wnt10b mice, circulating adiponectin was generally similar between WT and Ocn-Wnt10b mice; however, in females receiving rosiglitazone for 4 weeks, hyperadiponectinemia was significantly blunted in Ocn-Wnt10b compared to WT mice. Notably, this was also the only group in which tibial adiponectin expression was lower than in WT mice, suggesting a close association between MAT adiponectin production and circulating adiponectin. However, rosiglitazone significantly increased adiponectin protein expression in WAT, suggesting that WAT contributes to hyperadiponectinemia in this context. Finally, rosiglitazone upregulated uncoupling protein 1 in brown adipose tissue (BAT), but this protein was undetectable in tibiae, suggesting that MAT is unlikely to share thermogenic properties of BAT.ConclusionTZD-induced hyperadiponectinemia is closely associated with increased adiponectin production in MAT but is not prevented by the partial loss of MAT that occurs in Ocn-Wnt10b mice. Thus, more robust loss-of-MAT models are required for future studies to better establish MAT’s elusive functions, both on an endocrine level and beyond.

Development, regulation, metabolism and function of bone marrow adipose tissues

“…As described above, cBMAT is largely resistant to stimuli that positively or negatively influence rBMAT; however, this tissue is not immune to moderate expansion (~30%) in response to calorie restriction 27 or thiazolidinedione treatment 41 . Furthermore, cBMA number is modestly depleted by a prostaglandin E 2 receptor type 4 agonist in ovariectomized rats 25 .…”

Connecting Bone and Fat: the Potential Role for Sclerostin

“…Elevated levels of SOST have been detected in multiple myeloma patients and SOST has been shown to be increased in osteocytes directly exposed to tumor cells[62], suggesting that high SOST may contribute to conditions favorable to metastasis either directly or indirectly by regulating the cellular makeup of the bone marrow. Indeed, studies suggest that MAT contributes to systemic adiponectin levels[18], and that adiponectin levels may be related to myeloma susceptibility[63]. In mice, HFD may create permissible conditions for myeloma colonization of the bone marrow[64] and in humans, bone metastases more frequently occur in older patients who typically have increased bone marrow adiposity[65].…”

“…While the true progenitor cell for bone marrow adipocytes (BMAs) remains in dispute, it is widely accepted that the progenitor arises within the marrow cavity and is likely common to both BMAs and OBs [17]. Recent work has shown that MAT is similar to WAT in that it contributes to adiponectin levels under various metabolic conditions, but distinct from WAT in that it responds differently to both calorie restriction(starvation/anorexia)[13] and treatment with insulin-sensitizing, peroxisome proliferator-activated receptor gamma (PPARγ) agonists[18]. …”

“…1). Consistent with this hypothesis, transgenic mice overexpressing Wnt10b by bone cells (Ocn-Wnt10b) exhibit elevated numbers of OBs and increased bone formation and density[30], decreased bone marrow volume, and significantly less MAT[18]. Wnt signaling is also inhibited endogenously via the Dickkopf (DKK) family, and in bone DKK family members Dikkopf-1 (DKK1) and SOST have been specifically implicated in both BM maintenance and pathogenesis.…”

Reflections on Cancer in the Bone Marrow: Adverse Roles of Adipocytes

“…Adiponectin is a circulating insulin-sensitizing hormone derived from both WAT and BMAT, and is increased in BMAT during caloric restriction, but unlike most adipokines, adiponectin is decreased in obese individuals. [29]. Thus adiponectin may hold potential for a treatment for obesity-associated myeloma.…”