iBAT on Bone

Brown adipose tissue (BAT) induction emerges as a promising strategy to ameliorate metabolic diseases such as obesity, insulin resistance, and type 2 diabetes mellitus by promoting energy expenditure and insulin sensitivity. A recent study by Rahman et al (1) in this issue of Endocrinology provides intriguing evidence that inducible BAT (iBAT), also known as beige/brite fat, is also anabolic to the bone. In light of the skeletal fragility in diabetic patients and the bone loss side effects of current diabetic drugs, BAT induction holds an exciting potential as a strategy to simultaneously improve metabolic and skeletal fitness. iBAT suppresses many metabolic symptoms associated with obesity and diabetes (reviewed in Refs. 2 and 3). Clinical studies have reported that increased BAT activity in humans correlates with not only reduced metabolic disorders but also elevated bone mineral density and skeletal mass. Consistent with the epidemiological evidence, mouse genetic models with BAT ablation or uncoupling protein 1 (UCP1) deficiency exhibit increased propensity to develop diet-induced obesity and diabetes, whereas mouse genetic models with BAT induction confer resistance to obesity and insulin resistance. Nonetheless, whether and how BAT modulates skeletal homeostasis is an important yet underexplored question. This study by Rahman et al (1) begins to fill this void by reporting that BAT induction is accompanied by bone gain in mice. Using a previously described iBAT mouse model in which the transcription factor Forkhead box C2 (FoxC2) is overexpressed in the adipocytes (FoxC2AD+/Tg), this study shows that browning of the adipose tissue leads to an increase in bone mass and bone turnover via novel paracrine and endocrine mechanisms. Lineage tracing and molecular characterization has classified BAT into 2 distinct populations (4, 5): the developmentally programmed classical BAT that originates from Myf5+ progenitors and closely relates to muscle and the iBAT or beige/brite fat that originates from Myf5− progenitors that emerges from white adipose tissue (WAT) upon stimuli such as cold exposure. Bone marrow adipose tissue (BMAT) represents another type of fat, the lineage and function of which is less understood (6). BMAT has been reported to increase under various physiological, pathological, and pharmacological conditions. For example, BMAT increases during puberty as well as aging; in disorders such as estrogen deficiency, diabetes, and anorexia nervosa; and by drugs such as the insulin sensitizer rosiglitazone. The nature of BMAT under these various situations is unclear, but both WAT- and BAT-like characteristics have been attributed to BMAT and may be dynamically regulated. Marrow fat gain is often accompanied by bone loss, largely due to the differentiation competition between marrow adipocyte and osteoblast from mesenchymal stem cells. Several hormones and transcription factors that promote marrow adipogenesis also inhibit osteoblastogenesis, such as the nuclear receptor peroxisome proliferator-activated receptor γ (7, 8), fibroblast growth factor 21 (9) and the circadian deadenylase nocturnin (10). In contrast, hormones and transcription factors that promote osteoblastogenesis suppresses adipogenesis, such as β-catenin, semaphorin-3A, retinoblastoma 1, and type 1 cannabinoid receptor (CB1) (reviewed in Refs. 6 and 11). The current study provides evidence that browning of WAT and BMAT in FoxC2AD+/Tg mice leads to an increase in bone formation and bone turnover, thus turning fat from foe to friend of the skeleton. The anabolic effects on bone are accomplished by the cross talk between iBAT and bone cells including osteoblast and osteocytes (Figure 1). One mechanism involves the iBAT secretion of systemic and osseous factors, including IGF-binding protein 2 and Wnt10b, to increase osteoblastogenesis and enhance the levels of phosphor-Akt and β-catenin. Another mechanism involves the iBAT regulation of osteocyte function to suppress its expression of the Wnt antagonist sclerostin (Sost) and elevate its secretion of the osteoclastogenic cytokine receptor activator of nuclear factor κ-B ligand. Consequently, both bone formation and bone turnover are increased with a net result of higher bone mass. Figure 1. A simplified model for how iBAT benefits both skeletal and metabolic health via endocrine/paracrine mechanisms. iBAT or beige fat, which can be induced by FoxC2 overexpression in adipocytes, secretes IGF-binding protein 2 (IGFBP2) and Wnt10b to promote ... These studies are potentially clinically significant for the treatment of not only bone degenerative diseases such as osteoporosis but also metabolic disorders such as obesity and diabetes. Insulin resistance and type 2 diabetes are associated with bone loss and increased fractures. Unfortunately, current insulin-sensitizing drugs and drug candidates, such as the peroxisome proliferator-activated receptor γ agonist rosiglitazone and fibroblast growth factor 21, may exacerbate this skeletal fragility and promote further bone loss despite their metabolic benefits (7–9, 12). Indeed, rosiglitazone treatment has been associated with an increased rate of fractures in humans (13–18). Although it remains to be seen whether the bone anabolic effects are specific to the FoxC2AD+/Tg mouse model or general characteristics of iBAT, this study presents an exciting possibility that BAT induction may be a new avenue to simultaneously improve metabolic and skeletal fitness (Figure 1), which will undoubtedly stimulate future investigations.