The advances in brown adipose cell biology during the last decade have increased our understanding of the cellular origin (27
), function (8
), and adult human tissue distribution (2
) of BAT. The current study establishes that increasing BAT has advantageous effects on body composition and insulin sensitivity and suggests that BAT is an endocrine organ that can function to improve whole-body and tissue glucose homeostasis. Mice receiving transplanted BAT showed a significant decrease in body weight and an improvement in insulin sensitivity and glucose metabolism. The transplantation of BAT also ameliorated the harmful effects of a high-fat diet, reducing body weights and improving glucose tolerance in the BAT-transplanted mice beyond that of the sham-operated, chow-fed mice. The improvements in whole-body metabolism can be attributed to both paracrine and endocrine effects of the transplanted BAT on other tissues (specifically visceral WAT, heart, and endogenous BAT). While the transplanted BAT is actively taking up glucose, this effect may be relatively small compared with the larger effects observed in other tissues. These beneficial effects were due solely to the implantation of BAT, as mice transplanted with the same amount of WAT or with a glass bead did not show the same reduction in body weight or improvement in glucose metabolism.
To our knowledge, this is the first study to show improved metabolic parameters in mice receiving BAT transplants. Past studies differed from the current study in terms of location of transplantation, time course of study, and success of transplantation (15
), and none of these previous studies reported the effects of transplantation on whole-body glucose metabolism or insulin sensitivity (15
). The transplants from the current study were successful out to 12 weeks after transplantation, as indicated by the presence of innervation and vascular markers in the transplanted tissue. The tissue was also metabolically active, as it actively took up glucose upon stimulation, and mice receiving this tissue had a significant improvement in cold tolerance. Thus, our results demonstrate that transplantation of BAT to a location where it successfully reestablishes innervation results in an improved metabolic profile in the recipient mouse.
A remarkable finding from the current study was the ability of the BAT transplants to normalize glucose tolerance in the high-fat diet–fed mice. This demonstrates that the BAT transplants originating from the chow-fed donors maintain the characteristics of lean, healthy BAT and do not take on the characteristics of the insulin-resistant, high-fat diet–fed recipient mice. In contrast, in a study of the obese, insulin resistant ob/ob
mouse, transplantation of BAT from lean mice into ob/ob
mice resulted in the transplanted BAT taking on the characteristics of the ob/ob
). These data imply that the transplantation of BAT into mice on a high-fat diet ameliorates the effect of the high-fat feeding and results in beneficial effects on glucose metabolism.
Multiple findings from the current study, including the increases in circulating norepinephrine, IL-6, and FGF21, led us to postulate that the metabolic effects of the transplanted BAT originated from a paracrine or endocrine action. Indeed, another important finding of the current study was that transplanted BAT could exert its effect over whole-body metabolism through an IL-6–dependent mechanism, as mice receiving BAT transplants from Il6–/–
mice showed no improvement in glucose tolerance and no increase in circulating IL-6. These findings suggest that IL-6 functions as a brown adipokine, or “batokine,” in vivo and is critical for the beneficial effects of BAT transplantation on metabolic homeostasis. Interestingly, the phenotype of the mice transplanted with BAT in the current study is similar to that observed in transgenic mice in which IL-6 was overexpressed (Il6tg
mice had decreased fat mass and adipocyte cell size when compared with WT controls, effects that were amplified when these mice were placed on a high-fat diet (25
). An additional study showed that an i.c.v. injection of IL-6 resulted in increased energy expenditure, decreased body weight, decreased adiposity, and decreased circulating leptin in rats (33
). There has been much contradictory data on the effects of IL-6 on glucose tolerance and obesity, but our data support the concept that an increase in circulating IL-6 increases energy expenditure, reduces adiposity, decreases circulating insulin, and improves glucose tolerance.
Based on the evidence that epinephrine treatment of cultured brown adipocytes in culture media increases IL-6 (23
), and the well-established effects of IL-6 in promoting lipolysis in WAT (34
), we propose a model whereby BAT-derived IL-6 promotes lipolysis, resulting in the observed reduction in adipocyte size. Another potential mechanism through which IL-6 could promote increased insulin sensitivity and glucose metabolism is an increase in GLUT1 expression, which is observed in the WAT and hearts of mice receiving BAT. The increase in GLUT1 could be stimulated by the increase in IL-6 and/or FGF21, as IL-6 (24
) and FGF21 (21
) have been shown to increase GLUT1 expression in cultured brown adipocytes and 3T3-L1 cells, respectively.
BAT-derived IL-6 may contribute to the increases in circulating FGF21 and BAT FGF21 concentrations that occurred with BAT transplantation. This concept is supported by the findings that there are significant increases in circulating FGF21 and FGF21 protein in BAT from mice receiving transplants of WT BAT, but no such increase was observed in BAT of mice receiving Il6–/–
BAT. FGF21-transgenic mice have increased insulin sensitivity, improved glucose tolerance, resistance to diet-induced obesity, and an increase in GLUT1 in peripheral tissues (21
), similar to the mice in the current study that were transplanted with BAT. Whether this increase in FGF21 is a direct or indirect result of the increase in IL-6 has yet to be determined, but these finding suggest that in addition to IL-6, IL-6-stimulated FGF21 could contribute to the improved metabolic phenotype of the mice receivingt BATtransplants.
In conclusion, we have demonstrated that transplanted BAT can have beneficial effects on control of body composition and metabolism. These effects appear to be due to circulating IL-6, which is increased in these mice. The increase in IL-6 is linked to an improvement in glucose metabolism and provides another indication that BAT could be targeted for treatment of obesity-related diseases such as insulin resistance, metabolic syndrome, and diabetes. This is the first study to our knowledge to demonstrate that an increase in BAT significantly increases circulating IL-6, suggesting that an increase in BAT-derived IL-6 improves systemic glucose metabolism. This work reveals a previously underappreciated role of BAT in glucose metabolism and underscores the role for BAT to combat obesity-related diseases.