Brown adipose tissue regulates glucose homeostasis and insulin sensitivity

Abstract

Brown adipose tissue (BAT) is known to function in the dissipation of chemical energy in response to cold or excess feeding, and also has the capacity to modulate energy balance. To test the hypothesis that BAT is fundamental to the regulation of glucose homeostasis, we transplanted BAT from male donor mice into the visceral cavity of age- and sex-matched recipient mice. By 8-12 weeks following transplantation, recipient mice had improved glucose tolerance, increased insulin sensitivity, lower body weight, decreased fat mass, and a complete reversal of high-fat diet-induced insulin resistance. Increasing the quantity of BAT transplanted into recipient mice further improved the metabolic effects of transplantation. BAT transplantation increased insulin-stimulated glucose uptake in vivo into endogenous BAT, white adipose tissue (WAT), and heart muscle but, surprisingly, not skeletal muscle. The improved metabolic profile was lost when the BAT used for transplantation was obtained from Il6-knockout mice, demonstrating that BAT-derived IL-6 is required for the profound effects of BAT transplantation on glucose homeostasis and insulin sensitivity. These findings reveal a previously under-appreciated role for BAT in glucose metabolism.

Figure 1. BAT transplantation improves glucose tolerance and increases whole body insulin sensitivity.

(A–C) Mice received transplants of 0.1 g BAT, a 0.15-g glass bead, or 0.1 g WAT or were sham operated. For glucose tolerance tests (GTT), mice were injected with 2 g glucose/kg body weight, i.p. (A and B) Glucose AUC and (C) GTT curve at 12 weeks after transplantation. (D) For ITTs, mice were injected with 1 U insulin/kg i.p. and data expressed as absolute glucose. Data are mean ± SEM. n = 5–8/group. *P < 0.05 between BAT-transplanted mice and all control groups.

Figure 2. BAT transplantation ameliorates high-fat diet–induced insulin resistance and has dose-dependent effects on glucose tolerance.

(A–C) Mice were fed a high-fat diet (HF) for 18 weeks, with BAT transplanted after 6 weeks. (A) Body weight, (B) GTT AUC, and (C) GTT curve at 12 weeks after transplantation. Data are mean ± SEM. n = 6/group; *P < 0.05. For comparison, chow-fed, sham-operated mice from a separate cohort of animals are indicated with a dashed line (n = 17). (D–F) Mice received transplants of 0.1 g BAT or 0.4 g BAT or were sham operated. (D) Body weight, (E) GTT AUC, and (F) GTT curve at 12 weeks after transplantation. Data are mean ± SEM. n = 13–14/group; *P < 0.05, **P < 0.01, ^#P < 0.001 compared with sham.

Figure 3. BAT transplantation increases glucose uptake into WAT, BAT, and heart.

(A–E) Mice received transplants of 0.1 g BAT or 0.4 g BAT or were sham operated, and were studied 12 weeks after transplantation. Mice were fasted overnight and anesthetized, and [³H]2-deoxyglucose/g body weight was administered via retro-orbital injection in the presence of saline (Basal) or 1 mg/kg body weight glucose (Glucose); glucose uptake was measured in (A) visceral WAT, (B) endogenous BAT, (C) heart, (D) gastrocnemius muscle, (E) tibialis anterior muscle. Data are mean ± SEM. *P < 0.05 compared with sham mice (n = 6/group).

Figure 4. BAT transplantation increases circulating IL-6 and FGF21 concentrations, and Il6^–/– mice do not show beneficial effects of BAT transplantation.

(A–E) Mice underwent sham operation or transplantation with 0.1 or 0.4 g BAT and were studied 12 weeks after transplantation. (A) Serum FGF21 and (B) FGF21 protein levels in endogenous BAT, (C) FGF21 protein levels in liver, (D) serum IL-6, (E) and Il6 measured by qPCR in endogenous BAT. Data are mean ± SEM. n = 6–17/group; *P < 0.05 compared with sham. **P < 0.01. ***P < 0.001. (F–H) Mice underwent sham operation or transplantation with 0.1 g BAT from Il6^–/– or Il6^+/+ mice. (F) GTT AUC, (G) serum leptin, and (H) body weight. Data are mean ± SEM. *P < 0.05 compared with sham and mice receiving 0.1 g Il6^–/– BAT. n = 4–8/group.

Figure 5. Transplantation of Il6^–/– BAT does not alter fat mass or adipocyte size of serum FGF21.

(A–F) Mice underwent sham operation or transplantation with 0.1 g BAT from Il6^–/– or Il6^+/+mice. (A) Percent fat mass, (B) visceral WAT cell size at 12 weeks after transplantation, (C) qPCR of tyrosine hydroxylase in transplanted BAT, (D) serum FGF21, (E) endogenous BAT FGF21 protein, and (F) qPCR of Fgf21. Data are mean ± SEM. *P < 0.05 compared with sham and mice receiving 0.1 g Il6^–/– BAT. **P < 0.01. n = 4–8/group.