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Inducible brown adipose tissue, or beige fat, is anabolic for the skeleton.

ABSTRACT: It is known that insulin resistance and type 2 diabetes mellitus are associated with increased fractures and that brown adipose tissue (BAT) counteracts many if not all of the symptoms associated with type 2 diabetes. By the use of FoxC2(AD)(+/Tg) mice, a well-established model for induction of BAT, or beige fat, we present data extending the beneficial action of beige fat to also include a positive effect on bone. FoxC2(AD)(+/Tg) mice are lean and insulin-sensitive and have high bone mass due to increased bone formation associated with high bone turnover. Inducible BAT is linked to activation of endosteal osteoblasts whereas osteocytes have decreased expression of the Sost transcript encoding sclerostin and elevated expression of Rankl. Conditioned media (CM) collected from forkhead box c2 (FOXC2)-induced beige adipocytes activated the osteoblast phenotype and increased levels of phospho-AKT and ?-catenin in recipient cells. In osteocytes, the same media decreased Sost expression. Immunodepletion of CM with antibodies against wingless related MMTV integration site 10b (WNT10b) and insulin-like growth factor binding protein 2 (IGFBP2) resulted in the loss of pro-osteoblastic activity, and the loss of increase in the levels of phospho-AKT and ?-catenin. Conversely, CM derived from cells overexpressing IGFBP2 or WNT10b restored osteoblastic activity in recipient cells. In conclusion, beige fat secretes endocrine/paracrine activity that is beneficial for the skeleton.

SUBMITTER: Rahman S

PROVIDER: S-EPMC3713216 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Inducible brown adipose tissue, or beige fat, is anabolic for the skeleton.

Rahman Sima S Lu Yalin Y Czernik Piotr J PJ Rosen Clifford J CJ Enerback Sven S Lecka-Czernik Beata B

Endocrinology 20130521 8

It is known that insulin resistance and type 2 diabetes mellitus are associated with increased fractures and that brown adipose tissue (BAT) counteracts many if not all of the symptoms associated with type 2 diabetes. By the use of FoxC2(AD)(+/Tg) mice, a well-established model for induction of BAT, or beige fat, we present data extending the beneficial action of beige fat to also include a positive effect on bone. FoxC2(AD)(+/Tg) mice are lean and insulin-sensitive and have high bone mass due t ...[more]

PMID: 23696565

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Project description:Adult humans and mice possess significant classical brown adipose tissues (BAT) and, upon cold-induction, acquire brown-like adipocytes in certain depots of white adipose tissues (WAT), known as beige adipose tissues or WAT browning/beiging. Activating thermogenic classical BAT or WAT beiging to generate heat limits diet-induced obesity or type-2 diabetes in mice. Adiponectin is a beneficial adipokine resisting diabetes, and causing "healthy obese" by increasing WAT expansion to limit lipotoxicity in other metabolic tissues during high-fat feeding. However, the role of its receptors, especially adiponectin receptor 1 (AdipoR1), on cold-induced thermogenesis in vivo in BAT and in WAT beiging is still elusive. Here, we established a cold-induction procedure in transgenic mice over-expressing AdipoR1 and applied a live 3-D [18F] fluorodeoxyglucose-PET/CT (18F-FDG PET/CT) scanning to measure BAT activity by determining glucose uptake in cold-acclimated transgenic mice. Results showed that cold-acclimated mice over-expressing AdipoR1 had diminished cold-induced glucose uptake, enlarged adipocyte size in BAT and in browned WAT, and reduced surface BAT/body temperature in vivo. Furthermore, decreased gene expression, related to thermogenic Ucp1, BAT-specific markers, BAT-enriched mitochondrial markers, lipolysis and fatty acid oxidation, and increased expression of whitening genes in BAT or in browned subcutaneous inguinal WAT of AdipoR1 mice are congruent with results of PET/CT scanning and surface body temperature in vivo. Moreover, differentiated brown-like beige adipocytes isolated from pre-adipocytes in subcutaneous WAT of transgenic AdipoR1 mice also had similar effects of lowered expression of thermogenic Ucp1, BAT selective markers, and BAT mitochondrial markers. Therefore, this study combines in vitro and in vivo results with live 3-D scanning and reveals one of the many facets of the adiponectin receptors in regulating energy homeostasis, especially in the involvement of cold-induced thermogenesis.

Project description:BackgroundThe amount of intra-thoracic fat, of which mediastinal adipose tissue comprises the major depot, is related to various cardiometabolic risk factors. Autopsy and imaging studies indicate that the mediastinal depot in adult humans could contain brown adipose tissue (BAT). To gain a better understanding of this intra-thoracic fat depot, we examined possible BAT characteristics of human mediastinal in comparison with subcutaneous adipose tissue.Materials and methodsAdipose tissue biopsies from thoracic subcutaneous and mediastinal depots were obtained during open-heart surgery from 33 subjects (26 male, 63.7±13.8 years, body mass index 29.3±5.1?kg?m(-2)). Microarray analysis was performed on 10 patients and genes of interest confirmed by quantitative PCR (qPCR) in samples from another group of 23 patients. Adipocyte size was determined and uncoupling protein 1 (UCP1) protein expression investigated with immunohistochemistry.ResultsThe microarray data showed that a number of BAT-specific genes had significantly higher expression in the mediastinal depot than in the subcutaneous depot. Higher expression of UCP1 (24-fold, P<0.001) and PPARGC1A (1.7-fold, P=0.0047), and lower expression of SHOX2 (0.12-fold, P<0.001) and HOXC8 (0.14-fold, P<0.001) in the mediastinal depot was confirmed by qPCR. Gene set enrichment analysis identified two gene sets related to mitochondria, which were significantly more highly expressed in the mediastinal than in the subcutaneous depot (P<0.01). No significant changes in UCP1 gene expression were observed in the subcutaneous or mediastinal depots following lowering of body temperature during surgery. UCP1 messenger RNA levels in the mediastinal depot were lower than those in murine BAT and white adipose tissue. In some mediastinal adipose tissue biopsies, a small number of multilocular adipocytes that stained positively for UCP1 were observed. Adipocytes were significantly smaller in the mediastinal than the subcutaneous depot (cross-sectional area 2400±810 versus 3260±980??m(2), P<0.001).ConclusionsHuman mediastinal adipose tissue displays some characteristics of BAT when compared with the subcutaneous depot at microscopic and molecular levels.

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Inducible brown adipose tissue, or beige fat, is anabolic for the skeleton.

Publications

Inducible brown adipose tissue, or beige fat, is anabolic for the skeleton.

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