Inducible Brown Adipose Tissue, or Beige Fat, Is Anabolic for the Skeleton

Rahman, Sima; Lu, Yalin; Czernik, Piotr J.; Rosen, Clifford J.; Enerbäck, Sven; Lecka‐Czernik, Beata

doi:10.1210/en.2012-2162

Cited by 108 publications

(95 citation statements)

References 51 publications

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“…Irisin is known to activate the browning response in WAT, when injected daily at a dose of 500 μg kg −1 for 14 d (19,20). We therefore chose a substantially lower dose of r-irisin (100 μg kg −1 , weekly injections) to determine whether or not the skeletal action of irisin was dependent on the expansion of inducible BAT (iBAT).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, at a dose of 500 μg kg −1 daily (3,500 μg kg −1 per week), r-irisin increased Ucp1 expression and reduced body weight. However, because BAT, particularly iBAT, can be beneficial to the skeleton (20,48,49), it was imperative that we exclude indirect effects of irisin on the skeleton exerted through iBAT. We therefore used a 35-fold lower cumulative weekly dose of r-irisin than that used previously to induce browning (19).…”

Section: Discussionmentioning

confidence: 99%

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The myokine irisin increases cortical bone mass

Colaianni

Cuscito

Mongelli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

404

399

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It is unclear how physical activity stimulates new bone synthesis. We explored whether irisin, a newly discovered myokine released upon physical activity, displays anabolic actions on the skeleton. Young male mice were injected with vehicle or recombinant irisin (r-irisin) at a low cumulative weekly dose of 100 µg kg(-1). We observed significant increases in cortical bone mass and strength, notably in cortical tissue mineral density, periosteal circumference, polar moment of inertia, and bending strength. This anabolic action was mediated primarily through the stimulation of bone formation, but with parallel notable reductions in osteoclast numbers. The trabecular compartment of the same bones was spared, as were vertebrae from the same mice. Higher irisin doses (3,500 µg kg(-1) per week) cause browning of adipose tissue; this was not seen with low-dose r-irisin. Expectedly, low-dose r-irisin modulated the skeletal genes, Opn and Sost, but not Ucp1 or Pparγ expression in white adipose tissue. In bone marrow stromal cell cultures, r-irisin rapidly phosphorylated Erk, and up-regulated Atf4, Runx2, Osx, Lrp5, β-catenin, Alp, and Col1a1; this is consistent with a direct receptor-mediated action to stimulate osteogenesis. We also noted that, although the irisin precursor Fndc5 was expressed abundantly in skeletal muscle, other sites, such as bone and brain, also expressed Fndc5, albeit at low levels. Furthermore, muscle fibers from r-irisin-injected mice displayed enhanced Fndc5 positivity, and irisin induced Fdnc5 mRNA expression in cultured myoblasts. Our data therefore highlight a previously unknown action of the myokine irisin, which may be the molecular entity responsible for muscle-bone connectivity

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The myokine irisin increases cortical bone mass

Colaianni

Cuscito

Mongelli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

404

399

View full text Add to dashboard Cite

show abstract

“…10 During the same time, it has been reported that this inducible form of brown adipose (iBAT) is anabolic for the skeleton. 37 Studies on transgenic mice overexpressing FoxC2 in the adipose tissue, a well-established model for BAT induction, showed that these mice displayed a higher trabecular bone mass, as compared with age-matched WT animals, due to increased bone formation, triggered by Wnt10b and IGFBP2, two pivotal bone anabolic molecules released from BAT. 37 Another work by Zhang et al 38 demonstrated that therapeutic treatment of normal and obese mice with r-Irisin at a dose of 3500 mg kg À 1 per week strongly induced the browning…”

Section: A Possible Combined Direct and Indirect Effect Of Irisin On mentioning

confidence: 99%

Role of Irisin on the bone–muscle functional unit

Colaianni

Grano

2015

BoneKEy Reports

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Irisin was originally recognized as a hormone-like myokine secreted as a product of fibronectin type III domain containing 5 from skeletal muscle in response to exercise both in mice and humans. The first role attributed to Irisin was its ability to induce trans-differentiation of white adipose tissue into brown, but we recently demonstrated that Irisin also has a central role in the control of bone mass, even at lower concentration than required to induce the browning response. Considering how physical exercise is important for the development of an efficient load-bearing skeleton, we can now consider this myokine as one of the molecules responsible for the positive correlation between exercise and healthy bone, linking to the well-established relationship between muscle and bone. Recombinant Irisin (r-Irisin), administered at low dose in young mice, increases cortical bone mineral density and positively modifies bone geometry. Irisin exerts its effect prevalently on osteoblast lineage by enhancing differentiation and activity of bone-forming cells, through the increase in activating transcription factor 4 expression. Low-dose r-Irisin also increases osteopontin and decreases sclerostin synthesis but did not affect Uncoupling protein 1 expression in white adipose tissue, whose upregulation is known to cause browning of fat, when Irisin is administered at a higher dose. These findings offer an explanation to the positive outcome on the skeleton triggered by skeletal muscle during physical activity and prove that the bone tissue is more sensitive than the adipose tissue to the Irisin action.

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“…4 The induction of the presumably beige adipocytes is accompanied by protection against obesity and diet-induced insulin resistance in response to a high-fat diet. 4,42 Using this mouse strain as a model for increased 'BAT content', Rahman et al 43 recently showed that these mice have significantly higher trabecular bone mass, due to increased bone formation associated with high bone turnover, as compared with wild-type mice, suggesting that BAT is anabolic for the skeleton. Interestingly, the authors also shed some light on a potential mechanism by which BAT stimulates this effect.…”

Section: The Connection Between Bat and Bonementioning

confidence: 99%

Brown adipose tissue and bone

Lidell

Enerbäck

2015

Int J Obes Supp

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ME Lidell and S EnerbäckBrown adipose tissue (BAT) is capable of transforming chemically stored energy, in the form of triglycerides, into heat. Recent studies have shown that metabolically active BAT is present in a large proportion of adult humans, where its activity correlates with a favorable metabolic status. Hence, the tissue is now regarded as an interesting target for therapies against obesity and associated diseases such as type 2 diabetes, the hypothesis being that an induction of BAT would be beneficial for these disease states. Apart from the association between BAT activity and a healthier metabolic status, later studies have also shown a positive correlation between BAT volume and both bone cross-sectional area and bone mineral density, suggesting that BAT might stimulate bone anabolism. The aim of this review is to give the reader a brief overview of the BAT research field and to summarize and discuss recent findings regarding BAT being a potential player in bone metabolism.

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Inducible Brown Adipose Tissue, or Beige Fat, Is Anabolic for the Skeleton

Cited by 108 publications

References 51 publications

The myokine irisin increases cortical bone mass

The myokine irisin increases cortical bone mass

Role of Irisin on the bone–muscle functional unit

Brown adipose tissue and bone

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