Altered thermogenesis and impaired bone remodeling in Misty mice. (19th August 2013)

• Record Type: Journal Article
• Authors: Motyl, Katherine J; Bishop, Kathleen A; DeMambro, Victoria E; Bornstein, Sheila A; Le, Phuong; Kawai, Masanobu; Lotinun, Sutada; Horowitz, Mark C; Baron, Roland; Bouxsein, Mary L; Rosen, Clifford J
• Is Part Of: Journal of bone and mineral research. Volume 28:Number 9(2013:Sep.)
• Page Start: 1885
• Page End: 1897
• Publication Date: 2013-08-19
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.1943
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr1943-sec-0001" sec-type="section"> <p>Fat mass may be modulated by the number of brown‐like adipocytes in white adipose tissue (WAT) in humans and rodents. Bone remodeling is dependent on systemic energy metabolism and, with age, bone remodeling becomes uncoupled and brown adipose tissue (BAT) function declines. To test the interaction between BAT and bone, we employed <italic>Misty</italic> (<italic>m</italic>/<italic>m</italic>) mice, which were reported be deficient in BAT. We found that <italic>Misty</italic> mice have accelerated age‐related trabecular bone loss and impaired brown fat function (including reduced temperature, lower expression of <italic>Pgc1a</italic>, and less sympathetic innervation compared to wild‐type (<italic>+/</italic> <italic>+</italic>)). Despite reduced BAT function, <italic>Misty</italic> mice had normal core body temperature, suggesting heat is produced from other sources. Indeed, upon acute cold exposure (4°C for 6 hours), inguinal WAT from <italic>Misty</italic> mice compensated for BAT dysfunction by increasing expression of <italic>Acadl</italic>, <italic>Pgc1a</italic>, <italic>Dio2</italic>, and other thermogenic genes. Interestingly, acute cold exposure also decreased <italic>Runx2</italic> and increased <italic>Rankl</italic> expression in <italic>Misty</italic> bone, but only <italic>Runx2</italic> was decreased in wild‐type. Browning of WAT is under the control of the sympathetic nervous system (SNS) and, if present at room temperature, could impact bone metabolism. To test whether SNS activity could be responsible for accelerated trabecular bone loss, we treated wild‐type and <italic>Misty</italic> mice with the β‐blocker, propranolol. As predicted, propranolol slowed trabecular bone volume/total volume (BV/TV) loss in the distal femur of <italic>Misty</italic> mice without affecting wild‐type. Finally, the <italic>Misty</italic> mutation (a truncation of DOCK7) also has a significant cell‐autonomous role. We found DOCK7 expression in whole bone and osteoblasts. Primary osteoblast differentiation from <italic>Misty</italic> calvaria was impaired, demonstrating a novel role for DOCK7 in bone remodeling. Despite the multifaceted effects of the <italic>Misty</italic> mutation, we have shown that impaired brown fat function leads to altered SNS activity and bone loss, and for the first time that cold exposure negatively affects bone remodeling.</p> </sec> </abstract>