Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature

Abstract

Growing female mice housed at room temperature (22 • C) weigh the same but differ in body composition compared to mice housed at thermoneutrality (32 • C). Specifically, mice housed at room temperature have lower levels of white adipose tissue (WAT). Additionally, bone marrow adipose tissue (bMAT) and cancellous bone volume fraction in distal femur metaphysis are lower in room temperature-housed mice. The metabolic changes induced by sub-thermoneutral housing are associated with lower leptin levels in serum and higher levels of Ucp1 gene expression in brown adipose tissue. Although the precise mechanisms mediating adaptation to sub-thermoneutral temperature stress remain to be elucidated, there is evidence that increased sympathetic nervous system activity acting via β-adrenergic receptors plays an important role. We therefore evaluated the effect of the non-specific β-blocker propranolol (primarily β 1 and β 2 antagonist) on body composition, femur microarchitecture, and bMAT in growing female C57BL/6 mice housed at either room temperature or thermoneutral temperature. As anticipated, cancellous bone volume fraction, WAT and bMAT were lower in mice housed at room temperature. Propranolol had small but significant effects on bone microarchitecture (increased trabecular number and decreased trabecular spacing), but did not attenuate premature bone loss induced by room temperature housing. In contrast, propranolol treatment prevented housing temperature-associated differences in WAT and bMAT. To gain additional insight, we evaluated a panel of genes in tibia, using an adipogenesis PCR array. Housing temperature and treatment with propranolol had exclusive as well as shared effects on gene expression. Of particular interest was the finding that room temperature housing reduced, whereas propranolol increased, expression of the gene for acetyl-CoA carboxylase (Acacb), the rate-limiting step for fatty acid synthesis and a key regulator of β-oxidation. Taken together, these findings provide evidence that increased activation of β 1 and/or β 2 receptors contributes to reduced bMAT by regulating adipocyte metabolism, but that this pathway is unlikely to be responsible for premature cancellous bone loss in room temperature-housed mice.

Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

“…Adipose tissue may contribute to RA pathogenesis (51)(52)(53)(54)(55)(56)(57)(58). Marrow adipose tissue was present adjacent to the talocrural joint, and in the inter-trabecular spaces of Ctrl rats.…”

“…Bone marrow dendritic cells exposed to a b 2 -agonist can also promote Th2/Th17 cell expansion, whose activity is also influenced by marrow adipocytes (57). Moreover, the b 2antagonist, propranolol can promote trabecular bone formation in mice by regulating adipocyte metabolism (58).…”

TRPM8 modulates temperature regulation in a sex-dependent manner without affecting cold-induced bone loss

“…More recent studies, however, showed that thermoneutral (32°C) housing in C57BL/6J mice exerted a protective effect on the skeleton, which was associated with reduced expression of Ucp1 in BAT [ 1 , 8 ]. Interestingly, the non-selective β-blocker propranolol was recently shown to be protective against adipose tissue loss, but only partly protective against bone loss, in mice housed at room temperature compared to thermoneutrality [ 9 ]. It is clear that cold temperature influences bone and marrow adipose tissue, but what particular afferent thermoregulatory pathways may be involved in these processes is unknown.…”

Evidence for increased thermogenesis in female C57BL/6J mice housed aboard the international space station

“…Group housing attenuates the increase in non-shivering thermogenesis in BAT in mice exposed to a cool environment 11 but it is plausible that another aspect of the spaceflight environment increases sympathetic signaling, an important positive regulator of thermogenesis. Whatever the precise mechanism, increased thermogenesis is important because it influences multiple physiological processes [12][13][14][15] . Collateral changes associated with increased thermogenesis include cancellous bone loss, immune suppression, increases in glucocorticoid production, increases in blood pressure and heart rate, and altered tumor and tissue response to ionizing radiation [16][17][18] .…”

“…Collateral changes associated with increased thermogenesis include cancellous bone loss, immune suppression, increases in glucocorticoid production, increases in blood pressure and heart rate, and altered tumor and tissue response to ionizing radiation [16][17][18] . Mechanistically, at least some of these responses are mediated by increased sympathetic outflow 14,19,20 .…”