PDF(Pubmed)
Abstract：
Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11β-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11β-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restrining BMAT expansion and bone loss. To test this, we first confirmed that 11β-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11β-HSD1 knockout mice from 9 to 15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in bone marrow. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11β-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlights progesterone as a potential new regulator of bone marrow adiposity.
摘要：
在健康人中,骨髓脂肪组织(BMAT)占总脂肪量的>10%。它在不同的条件下增加，包括老化,肥胖，骨质疏松,糖皮质激素治疗和，特别是,在热量限制（CR）。BMAT可能会影响骨骼，代谢和免疫功能，但BMAT扩张的机制仍然知之甚少。我们的假设是，在CR期间，过度的糖皮质激素活性驱动BMAT扩张。酶11β-羟基类固醇脱氢酶1型（11β-HSD1）通过催化惰性11酮形式的活性糖皮质激素的细胞内再生来增强糖皮质激素活性。缺乏11β-HSD1的小鼠在外源性糖皮质激素过量期间抵抗代谢失调和骨丢失；因此，我们假设11β-HSD1敲除小鼠在CR期间也会抵抗过度的糖皮质激素作用，从而抑制BMAT扩张和骨丢失。为了测试这个，我们首先证实11β-HSD1在小鼠和人骨髓中表达。然后，我们研究了CR在9-15周龄的雄性和雌性对照和11β-HSD1敲除小鼠中的作用。CR增加脂肪组织和骨髓中的Hsd11b1mRNA。Hsd11b1的缺失不会改变喂食对照饮食的小鼠的骨骼或BMAT特征，并且在CR期间对胫骨骨微结构几乎没有影响。值得注意的是,Hsd11b1缺失减弱了CR诱导的BMAT增加，并阻止了男性而非女性的骨髓皮质酮增加。这与BM中糖皮质激素靶基因的抑制无关。相反，基因敲除的男性血浆和骨髓中的孕酮增加。一起,我们的研究结果表明,11β-HSD1基因敲除以性别特异性方式阻止CR诱导的BMAT扩增,并突出说明孕酮是BM肥胖的潜在新调节因子.
