Myostatin Attenuation In Vivo Reduces Adiposity, but Activates Adipogenesis.

A potentially novel approach for treating obesity includes attenuating myostatin as this increases muscle mass and decreases fat mass. Notwithstanding, conflicting studies report that myostatin stimulates or inhibits adipogenesis and it is unknown whether reduced adiposity with myostatin attenuation results from changes in fat deposition or adipogenesis. We therefore quantified changes in the stem, transit amplifying and progenitor cell pool in white adipose tissue (WAT) and brown adipose tissue (BAT) using label-retaining wild-type and mstn(-/-) (Jekyll) mice. Muscle mass was larger in Jekyll mice, WAT and BAT mass was smaller and label induction was equal in all tissues from both wild-type and Jekyll mice. The number of label-retaining cells, however, dissipated quicker in WAT and BAT of Jekyll mice and was only 25% and 17%, respectively, of wild-type cell counts 1 month after induction. Adipose cell density was significantly higher in Jekyll mice and increased over time concomitant with label-retaining cell disappearance, which is consistent with enhanced expansion and differentiation of the stem, transit amplifying and progenitor pool. Stromal vascular cells from Jekyll WAT and BAT differentiated into mature adipocytes at a faster rate than wild-type cells and although Jekyll WAT cells also proliferated quicker in vitro, those from BAT did not. Differentiation marker expression in vitro, however, suggests that mstn(-/-) BAT preadipocytes are far more sensitive to the suppressive effects of myostatin. These results suggest that myostatin attenuation stimulates adipogenesis in vivo and that the reduced adiposity in mstn(-/-) animals results from nutrient partitioning away from fat and in support of muscle.

一种治疗肥胖的潜在新方法包括减弱肌肉生长抑制素，因为这会增加肌肉量并减少脂肪量。然而，相互矛盾的研究报告称肌肉生长抑制素会刺激或抑制脂肪生成，并且尚不清楚通过减弱肌肉生长抑制素而减少的肥胖是由于脂肪沉积还是脂肪生成的变化所致。因此，我们使用标记保留的野生型和mstn(-/-)（杰基尔）小鼠量化了白色脂肪组织（WAT）和棕色脂肪组织（BAT）中干细胞、过渡放大细胞和祖细胞群的变化。杰基尔小鼠的肌肉量更大，WAT和BAT质量更小，并且野生型和杰基尔小鼠所有组织中的标记诱导相同。然而，标记保留细胞的数量在杰基尔小鼠的WAT和BAT中消散得更快，在诱导1个月后分别仅为野生型细胞计数的25%和17%。杰基尔小鼠的脂肪细胞密度显著更高，并且随着时间的推移随着标记保留细胞的消失而增加，这与干细胞、过渡放大细胞和祖细胞群的增强扩增和分化是一致的。来自杰基尔WAT和BAT的基质血管细胞比野生型细胞更快地分化为成熟脂肪细胞，尽管杰基尔WAT细胞在体外也增殖得更快，但来自BAT的细胞则没有。然而，体外分化标志物的表达表明mstn(-/-) BAT前脂肪细胞对肌肉生长抑制素的抑制作用更为敏感。这些结果表明，肌肉生长抑制素的减弱在体内刺激脂肪生成，并且mstn(-/-)动物中肥胖的减少是由于营养物质从脂肪分配到支持肌肉。