Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
FASEB J. 2021 Dec;35(12):e22018. doi: 10.1096/fj.202101244R.
Adipose tissue is the primary site of energy storage, playing important roles in health. While adipose research largely focuses on obesity, fat also has other critical functions, producing adipocytokines and contributing to normal nutrient metabolism, which in turn play important roles in satiety and total energy homeostasis. SMAD2/3 proteins are downstream mediators of activin signaling, which regulate critical preadipocyte and mature adipocyte functions. Smad2 global knockout mice exhibit embryonic lethality, whereas global loss of Smad3 protects mice against diet-induced obesity. The direct contributions of Smad2 and Smad3 in adipose tissues, however, are unknown. Here, we sought to determine the primary effects of adipocyte-selective reduction of Smad2 or Smad3 on diet-induced adiposity using Smad2 or Smad3 "floxed" mice intercrossed with Adiponectin-Cre mice. Additionally, we examined visceral and subcutaneous preadipocyte differentiation efficiency in vitro. Almost all wild type subcutaneous preadipocytes differentiated into mature adipocytes. In contrast, visceral preadipocytes differentiated poorly. Exogenous activin A suppressed differentiation of preadipocytes from both depots. Smad2 conditional knockout (Smad2cKO) mice did not exhibit significant effects on weight gain, irrespective of diet, whereas Smad3 conditional knockout (Smad3cKO) male mice displayed a trend of reduced body weight on high-fat diet. On both diets, Smad3cKO mice displayed an adipose depot-selective phenotype, with a significant reduction in subcutaneous fat mass but not visceral fat mass. Our data suggest that Smad3 is an important contributor to the maintenance of subcutaneous white adipose tissue in a sex-selective fashion. These findings have implications for understanding SMAD-mediated, depot selective regulation of adipocyte growth and differentiation.
脂肪组织是能量储存的主要场所，在健康中发挥着重要作用。虽然脂肪研究主要集中在肥胖上，但脂肪还有其他关键功能，它能产生脂肪细胞因子，有助于正常的营养代谢，而这反过来又在饱腹感和总能量平衡中发挥重要作用。SMAD2/3 蛋白是激活素信号的下游介质，调节关键的前体脂肪细胞和成熟脂肪细胞功能。Smad2 全局敲除小鼠表现出胚胎致死性，而 Smad3 的全局缺失则能保护小鼠免受饮食诱导的肥胖。然而，Smad2 和 Smad3 在脂肪组织中的直接贡献尚不清楚。在这里，我们使用 Smad2 或 Smad3“floxed”小鼠与脂联素-Cre 小鼠杂交，旨在确定脂肪细胞选择性减少 Smad2 或 Smad3 对饮食诱导肥胖的主要影响。此外，我们还研究了体外内脏和皮下前体脂肪细胞分化效率。几乎所有野生型皮下前体脂肪细胞都分化为成熟脂肪细胞。相比之下，内脏前体脂肪细胞分化较差。外源性激活素 A 抑制了两个部位的前体脂肪细胞的分化。Smad2 条件性敲除（Smad2cKO）小鼠无论饮食如何，体重增加均无显著影响，而 Smad3 条件性敲除（Smad3cKO）雄性小鼠在高脂肪饮食中体重呈下降趋势。在两种饮食中，Smad3cKO 小鼠均表现出脂肪组织选择性表型，皮下脂肪量显著减少，但内脏脂肪量没有减少。我们的数据表明，Smad3 是维持雌性皮下白色脂肪组织的重要因素。这些发现对于理解 SMAD 介导的、脂肪组织选择性调节脂肪细胞生长和分化具有重要意义。
