Gavaldà-Navarro Aleix, Moreno-Navarrete José M, Quesada-López Tania, Cairó Montserrat, Giralt Marta, Fernández-Real José M, Villarroya Francesc
Department of Biochemistry and Molecular Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Catalonia, Spain.
The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain.
Diabetologia. 2016 Oct;59(10):2208-18. doi: 10.1007/s00125-016-4028-y. Epub 2016 Jun 25.
AIMS/HYPOTHESIS: Adipocyte lipopolysaccharide-binding protein (LBP) biosynthesis is associated with obesity-induced adipose tissue dysfunction. Our purpose was to study the role of LBP in regulating the browning of adipose tissue.
Adult mice were maintained at 4°C for 3 weeks or treated with the β3-adrenergic agonist, CL316,243, for 1 week to induce the browning of white fat. Precursor cells from brown and white adipose tissues were cultured under differentiation-inducing conditions to yield brown and beige/brite adipocytes, respectively. In vitro, Lbp was knocked down in 3T3-L1 adipocytes, and cells were treated with recombinant LBP or co-cultured in transwells with control 3T3-L1 adipocytes. Wild-type and Lbp-null mice, fed a standard or high fat diet (HFD) for 15 weeks, were also used in investigations. In humans, subcutaneous and visceral adipose tissue samples were obtained from a cohort of morbidly obese participants.
The induction of white fat browning by exposure of mice to cold or CL316,243 treatment was strongly associated with decreased Lbp mRNA expression in white adipose tissue. The acquisition of the beige/brite phenotype in cultured cells was associated with downregulation of Lbp. Moreover, silencing of Lbp induced the expression of brown fat-related genes in adipocytes, whereas LBP treatment reversed this effect. Lbp-null mice exhibited the spontaneous induction of subcutaneous adipose tissue browning, as evidenced by a remarkable increase in Ucp1 and Dio2 gene expression and the appearance of multivacuolar adipocyte clusters. The amount of brown adipose tissue, and brown adipose tissue activity were also increased in Lbp-null mice. These changes were associated with decreased weight gain in Lbp-null mice and protection against HFD-induced inflammatory responses, as shown by reduced IL-6 levels. However, rather than improving glucose homeostasis, these effects led to glucose intolerance and insulin resistance.
CONCLUSIONS/INTERPRETATION: LBP is identified as a negative regulator of the browning process, which is likely to contribute to the obesity-promoting action of LBP. The deleterious metabolic effects of LBP deletion are compatible with the concept that the appropriate regulation of inflammatory pathways is necessary for a healthy systemic metabolic profile, regardless of body weight regulation.
目的/假设：脂肪细胞脂多糖结合蛋白（LBP）的生物合成与肥胖诱导的脂肪组织功能障碍有关。我们的目的是研究LBP在调节脂肪组织褐变中的作用。
将成年小鼠置于4°C环境中3周，或用β3 - 肾上腺素能激动剂CL316,243处理1周，以诱导白色脂肪褐变。将棕色和白色脂肪组织的前体细胞在诱导分化条件下培养，分别产生棕色和米色/明亮型脂肪细胞。在体外，敲低3T3 - L1脂肪细胞中的Lbp，并用重组LBP处理细胞，或将其与对照3T3 - L1脂肪细胞在Transwell中共培养。还使用了喂食标准或高脂饮食（HFD）15周的野生型和Lbp基因敲除小鼠进行研究。在人类中，从一组病态肥胖参与者中获取皮下和内脏脂肪组织样本。
小鼠暴露于寒冷环境或接受CL316,243处理诱导白色脂肪褐变，这与白色脂肪组织中Lbp mRNA表达降低密切相关。培养细胞中获得米色/明亮型表型与Lbp下调有关。此外，Lbp沉默诱导脂肪细胞中棕色脂肪相关基因的表达，而LBP处理则逆转了这种效应。Lbp基因敲除小鼠表现出皮下脂肪组织的自发褐变，Ucp1和Dio2基因表达显著增加以及多泡脂肪细胞簇的出现证明了这一点。Lbp基因敲除小鼠的棕色脂肪组织量和棕色脂肪组织活性也增加。这些变化与Lbp基因敲除小鼠体重增加减少以及对HFD诱导的炎症反应的保护作用有关，如IL - 6水平降低所示。然而，这些作用并未改善葡萄糖稳态，反而导致葡萄糖不耐受和胰岛素抵抗。
结论/解读：LBP被确定为褐变过程的负调节因子，这可能有助于LBP促进肥胖的作用。LBP缺失的有害代谢效应与以下概念相符，即无论体重调节如何，适当调节炎症途径对于健康的全身代谢状况是必要的。
