Slutsky N, Vatarescu M, Haim Y, Goldstein N, Kirshtein B, Harman-Boehm I, Gepner Y, Shai I, Bashan N, Blüher M, Rudich A
Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Soroka Academic Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Int J Obes (Lond). 2016 Jun;40(6):912-20. doi: 10.1038/ijo.2016.5. Epub 2016 Jan 20.
BACKGROUND/OBJECTIVES: Adipose tissue (AT) autophagy gene expression is elevated in human obesity, correlating with increased metabolic risk, but mechanistic links between the two remain unclear. Thus, the objective of this study was to assess whether elevated autophagy may cause AT endocrine dysfunction, emphasizing the putative role of adiponectin in fat-liver endocrine communication.
SUBJECTS/METHODS: We utilized a large (N=186) human AT biobank to assess clinical associations between human visceral AT autophagy genes, adiponectin and leptin, by multivariate models. A broader view of adipocytokines association with elevated autophagy was assessed using adipocytokine array. Finally, to establish causality, ex vivo studies utilizing a murine AT-hepatocyte cell line co-culture system was used.
Circulating high-molecular-weight adiponectin and leptin levels were associated with human omental-AT expression of ATG5 mRNA, associations that remained significant (β=-0.197, P=0.011; β=0.267, P<0.001, respectively) in a multivariate model adjusted for age, sex, body mass index and interleukin-6 (IL-6). A similar association was observed with omental-AT LC3A mRNA levels. Bafilomycin-A1 (Baf A) pretreatment of AT explants from high-fat-fed (HFF) mice had no effect on the secretion of some AT-derived endocrine factors, but partially or fully reversed obesity-related changes in secretion of a subset of adipocytokines by >30%, including the obesity-associated upregulation of IL-6, vascular endothelial growth factor, tumor necrosis factor alpha (TNFα) and certain insulin-like growth factor-binding proteins, and the HFF-induced downregulated secretion of IL-10 and adiponectin. Similarly, decreased adiponectin and increased leptin secretion from cultured adipocytes stimulated with TNFα+IL-1β was partially reversed by small interfering RNA-mediated knockdown of ATG7. AT explants from HFF mice co-cultured with Hepa1c hepatoma cells impaired insulin-induced Akt and GSK3 phosphorylation. This effect was significantly reversed by pretreating explants with Baf A, but not if adiponectin was immunodepleted from the conditioned media.
Reduced secretion of adiponectin may link obesity-associated elevated AT autophagy/lysosomal activity with adipose endocrine dysfunction.
背景/目的：人类肥胖时脂肪组织（AT）自噬基因表达升高，与代谢风险增加相关，但二者之间的机制联系尚不清楚。因此，本研究的目的是评估自噬增加是否会导致AT内分泌功能障碍，重点研究脂联素在脂肪-肝脏内分泌通讯中的假定作用。
受试者/方法：我们利用一个大型（N = 186）人类AT生物样本库，通过多变量模型评估人类内脏AT自噬基因、脂联素和瘦素之间的临床关联。使用脂肪细胞因子阵列评估脂肪细胞因子与自噬增加的更广泛关联。最后，为了确定因果关系，采用了利用小鼠AT-肝细胞系共培养系统的体外研究。
循环中高分子量脂联素和瘦素水平与网膜AT中ATG5 mRNA的表达相关，在调整了年龄、性别、体重指数和白细胞介素-6（IL-6）的多变量模型中，这种关联仍然显著（β = -0.197，P = 0.011；β = 0.267，P < 0.001）。在网膜AT的LC3A mRNA水平上也观察到类似的关联。用巴弗洛霉素A1（Baf A）预处理高脂喂养（HFF）小鼠的AT外植体对一些AT衍生的内分泌因子的分泌没有影响，但部分或完全逆转了肥胖相关的一部分脂肪细胞因子分泌变化的>30%，包括肥胖相关的IL-6、血管内皮生长因子、肿瘤坏死因子α（TNFα）和某些胰岛素样生长因子结合蛋白的上调，以及HFF诱导的IL-10和脂联素分泌下调。同样，用小干扰RNA介导的ATG7敲低部分逆转了用TNFα + IL-1β刺激的培养脂肪细胞中脂联素分泌减少和瘦素分泌增加的情况。与Hepa1c肝癌细胞共培养的HFF小鼠的AT外植体损害了胰岛素诱导的Akt和GSK3磷酸化。用Baf A预处理外植体可显著逆转这种作用，但如果从条件培养基中免疫去除脂联素则不能逆转。
脂联素分泌减少可能将肥胖相关的AT自噬/溶酶体活性升高与脂肪内分泌功能障碍联系起来。
