Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Int J Obes (Lond). 2018 Mar;42(3):376-383. doi: 10.1038/ijo.2017.214. Epub 2017 Aug 30.
BACKGROUND/OBJECTIVES: Mutations in the Tubby gene (TUB) cause late-onset obesity and insulin resistance in mice and syndromic obesity in humans. Although TUB gene function has not yet been fully elucidated, studies in rodents indicate that TUB is involved in the hypothalamic pathways regulating food intake and adiposity. Aside from the function in central nervous system, TUB has also been implicated in energy metabolism in adipose tissue in rodents. We aimed to determine the expression and distribution patterns of TUB in man as well as its potential association with obesity.
SUBJECTS/METHODS: In situ hybridization was used to localize the hypothalamic regions and cells expressing TUB mRNA. Using RT-PCR, we determined the mRNA expression level of the two TUB gene alternative splicing isoforms, the short and the long transcript variants, in the hypothalami of 12 obese and 12 normal-weight subjects, and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissues from 53 severely obese and 24 non-obese control subjects, and correlated TUB expression with parameters of obesity and metabolic health.
Expression of both TUB transcripts was detected in the hypothalamus, whereas only the short TUB isoform was found in both VAT and SAT. TUB mRNA was detected in several hypothalamic regions involved in body weight regulation, including the nucleus basalis of Meynert and the paraventricular, supraoptic and tuberomammillary nuclei. We found no difference in the hypothalamic TUB expression between obese and control groups, whereas the level of TUB mRNA was significantly lower in adipose tissue of obese subjects as compared to controls. Also, TUB expression was negatively correlated with indices of body weight and obesity in a fat-depot-specific manner.
Our results indicate high expression of TUB in the hypothalamus, especially in areas involved in body weight regulation, and the correlation between TUB expression in adipose tissue and obesity. These findings suggest a role for TUB in human obesity.
背景/目的：Tubby 基因（TUB）的突变会导致小鼠的迟发性肥胖和胰岛素抵抗以及人类的综合征性肥胖。尽管 TUB 基因的功能尚未完全阐明，但啮齿动物的研究表明，TUB 参与了调节食物摄入和肥胖的下丘脑途径。除了在中枢神经系统中的功能外，TUB 还与啮齿动物脂肪组织中的能量代谢有关。我们旨在确定 TUB 在人体中的表达和分布模式及其与肥胖的潜在关联。
受试者/方法：使用原位杂交技术定位表达 TUB mRNA 的下丘脑区域和细胞。通过 RT-PCR，我们确定了 12 名肥胖和 12 名正常体重受试者下丘脑两种 TUB 基因选择性剪接异构体（短和长转录变体）的 mRNA 表达水平，以及 53 名严重肥胖和 24 名非肥胖对照受试者的内脏（VAT）和皮下（SAT）脂肪组织活检中的 TUB 表达，并将 TUB 表达与肥胖和代谢健康的参数相关联。
两种 TUB 转录本均在下丘脑检测到，而仅在 VAT 和 SAT 中检测到短 TUB 异构体。TUB mRNA 存在于几个参与体重调节的下丘脑区域，包括梅尼埃基底核和室旁核、视上核和结节乳头核。我们在肥胖组和对照组之间没有发现下丘脑 TUB 表达的差异，而肥胖受试者的脂肪组织中 TUB mRNA 的水平明显低于对照组。此外，TUB 表达与脂肪组织特异性的体重和肥胖指数呈负相关。
我们的结果表明 TUB 在下丘脑，尤其是在参与体重调节的区域中表达较高，并且 TUB 在脂肪组织中的表达与肥胖相关。这些发现表明 TUB 在人类肥胖中起作用。
