Heterotrimeric Gai2 protein function in insulin-secreting beta-cells and insulin-sensitive adipocytes

异三聚体 Gai2 蛋白在胰岛素分泌 β 细胞和胰岛素敏感脂肪细胞中的功能

• 批准号: 212091437
• 负责人: Professor Dr. Bernd Nürnberg
• 金额: --
• 依托单位: Abteilung Pharmakologie, Experimentelle Therapie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/212091437?language=en
• 关键词: Heterotrimeric; Gai2; protein; function; insulin

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder, which affects more than 300 million people globally. The prominent feature of uncontrolled T2DM is hyperglycemia, which results from beta-cell dysfunction and insulin resistance. In most people suffering T2DM a characteristic set of symptoms is found, which is known as metabolic syndrome: insulin resistance, hyperlipidemia, hypertension and obesity. Lifestyle interventions such as diet and/or exercise have often limited effects. Hence, novel pharmacological interventions are needed to reduce body weight, improve insulin sensitivity and hyperlipidemia in order to prevent the progression of T2DM. G protein coupled receptors (GPCR) are quite frequent pharmacological targets. Upon ligand binding GPCRs activate heterotrimeric G proteins which in turn are eliciting cellular responses through the regulation of intracellular second messenger-generating systems. The class of inhibitory G proteins (Gi) forms one subfamily including the predominantly expressed Gi2 isoform which is found in pancreatic islets and white adipose tissue (WAT). However, the mechanisms and biological implication of Gi2-dependent pathways in insulin-secreting beta-cells and WAT remain cryptic. Within the first funding period we identified beta-cell-Gi2 as a stimulator of L arginine- and L ornithine-induced insulin secretion. Surprisingly, although Gi2 is a PTx-sensitive G protein and therefore thought to inhibit insulin secretion, Gi2 deletion in beta-cells resulted in a decreased glucose tolerance and impaired insulin secretion in vivo, a situation also found in patients suffering from T2DM. Interestingly, our studies in global Gi2-deficient mice demonstrated a lean phenotype of these mice on control (CD) and on a 45% high-fat diet (HFD). Both, CD and HFD-fed Gi2-deficient mice were significantly leaner and accumulated significantly less body fat mass than their littermate controls. First studies on adipocyte-specific Gi2-deficient mice showed also significantly reduced body weight on HFD. Therefore, we hypothesize that Gi2 is not only relevant for proper insulin secretion but also important for adipocyte differentiation and plays a role in diet-induced obesity. Consequently, on the one hand a major aim of our grant proposal is to elucidate the molecular Gi2 signalling pathway in beta-cells by analyzing beta-cell-specific Gi2-deficient islets. On the other hand we want to clarify the function of Gi2 in adipocytes. Therefore, we intend to examine global and adipocytes-specific Gi2-deficient mice. We will study adipocyte differentiation, maturation and organization in vitro and weight gain, glucose homeostasis, body consumption, fat mass distribution and energy expenditure in mice on CD and HFD. Taken together, this study will provide new insights into T2DM-relevant signalling pathways and will help to develop new pharmacological interventions for T2DM.

2型糖尿病（T2DM）是一种常见的代谢紊乱疾病，影响全球3亿多人。不受控制的T2DM的突出特征是高血糖症，其由β细胞功能障碍和胰岛素抵抗引起。在大多数患有T2DM的人中，发现了一组特征性症状，其被称为代谢综合征：胰岛素抵抗、高脂血症、高血压和肥胖。饮食和/或运动等生活方式干预措施的效果往往有限。因此，需要新的药物干预来减轻体重，改善胰岛素敏感性和高脂血症，以防止T2DM的进展。G蛋白偶联受体（GPCR）是非常常见的药理学靶点。在配体结合后，GPCR激活异源三聚体G蛋白，其进而通过调节细胞内第二信使产生系统引发细胞应答。抑制性G蛋白（Gi）的类别形成一个亚家族，包括在胰岛和白色脂肪组织（WAT）中发现的主要表达的Gi2同种型。然而，胰岛素分泌β细胞和WAT中Gi2依赖性途径的机制和生物学意义仍然是神秘的。在第一个资助期内，我们将β细胞Gi2鉴定为L精氨酸和L鸟氨酸诱导的胰岛素分泌的刺激物。令人惊讶的是，尽管Gi2是PTX敏感性G蛋白，因此被认为抑制胰岛素分泌，但β细胞中的Gi2缺失导致体内葡萄糖耐量降低和胰岛素分泌受损，这也是在患有T2DM的患者中发现的情况。有趣的是，我们在全局Gi2缺陷小鼠中的研究证明了这些小鼠在对照（CD）和45%高脂饮食（HFD）下的瘦表型。CD和HFD喂养的Gi2缺陷小鼠都比其同窝对照显著更瘦，并且累积的体脂量显著更少。对脂肪细胞特异性Gi2缺陷小鼠的第一项研究也显示HFD显著降低的体重。因此，我们假设Gi2不仅与适当的胰岛素分泌有关，而且对脂肪细胞分化也很重要，并在饮食诱导的肥胖中起作用。因此，一方面，我们的资助提案的主要目的是通过分析β细胞特异性Gi2缺陷胰岛来阐明β细胞中的分子Gi2信号传导途径。另一方面，我们希望阐明Gi2在脂肪细胞中的功能。因此，我们打算检查全局和脂肪细胞特异性Gi2缺陷小鼠。我们将在体外研究脂肪细胞的分化、成熟和组织化，以及CD和HFD小鼠的体重增加、葡萄糖稳态、身体消耗、脂肪质量分布和能量消耗。总之，这项研究将为T2DM相关信号通路提供新的见解，并将有助于开发新的T2DM药物干预措施。

项目成果

Diabetic lung disease: fact or fiction?

• DOI: 10.1007/s11154-019-09516-w
• 发表时间: 2019-10-21
• 期刊: REVIEWS IN ENDOCRINE & METABOLIC DISORDERS
• 影响因子: 8.2
• 作者: Kolahian, Saeed;Leiss, Veronika;Nuernberg, Bernd
• 通讯作者: Nuernberg, Bernd

Selective protection of murine cerebral Gi/o-proteins from inactivation by parenterally injected pertussis toxin

• DOI: 10.1007/s00109-019-01854-1
• 发表时间: 2020-01-01
• 期刊: JOURNAL OF MOLECULAR MEDICINE-JMM
• 影响因子: 4.7
• 作者: Vega, Salvador Castaneda;Leiss, Veronika;Nuernberg, Bernd
• 通讯作者: Nuernberg, Bernd

Obesogenic and Diabetogenic Effects of High-Calorie Nutrition Require Adipocyte BK Channels

高热量营养的致肥胖和致糖尿病作用需要脂肪细胞 BK 通道

• DOI: 10.2337/db16-0245
• 发表时间: 2016
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Illison J;Tian L;McClafferty H;Werno M;Chamberlain LH;Leiss V;Sassmann A;Offermanns S;Ruth P;Shipston MJ;Lukowski R
• 通讯作者: Lukowski R