Protection from disproportionate fat accumulation through modulation of neuroendocrine pathways in fat cells and the CNS of large-conductance, CA2+-and voltage-activated K+ (BK) channel deficient mice

通过调节大电导、CA2 和电压激活 K (BK) 通道缺陷小鼠的脂肪细胞和 CNS 中的神经内分泌途径，防止不成比例的脂肪堆积

• 批准号: 445878942
• 负责人: Professor Dr. Robert Lukowski
• 金额: --
• 依托单位: Fachrichtung Pharmakologie, Toxikologie und Klinische Pharmazie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/445878942?language=en
• 关键词: Protection; disproportionate; fat; accumulation; through

Adult mice globally lacking the Ca2+-activated K+ channel with high conductivity (BK) are resistant to excessive body mass accumulation under high-fat diet. Two complementary mouse models lacking BK specifically in either adipocytes or neurons of the central nervous system (CNS) present a similar, albeit less pronounced phenotype under analogous feeding conditions. Based on these findings, we propose that K+ channels in adipocytes as well as in the CNS regulate energy homeostasis, body composition, body-weight control, and metabolic state under conditions of high caloric intake. Indeed, we observe that obesity resistance of adipocyte-specific BK-null mutants is accompanied by reduced expression of pro-inflammatory cytokines, elevated body temperature, improved insulin sensitivity, and adipocyte hyperplasia. The first aim of the current proposal is to clarify the mechanisms by which BK located in adipose tissue controls growth, differentiation, as well as function of white and brown adipocytes, and how BK-deficiency prevents pathological fat accumulation in vivo. The second aim is the cell-specific investigation of BK function in defined orexigenic and anorexigenic areas of the CNS under high-fat diet in order to explain in more detail the obesity resistance of the CNS-specific BK-null mutant. Characterizing the contribution of central and peripheral K+ channels to the emergence of obesity should help to establish new pharmacological targets that modulate or even prevent obesity and associated metabolic and cardiovascular complications.

缺乏高电导率Ca2+激活的K+通道（BK）的成年小鼠在高脂肪饮食下抵抗过度的体重积累。在类似的喂养条件下，两种互补的小鼠模型在中枢神经系统（CNS）的脂肪细胞或神经元中特异性缺乏BK，尽管不太明显，但表现出相似的表型。基于这些发现，我们提出脂肪细胞和中枢神经系统中的K+通道在高热量摄入条件下调节能量稳态、身体成分、体重控制和代谢状态。事实上，我们观察到脂肪细胞特异性BK-null突变体的肥胖抵抗伴随着促炎细胞因子表达减少、体温升高、胰岛素敏感性改善和脂肪细胞增生。本研究的第一个目的是阐明脂肪组织中BK控制白色和棕色脂肪细胞生长、分化和功能的机制，以及BK缺乏如何阻止体内病理性脂肪堆积。第二个目标是在高脂肪饮食条件下，对BK在中枢神经系统特定的厌氧区和厌氧区功能进行细胞特异性研究，以更详细地解释中枢神经系统特异性BK-null突变体的肥胖抗性。描述中枢和外周K+通道对肥胖发生的贡献有助于建立新的药理学靶点，以调节甚至预防肥胖及相关的代谢和心血管并发症。