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

在全球范围内，缺乏高电导率(BK)的钙激活K+通道的成年小鼠对高脂饮食下过多的体重积累具有抵抗力。在相似的饲养条件下，两个在脂肪细胞或中枢神经系统(CNS)神经元中特异性缺乏BK的互补小鼠模型呈现出相似的表型，尽管不那么明显。基于这些发现，我们认为，在高热量摄入条件下，脂肪细胞和中枢神经系统中的K+通道调节能量平衡、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缺失突变体的肥胖抵抗伴随着促炎症细胞因子的表达减少、体温升高、胰岛素敏感性改善和脂肪细胞增殖。本提案的第一个目的是阐明BK在脂肪组织中定位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积累。第二个目的是在高脂饮食下对中枢神经系统特定的厌食区和厌氧区的BK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的BK缺失突变体的肥胖抵抗。确定中枢和外周K+通道在肥胖发生中的作用将有助于建立新的药理靶点，以调节甚至预防肥胖症及其相关的代谢和心血管并发症。

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.