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

成年小鼠普遍缺乏高电导率的Ca2+激活的K+通道（BK），在高脂饮食下抵抗过度的体重积累。两个互补的小鼠模型缺乏BK特异性的脂肪细胞或中枢神经系统（CNS）的神经元在类似的喂养条件下呈现出相似的，虽然不太明显的表型。基于这些发现，我们提出，K+通道在脂肪细胞以及中枢神经系统调节能量稳态，身体成分，体重控制，和代谢状态下的高热量摄入的条件下。事实上，我们观察到脂肪细胞特异性BK无效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。目前的建议的第一个目的是澄清的BK位于脂肪组织控制生长，分化，以及白色和棕色脂肪细胞的功能，以及如何BK缺乏防止病理性脂肪堆积在体内的机制。第二个目的是BK功能的细胞特异性调查，在高脂肪饮食下的中枢神经系统的orexigenic和orexigenic领域，以更详细地解释的CNS特异性BK无效突变体的肥胖抵抗。描述中枢和外周K+通道对肥胖症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症以及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.