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

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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.