Selective estrogen receptor alpha modulation during body weight cycling

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Body weight (BW) cycling including BW -regain after weight loss is associated with marked changes in energy expenditure (EE) and adipose tissue (AT) metabolism. Since these processes are sex-specifically controlled, we focus on sexual dimorphisms in metabolic processes during BW-cycling and aimed to elucidate the role of ER! in lipogenesis and lipolysis in the AT. We established a diet-induced (DIO) mouse model with a subsequent reduction of BW by caloric restriction (CR) followed by adaptive feeding, and a regain-period. We observed that female mice responded to CR with an increase in lipolytic activity, and augmented lipid-oxidation leading to more efficient weight loss compared to male animals. These processes likely involve sexual dimorphic regulation of ATGL and estrogen receptor alpha (ERα)-dependent signaling in AT. In addition, female mice showed higher levels of EE during BW-cycling. This is in accordance with a recently published report demonstrating that ERα-deletion in neurons of the ventromedial hypothalamic nucleus (VMH) results in reduced EE. Based on these data we hypothesize that ERα mediates its metabolic action during BW-cycling in a bimodal manner in the VMH and AT. Thus, the aim of the present project for a second funding period is the detailed analysis of ERα in the VMH and AT as a pharmacological target for the support of BW-reduction and prevention of BW-regain after initial weight loss. Our studies will focus on the characterization of subtype- and tissue/ cellselective activation of ERα following the concept of selective estrogen receptor modulation (SERM). After phenotyping of AT-specific ERα-deficient mice during the first funding phase, we will start with the metabolic analysis of VMH-specific ERα-deficient (ERαlox/lox/ SF-1 Cre) mice during BW-cycling. In parallel we will study molecular SERM-components (ERα, nuclear cofactors, target genes) in the VMH and AT during BW-cycling and in-vitro. Finally, newly synthesized SERM-compounds specific for ER! will be tested in-vitro and in-vivo. This projects aims for an improved understanding of SERM compounds as a pharmacological intervention in obesity.