Selective estrogen receptor alpha modulation during body weight cycling

• Antragsteller: Professor Dr. Ulrich Kintscher
• Subject Area: Kinder- und Jugendmedizin ; Endokrinologie, Diabetologie, Metabolismus
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 101434729

• Final Report Year: 2019

Final Report Abstract

The aim of the present project in the second funding phase was the detailed analysis of ERα (estrogen receptor alpha) as a pharmacological target for the support of body weight (BW) reduction and prevention of BW-regain. Our studies aimed on the characterization of subtype and tissue/ cell-selective activation of ERα following the concept of selective ER modulation. In particular, we wanted concentrate on the role of ERα in the regulation of energy expenditure in the hypothalamus and in white adipose tissue (WAT) lipolysis. We identified a new mechanism of ERα modulation by dietary fatty acids. We discovered an unexpected phenotype of ERαlox/lox/aP2 Cre+/- (atERαKO) mice fed HFD characterized by increased mortality likely due to fatal bacterial uterine infections driven by commensal microbes. This phenotype pointed towards a previously unknown interaction of ERα signaling and FAs in macrophages. In particular, we showed that C18:0 provided by HFD modulates E2-ERα action in macrophages resulting in the perturbation of M2-macrophage polarization required for regular neutrophil-mediated defense. These processes likely result from intracellular ERα acylation leading to inhibition of its transcriptional activity and E2-dependent regulation of target genes. We believe that this new non-pharmacological way of ERα- modulation may provide a starting point for the development of new dietary ERα-modulators during BW-cycling. The possibility of dietary FA-modifications to modulate ERα thereby preventing BW-regain after an initial BW-loss should be tested in future experiments.

Publications

• Sexual dimorphic regulation of body weight dynamics and adipose tissue lipolysis. PLoS One. 2012;7:e37794
  Benz V, Bloch M, Wardat S, Bohm C, Maurer L, Mahmoodzadeh S, Wiedmer P, Spranger J, Foryst-Ludwig A, Kintscher U
  
• ANP system activity predicts variability of fat mass reduction and insulin sensitivity during weight loss. Metabolism. 2016;65:935-943
  Brachs M, Wiegand S, Leupelt V, Ernert A, Kintscher U, Jumpertz von Schwarzenberg R, Decker AM, Bobbert T, Hubner N, Chen W, Krude H, Spranger J, Mai K
  
• High-Fat Diet Induces Unexpected Fatal Uterine Infections in Mice with aP2-Cre-mediated Deletion of Estrogen Receptor Alpha. Sci Rep 2017
  Ban Z, Maurischat P, Benz V, Brix S, Sonnenburg A, Schuler G, Klopfleisch R, Rothe M, Gustafsson JA, Foryst-Ludwig A, Kintscher U