Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A

Kazutaka Ueda; Eiki Takimoto; Qing Lu; Pangyen Liu; Nobuaki Fukuma; Yusuke Adachi; Ryo Suzuki; Shengpu Chou; Wendy Baur; Mark J Aronovitz; Andrew S Greenberg; Issei Komuro; Richard H Karas

doi:10.2337/db17-1342

Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A

Diabetes. 2018 Aug;67(8):1524-1537. doi: 10.2337/db17-1342. Epub 2018 May 15.

Authors

Affiliations

¹ Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
² Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
³ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁴ Obesity and Metabolism Laboratory, U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
⁵ Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [email protected] [email protected].
⁶ Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA [email protected] [email protected].

Abstract

Women gain weight and their diabetes risk increases as they transition through menopause; these changes can be partly reversed by hormone therapy. However, the underlying molecular mechanisms mediating these effects are unknown. A novel knock-in mouse line with the selective blockade of the membrane-initiated estrogen receptor (ER) pathway was used, and we found that the lack of this pathway precipitated excessive weight gain and glucose intolerance independent of food intake and that this was accompanied by impaired adaptive thermogenesis and reduced physical activity. Notably, the central activation of protein phosphatase (PP) 2A improved metabolic disorders induced by the lack of membrane-initiated ER signaling. Furthermore, the antiobesity effect of estrogen replacement in a murine menopause model was abolished by central PP2A inactivation. These findings define a critical role for membrane-initiated ER signaling in metabolic homeostasis via the central action of PP2A.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Adipocytes / drug effects
Adipocytes / metabolism
Adipocytes / pathology
Adiposity / drug effects
Amino Acid Substitution
Animals
Cells, Cultured
Diet, High-Fat / adverse effects
Enzyme Activation / drug effects
Estradiol / pharmacology
Estradiol / therapeutic use
Estrogen Receptor alpha / agonists*
Estrogen Receptor alpha / genetics
Estrogen Receptor alpha / metabolism
Estrogen Replacement Therapy*
Female
Gene Knock-In Techniques
Glucose Intolerance / etiology
Glucose Intolerance / metabolism
Glucose Intolerance / pathology
Glucose Intolerance / prevention & control*
Insulin Resistance
Menopause*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscle, Smooth, Vascular / drug effects
Muscle, Smooth, Vascular / metabolism
Muscle, Smooth, Vascular / pathology
Obesity / etiology
Obesity / metabolism
Obesity / pathology
Obesity / prevention & control*
Ovariectomy
Point Mutation
Protein Phosphatase 2 / chemistry
Protein Phosphatase 2 / metabolism*
Signal Transduction / drug effects*

Substances

Estrogen Receptor alpha
Estradiol
Protein Phosphatase 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding