Journal
DIABETES
Volume 67, Issue 8, Pages 1524-1537Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-1342
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Funding
- Japan Society for the Promotion of Science [16K20174]
- Suzuken Memorial Foundation
- Uehara Memorial Foundation
- Kanzawa Medical Research Foundation
- Japan Heart Foundation Research grant
- Inamori Foundation
- Sakakibira Memorial Research grant from Japan Research Promotion Society for Cardiovascular Diseases
- Banyu Life Science Foundation
- Tokyo Society of Medical Sciences
- Takeda Science Foundation
- Yamaguchi Endocrine Research Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- National Institutes of Health [R01-HL-61298]
- Grants-in-Aid for Scientific Research [16K20174] Funding Source: KAKEN
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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.
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