Impaired ER1 action due to genetic inactivating mutations and reductions in ER1 levels in the context of obesity and menopause are associated with features of the metabolic syndrome (MS). We have recently recapitulated aspects of this syndrome in whole body ER1-/- mice. Clinical observations and findings from rodent studies conducted in our laboratory support the hypothesis that reduced ER1 expression may in part underlie the dramatic rise in the MS in women and potentially explain the lack of anticipated health benefit of postmenopausal estrogen replacement. To date, little is known regarding the mechanisms causing reduced ER1 levels in obese subjects or the specific tissue(s) conferring ER1-mediated effects on insulin sensitivity. Our research efforts are focused on defining the role of ER1 in skeletal muscle, given that muscle is a primary tissue contributing to whole body oxidative metabolism and insulin-mediated glucose disposal.
In Aim1, we propose the use of mouse genetics, in combination with in vivo and in vitro approaches to generate muscle-specific ER1 loss- and gain-of-function mutations to test whether skeletal muscle ER1 is an important regulator of insulin sensitivity and adiposity. We provide compelling data showing that muscle ER1 maintains insulin action and protects against obesity, due in large part to its role in promoting oxidative metabolism and preventing tissue inflammation. Herein, we identify a novel role for ER1 in the regulation of mitochondrial morphology and turnover, as mitochondria are enlarged and misaligned, and mitophagy and biogenesis-related factors (e.g. the PINK1/Parkin pathway and Pgc11) are dysregulated in mice with muscle- specific ER1 deletion.
In Aim 2, we will examine the role of ER1 in adaptations to endurance exercise.
This aim i s of particular clinical interest especially if the full health benefit of exercise cannot be achieved in muscle deficient in ER1. Indeed our findings show accelerated muscle fatigue and impaired exercise-mediated induction of factors controlling mitochondrial turnover in muscle-specific ER1 knockout mice.
In Aim 3, we will test the hypothesis that reduced ER1 levels, as we observe in aged human muscle, results from protein hyperacetylation and targeted proteasomal degradation. Using newly generated tagged ER1 mutants that mimic or are resistant to acetylation coupled with an ERE-luciferase reporter system, we will investigate the relationship between acetylation state, transcriptional cofactor expression, and ER1 abundance. We now provide evidence that SIRT1, a class III HDAC with protein deacetylase function, is a central regulator of the "acetylation-phosphorylation switch" that appears to control ER1 levels and action in muscle. We anticipate that our findings will exert an important and lasting impact on the field of research and provide the critical foundation for the advancement of therapeutic strategies to treat metabolic dysfunction that underlies many female-related chronic diseases.

Public Health Relevance

The incidence of the metabolic syndrome is rising dramatically in women and is associated with elevated morbidity and mortality secondary to type 2 diabetes, cardiovascular disease, hepatic dysfunction, and certain types of cancer. Human inactivating mutations in the estrogen receptor (ER) alpha are associated with features of the metabolic syndrome including insulin resistance and obesity, and we find that skeletal muscle-specific ERalpha knockout mice recapitulate a similar phenotype. Thus, we propose that strategies to maintain expression of ERalpha in glucoregulatory tissues, particularly skeletal muscle, may help prevent or ameliorate chronic disease in women.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089109-02
Application #
8320239
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Margolis, Ronald N
Project Start
2011-08-15
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$334,950
Indirect Cost
$117,450
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Drew, Brian G; Ribas, Vicente; Le, Jamie A et al. (2014) HSP72 is a mitochondrial stress sensor critical for Parkin action, oxidative metabolism, and insulin sensitivity in skeletal muscle. Diabetes 63:1488-505
Henstridge, Darren C; Bruce, Clinton R; Drew, Brian G et al. (2014) Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance. Diabetes 63:1881-94
Kim, Jun Ho; Meyers, Matthew S; Khuder, Saja S et al. (2014) Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. Mol Metab 3:177-90
Mauvais-Jarvis, Franck; Clegg, Deborah J; Hevener, Andrea L (2013) The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev 34:309-38