Hypothalamic PGC-1α protects against high-fat diet exposure by regulating ERα.
High-fat diets (HFDs) lead to obesity and inflammation in the central nervous system (CNS). Estrogens and estrogen receptor α (ERα) protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1α regulates ERα and inflammation in vivo. HFD significantly increased palmitic acid (PA) and sphingolipids in the CNS of male mice when compared to female mice. PA, in vitro, and HFD, in vivo, reduced PGC-1α and ERα in hypothalamic neurons and astrocytes of male mice and promoted inflammation. PGC-1α depletion with ERα overexpression significantly inhibited PA-induced inflammation, confirming that ERα is a critical determinant of the anti-inflammatory response. Physiologic relevance of ERα-regulated inflammation was demonstrated by reduced myocardial function in male, but not female, mice following chronic HFD exposure. Our findings show that HFD/PA reduces PGC-1α and ERα, promoting inflammation and decrements in myocardial function in a sex-specific way.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile.
Eugenia
E
Morselli
Institute for Diabetes and Obesity, Helmholtz Zentrum München and Department of Medicine, Technical university Munich, 85748 Munich, Germany.
Esther
E
Fuente-Martin
Institute for Diabetes and Obesity, Helmholtz Zentrum München and Department of Medicine, Technical university Munich, 85748 Munich, Germany.
Brian
B
Finan
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA.
Min
M
Kim
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA.
Aaron
A
Frank
Institute for Diabetes and Obesity, Helmholtz Zentrum München and Department of Medicine, Technical university Munich, 85748 Munich, Germany.
Cristina
C
Garcia-Caceres
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA.
Carlos Rodriguez
CR
Navas
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA.
Ruth
R
Gordillo
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA.
Michael
M
Neinast
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA.
Sarada P
SP
Kalainayakan
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Dan L
DL
Li
Institute for Diabetes and Obesity, Helmholtz Zentrum München and Department of Medicine, Technical university Munich, 85748 Munich, Germany.
Yuanqing
Y
Gao
Institute for Diabetes and Obesity, Helmholtz Zentrum München and Department of Medicine, Technical university Munich, 85748 Munich, Germany.
Chun-Xia
CX
Yi
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA.
Lisa
L
Hahner
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA.
Biff F
BF
Palmer
Institute for Diabetes and Obesity, Helmholtz Zentrum München and Department of Medicine, Technical university Munich, 85748 Munich, Germany.
Matthias H
MH
Tschöp
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA; Department of Biomedical Research, Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: deborah.clegg@cshs.org.
Deborah J
DJ
Clegg
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D019308:Palmitic Acid / Q000009:adverse effects / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012737:Sex Factors; D013107:Sphingolipids / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018754:Ventricular Dysfunction / Q000209:etiology / Q000378:metabolism
D047628:Estrogen Receptor alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D013107:Sphingolipids; D014157:Transcription Factors; D019308:Palmitic Acid