Abstract

High-fat diets (HFDs) lead to obesity and inflammation in the central nervous system (CNS). Estrogens and estrogen receptor alpha (ER alpha) protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1 alpha regulates ER alpha 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-1 alpha and ER alpha in hypothalamic neurons and astrocytes of male mice and promoted inflammation. PGC-1 alpha depletion with ER alpha overexpression significantly inhibited PA-induced inflammation, confirming that ER alpha is a critical determinant of the anti-inflammatory response. Physiologic relevance of ER alpha-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-1 alpha and ER alpha, promoting inflammation and decrements in myocardial function in a sex-specific way.