Increases in sympathetic nerve activity (SNA) significantly contributes to the heightened risk for hypertension and in turn cardiovascular diseases in obesity. Previous studies from our lab demonstrate that pathological changes including oxidative stress and inflammation in the brain- stem regions regulating sympathetic tone, critically contributes to obesity-induced sympathoexcitation. Our findings point to a potential role for brainstem astrocyte dysfunction in mediating the effects of obesity on SNA. Emerging evidence indicates that altered lipid composition, particularly elevations in saturated fatty acids, may be a key driver of astrocytic dysfunction in obesity. Notably, clinical studies have reported increased levels of palmitic acid (PA), a major dietary and endogenously synthesized saturated fatty acid, in the cerebrospinal fluid of obese individuals, implicating PA as a potential metabolic signal linking peripheral obesity to central neural dysfunction. Building on this observation, we employed complementary in vivo (tissues from diet-induced obese mice) and in vitro (PA treatment in human primary brainstem astrocytes) approaches to directly test the hypothesis whether PA exposure induces structural and functional alterations in brainstem astrocytes that regulate sympathetic tone. Our results showed that PA treatment triggered structural remodeling marked by transition from their normal star-shaped morphology to a rounded phenotype with process retraction in human brainstem astrocytes. Likewise, we also observed a similar phenotype in the brainstem astrocytes from high-fat diet induced mice when compared to chow fed controls. Importantly, these structural changes were also accompanied by increased lipid droplet accumulation in brainstem astrocytes following PA treatment. These findings emphasize the causal link between dietary lipids and astrocytic dysfunction. This study provides novel insights into obesity-induced astrocytic dysfunction, highlighting astrocytes as potential therapeutic targets for mitigating lipotoxicity and neuroinflammation. Funding Information: R01HL163775 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Nanayakkara et al. (Fri,) studied this question.