Abstract
Obesity promotes the onset and progression of metabolic and inflammatory diseases such as type 2 diabetes. The chronic low-grade inflammation that occurs during obesity triggers multiple signaling mechanisms that negatively affect organismal health. One such mechanism is the persistent activation and mitochondrial translocation of STAT3, which is implicated in inflammatory pathologies and many types of cancers. STAT3 in the mitochondria (mitoSTAT3) alters electron transport chain activity, thereby influencing nutrient metabolism and immune response. PBMCs and CD4+ T cells from obese but normal glucose-tolerant (NGT) middle-aged subjects had higher phosphorylation of STAT3 on residue serine 727 and more mitochondrial accumulation of STAT3 than cells from lean subjects. To evaluate if circulating lipid overabundance in obesity is responsible for age- and sex-matched mitoSTAT3, cells from lean subjects were challenged with physiologically relevant doses of the saturated and monounsaturated fatty acids, palmitate and oleate, respectively. Fatty acid treatment caused robust accumulation of mitoSTAT3 in all cell types, which was independent of palmitate-induced impairments in autophagy. Co-treatment of cells with fatty acid and trehalose prevented STAT3 phosphorylation and mitochondrial accumulation in an autophagy-independent but cellular peroxide–dependent mechanism. Pharmacological blockade of mitoSTAT3 either by a mitochondria-targeted STAT3 inhibitor or ROS scavenging prevented obesity and fatty acid–induced production of proinflammatory cytokines IL-17A and IL-6, thus establishing a mechanistic link between mitoSTAT3 and inflammatory cytokine production.
Original language | English |
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Article number | 924003 |
Journal | Frontiers in Aging |
Volume | 3 |
DOIs | |
State | Published - 2022 |
Bibliographical note
Publisher Copyright:Copyright © 2022 Conway, Rockhold, SantaCruz-Calvo, Zukowski, Pugh, Hasturk, Kern, Nikolajczyk and Bharath.
Funding
This work was also supported by the Pasini Fellowship (LB). This work was supported by R15AG068957 (LB), R56AG06985 (BN), and CTSA Grant UL1 TR001998 (PK), college of Health Sciences Faculty Development grant (FDG) (LB) and Sakowich Center for Undergraduate Research and Creative Activities grant (SCURCA), Merrimack College (LB), College of Health Sciences, Merrimack College and Barnstable Brown Diabetes Center, and the University of Kentucky College of Medicine.
Funders | Funder number |
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Merrimack College | |
Sakowich Center for Undergraduate Research and Creative Activities | |
University of Kentucky College of Medicine |
Keywords
- ROS
- T cells
- cytokines
- inflammation
- mitochondrial STAT3
- obesity
- peroxide
ASJC Scopus subject areas
- Aging
- Genetics
- Molecular Biology
- Physiology