title: Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury.
abstract: Extensively burned patients often suffer from sepsis, a complication that enhances postburn hypermetabolism and contributes to increased incidence of multiple organ failure, morbidity and mortality. Despite the clinical importance of burn sepsis, the molecular and cellular mechanisms of such infection-related metabolic derangements and organ dysfunction are still largely unknown. We recently found that upon endoplasmic reticulum (ER) stress, the white adipose tissue (WAT) interacts with the liver via inflammatory and metabolic signals leading to profound hepatic alterations, including hepatocyte apoptosis and hepatic fatty infiltration. We therefore hypothesized that burn plus infection causes an increase in lipolysis of WAT after major burn, partially through induction of ER stress, contributing to hyperlipidemia and profound hepatic lipid infiltration. We used a two-hit rat model of 60% total body surface area scald burn, followed by intraperitoneal (IP) injection ofPseudomonas Aeruginosa-derived lipopolysaccharide (LPS) 3 d postburn. One day later, animals were euthanized and liver and epididymal WAT (EWAT) samples were collected for gene expression, protein analysis and histological study of inflammasome activation, ER stress, apoptosis and lipid metabolism. Our results showed that burn plus LPS profoundly increased lipolysis in WAT associated with significantly increased hepatic lipid infiltration. Burn plus LPS augmented ER stress by upregulating CHOP and activating ATF6, inducing NLRP3 inflammasome activation and leading to increased apoptosis and lipolysis in WAT with a distinct enzymatic mechanism related to inhibition of AMPK signaling. In conclusion, burn sepsis causes profound alterations in WAT and liver that are associated with changes in organ function and structure.
authors.affiliation: Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Li
authors.initials: L
authors.lastname: Diao
authors.affiliation: Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Patsouris
authors.affiliation: Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Ali-Reza
authors.initials: AR
authors.lastname: Sadri
authors.affiliation: Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Dai
authors.affiliation: Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Surgery, Division of Plastic Surgery, Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Saeid
authors.initials: S
authors.lastname: Amini-Nik
authors.affiliation: Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Surgery, Division of Plastic Surgery, Department of Immunology, University of Toronto, Toronto, Ontario, Canada.|Ross Tilley Burn Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Jeschke