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 of Pseudomonas 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.

Adipose tissue: between the extremes

“…Catecholamines are also major drivers of adipocyte lipolysis. Interestingly, a recent study showed that adipose tissue loss due to septic burn injury could be traced back to a loss in AMPK-dependent inhibition of lipolysis in the adipose tissue (Diao et al, 2015). Interestingly, a recent study showed that adipose tissue loss due to septic burn injury could be traced back to a loss in AMPK-dependent inhibition of lipolysis in the adipose tissue (Diao et al, 2015).…”

“…Lipolysis and fatty acid release into the circulation have been shown to be elevated upon burn injury (Williams et al, 2009). Interestingly, a recent study showed that adipose tissue loss due to septic burn injury could be traced back to a loss in AMPK-dependent inhibition of lipolysis in the adipose tissue (Diao et al, 2015). Similar to cachexia, burn injury often presents with elevated levels of inflammatory cytokines such as IL-6 (Abdullahi et al, 2017).…”

White Adipose Tissue Browning: A Double-edged Sword

“…For example, mice lacking the IL-6 gene have impaired WAT browning in response to burn injury. Other recent data also support these findings, as prolonged activation of IL-6 signaling induces WAT browning and increases energy expenditure in the context of cancer [71]. It is believed that IL-6 mediates WAT browning during the hypermetabolic response via macrophage polarization, as it has been shown to do so in other metabolic conditions like obesity [35].…”

“…In fact, the activation of the NLRP3 inflammasome in the adipose tissue of burn patients has been implicated in insulin resistance and hyperglycemia [68]. It is believed that SFAs and in particular palmitate, an abundant FFA in the serum of burn patients, can induce the activation of the NLRP3-ASC inflammasome, subsequently causing interleukin 1 (IL-1β) secretion in both hepatocytes and adipocytes [69] [70, 71]. In addition, the enhanced inflammatory environment of obese fat pads has also been associated with tumor growth, through the secretion of cytokines like interleukin 18 [72].…”

Increased proliferation of hepatic periportal ductal progenitor cells contributes to persistent hypermetabolism after trauma

“…19,20 Primary antibodies were the same as in Western blotting. 19,20 Primary antibodies were the same as in Western blotting.…”