Obesity enhances sepsis‐induced liver inflammation and injury in mice

Abstract

Objective How obesity affects the response to sepsis is not completely understood. We hypothesize that obesity alters adipose and hepatic tissue inflammation through STAT3 activation. Methods Male C57BL/6 mice at six-weeks of age were randomized to a high-fat (HFD) (60% kcal fat) or normal diet (ND) (16% kcal fat) for 6–7 weeks. Sepsis was then induced by cecal ligation and puncture (CLP) and animals were monitored for survival or sacrificed and tissue collected. Results HFD-fed mice gained more weight, had increased fat mass and were glucose intolerant compared to ND-fed mice. Obesity increased hepatic neutrophil infiltration and injury after sepsis. Obese mice had higher plasma leptin levels compared to non-obese mice. Adipose tissue expression of adiponectin receptor 2, TNFα and PPARγ were altered during sepsis and affected by obesity but the greatest change in adipose tissue expression was in leptin. Septic obese mice had lower plasma IL-17a, IL-23 and TNFα levels and increased hepatic STAT3 and Activator Protein-1 activation compared to non-obese septic mice. Ultimately, obese mice had a lower probability of survival following sepsis. Conclusions Obese mice are more susceptible to sepsis and have higher mortality, in part, through activation of the STAT3 signaling pathway and through AP-1 activation.

High fat diet-induced obesity increases myocardial injury and alters cardiac STAT3 signaling in mice after polymicrobial sepsis

“…Overweight and obese patients may have protection from critical illness in certain diseases, the obesity paradox, although equipoise remains regarding this concept. The results from this current study, together with published data from our laboratory, suggest that obesity is detrimental during murine sepsis [6, 7]. …”

“…Published data from our laboratory demonstrates a higher mortality in obese mice after CLP compared to non-obese [6]. Mice start dying around 6 hours after CLP and by 24 hours only ~20% of obese mice (compared to ~40% in non-obese mice) remain alive [6]. Therefore, for the current study, we focused on the mechanistic changes that occur in the heart early after CLP (at 6h).…”

“…Obesity is associated with chronic inflammation however in response to an acute insult such as trauma, obese human subjects have a depressed cytokine response compared to non-obese subjects [5]. Data from our laboratory also demonstrate a diminished cytokine response in obese mice after sepsis [6]. Additionally, obese mice have higher mortality after sepsis [6, 7].…”

“…Data from our laboratory also demonstrate a diminished cytokine response in obese mice after sepsis [6]. Additionally, obese mice have higher mortality after sepsis [6, 7]. …”

Understanding the inflammation-cancer transformation in the development of primary liver cancer

“…Inflammatory cytokines are critically important in the liver injury development. When liver tissue or cells stimulate with stimulants like alcohol and fatty acid, liver tissue synthesizes various types of cytokines to defend that [20][21][22][23][24][25] . The well-studied cytokines include tumor necrosis factor-α (TNF-α) [26,27] , interleukin family (IL-6, IL-1β) [7,28,29] , chemokines (VCAM-1, ICAM-1 and MCP-1) [30][31][32][33] , etc.…”