Role of adipose tissue inflammaging and metabolic dysfunction during sepsis

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SUMMARY Sepsis is a life-threatening, systemic response to infection and is 13-times more likely to occur in individuals over 65, leading to hospitalization, increased mortality, and chronic repercussions. Why older persons are more susceptible to sepsis is poorly defined, although hyperactivation of the immune system is an underlying feature. Visceral white adipose tissue (vWAT) is the organ that ages first; changes include tissue expansion and increased immune cell activation. We demonstrated that a hyperinflammatory state in old organisms contributes to increased mortality in response to infection, whereas young mice remain healthy. We also discovered that there is an accumulation of aged adipose B cells (AABs) and inflammatory macrophages in vWAT of old mice. We showed that these immune cells inhibit lipolysis, a metabolic pathway essential for maintaining energy homeostasis. Lipolysis is also necessary to keep inflammation in check in mice challenged with lipopolysaccharide (LPS), a bacterial pathogen-associated molecular pattern from gram-negative bacteria. Together these studies support the premise that age-related inflammation mediated by the vWAT contributes to risk of sepsis. This proposal seeks to identify how signaling events from vWAT immune cells, which regulate lipolysis in adipocytes, are altered with age and sepsis. We recently described a role for the NLRP3 inflammasome activation and the expansion of AABs that increase inflammation, and reduce tissue function, including lipolysis and insulin sensitivity. These findings have led to our hypothesis that vWAT lipolysis is impaired in old organisms due to exacerbated inflammasome activation and altered signaling by AABs, and this negatively impacts responses to endotoxemia and sepsis. We will test this hypothesis in three aims that focus on a mouse model of endotoxemia. Aim 1: Define the lipolytic response of adipocytes from old vs. young mice. Aim 2: Determine if inflammasome activation and GDF3 mediate reduced lipolysis and increased inflammation in vWAT upon LPS challenge of old mice. Aim 3: Determine the role of adenosine signaling on lipolysis in old vWAT during LPS challenge. This information will contribute to the identification of new signaling pathways that can be targeted to treat sepsis in the elderly.