Are all metabolic changes during inflammation pathologic?
We study how metabolic adaption promotes survival during sepsis and how the kidneys contribute to systemic metabolism during inflammation.
Sepsis is a significant cause for mortality among critically ill patients. Alterations in metabolism during sepsis are multifaceted and are incompletely understood as distinguishing the difference between protective and pathophysiologic responses is difficult.
Acute anorexia during infection is a highly conserved response, suggesting a protective role of anorexia in the host response to infection. The purpose of anorexia resulting from inflammation remains incompletely understood. The clinical implications of understanding how and why anorexia is a conserved sickness behavior are far reaching. Optimal nutritional support in septic patients remains elusive, and controversy over the timing, nutritional composition, and route of administration persists.
Previous work has shown that caloric supplementation, specifically glucose, during the period of anorexia increased mortality in mouse models of bacterial inflammation induced by Listeria monocytogenes or lipopolysaccharide (LPS). Glucose treatment during LPS sepsis suppressed the induction of circulating beta-hydroxybutyrate, one of the main ketone bodies, and Fibroblast growth factor 21 (FGF21), a hormone known to be induced by starvation and has wide-ranging effects on glucose and fatty acid metabolism. Mice deficient of PPARa fail to produce ketones during LPS sepsis and are more susceptible to death. Mice lacking FGF21 are also more susceptible to mortality in LPS sepsis.
Current projects in the lab include investigating the mechanism by which FGF21 promotes survival during sepsis, the source and regulation of ketogenesis during septic inflammation, and how the kidney participates as a metabolic organ during states of inflammation.