THE METABOLIC AND INFLAMMATORY EFFECTS OF NUCLEOTIDE OLIGOMERIZATION DOMAIN (NOD) PROTEIN SIGNALING DURING OBESITY AND BACTERIAL STRESS

Abstract

Intestinal dysbiosis contributes to obesity and insulin resistance, but intervening with antibiotics, prebiotics, or probiotics can be limited by specificity or sustained changes in microbial composition. Postbiotics include bacterial components such as lipopolysaccharides, which have been shown to promote insulin resistance during metabolic endotoxemia. The data presented in this thesis demonstrates that bacterial cell wall-derived muramyl dipeptide (MDP) is an insulin-sensitizing postbiotic that requires the nucleotide oligomerization domain 2 (NOD2) protein. Injecting MDP lowered adipose inflammation and reduced glucose intolerance in obese mice without causing weight loss. MDP reduced hepatic insulin resistance during obesity and low-level endotoxemia. NOD1-activating peptidoglycan worsened glucose tolerance. The transcription factor interferon regulatory factor 4 (IRF4) distinguished opposing glycemic responses to different types of peptidoglycan. IRF4 was dispensable for exacerbated glucose intolerance via NOD1, but was required for MDP/NOD2-induced insulin sensitization and lower metabolic tissue inflammation during obesity and endotoxemia.