Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2

Abstract

In addition to their classical roles as bacterial sensors, NOD1 and NOD2 have been implicated as mediators of metabolic disease. Increased expression of NOD1 and/or NOD2 has been reported in a range of human metabolic diseases, including obesity, diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Although NOD1 and NOD2 share intracellular signaling pathway components, they are differentially upregulated on a cellular level and have opposing impacts on metabolic disease development in mouse models. These NOD-like receptors may directly mediate signaling downstream of cell stressors, such as endoplasmic reticulum stress and calcium influx, or in response to metabolic signals, such as fatty acids and glucose. Other studies suggest that stimulation of NOD1 or NOD2 by their bacterial ligands can result in inflammation, altered insulin responses, increased reactive oxygen signaling, and mitochondrial dysfunction. The activating stimuli for NOD1 and NOD2 in the context of metabolic disease are controversial and may be a combination of both metabolic and circulating bacterial ligands. In this review, we will summarize the current knowledge of how NOD1 and NOD2 may mediate metabolism in health and disease, as well as highlight areas of future investigation.

NOD1-Targeted Immunonutrition Approaches: On the Way from Disease to Health

“…It is directly involved in signaling pathways of cell stressors (e.g., calcium influx or endoplasmic reticulum mechanisms, as indicated later) and regulates downstream pathways in response to metabolic mediators such as glucose and fatty acids. NOD1 stimulation is believed to be the result of a combination of bacterial and metabolic ligands [ 50 , 51 ].…”

“…Therefore, nutritional interventions targeting fat and the immune system at the same time would be promising. Fat-enriched diets are well-known drivers of metabolic syndrome and cardiovascular diseases [ 50 , 56 ]. In this context, the administration of immunonutritional protease inhibitors has been shown to be effective in modulating lipid homeostasis and shaping the gut microbiota, ameliorating the severity of hepatocarcinoma under HFD [ 10 ].…”

“…For example, high glucose levels can activate NOD1 in mesangial cells. In fact, adipocytes stimulated with iE-DAP or other NOD1 ligands exhibit enhanced pro-inflammatory responses and diminished insulin receptor signaling, leading to a decreased glucose uptake by insulin and to insulin resistance [ 50 ]. In addition, diabetes, obesity, and hyperglycemia cause dysbiosis of the intestinal microbiota favoring gut permeability and the consequent increase in circulating bacterial products.…”

“…In addition, diabetes, obesity, and hyperglycemia cause dysbiosis of the intestinal microbiota favoring gut permeability and the consequent increase in circulating bacterial products. Activation of NOD1 by these microbe-derived molecules can disrupt other signaling pathways and metabolic routes, thus establishing a self-feedback loop [ 50 , 73 ]. For example, microbiota recognition by NOD1 in bone marrow mesenchymal stromal cells can modulate hematopoiesis in mice [ 74 ].…”

Strategies for Using Muramyl Peptides - Modulators of Innate Immunity of Bacterial Origin - in Medicine

“…MDP analogs which are present in the body of animals and humans, affect the nervous (22) and immune system (23)(24)(25), they are involved in the regulation of host metabolism (26). The wide range of immunological activities gave a reason to consider muramyl peptides "vitamins of the immune system" (23,27).…”