Nutrient sensing and inflammation in metabolic diseases

Abstract

Mounting an immune response is a metabolically costly endeavour and cannot operate well under conditions of energy deficit. Energy surplus (for example, in individuals that are obese or suffer from metabolic syndrome) can also impair immune responses and induce chronic inflammation. The integrated and proper functioning of each system is paramount to the health of the other. Chronic inflammation, particularly when it occurs in metabolically important organs such as the liver and adipose tissue, has a crucial role in the emergence of many chronic metabolic diseases, including diabetes, fatty liver disease and cardiovascular disease. It is important to recognize that this is not a response that resembles classic inflammation and perhaps could be considered as an aberrant form of immunity that is triggered by nutrients or other intrinsic cues. During most conditions of stress and inflammation, changes in metabolism occur, and insulin signalling is impaired through protein modifications, such as serine phosphorylation of insulin-receptor substrate proteins. These modifications resemble the events that occur during conditions of obesity, insulin resistance and type 2 diabetes. Nutrient overload and/or lack of protection from the inflammatory response lead to deterioration of metabolic health. Recent studies have given rise to the concept that metabolic stress might be sensed by organelles, particularly the endoplasmic reticulum (ER) and mitochondria, and the resulting organelle dysfunction could trigger a network of stress signalling that could disrupt metabolic homeostasis. The ER can also serve as a convergence point of nutrient and pathogen responses. Intriguingly, many of the nutrient-sensing pathways are subverted by pathogens for their proliferation and survival, and revisiting some of these links may provide a basis for the emergence of metabolic diseases and present new platforms for research in the fields of metabolism and infection.