Regulation of energy metabolism by inflammation: a feedback response in obesity and calorie restriction

Abstract

Caloric restriction (CR), in the absence of malnutrition, delays aging and prevents aging-related diseases through multiple mechanisms. A reduction in chronic inflammation is widely observed in experimental models of caloric restriction. The low inflammation status may contribute to the reduced incidence of osteoporosis, Alzheimer's disease, cardiovascular diseases and cancer in the aging subjects. The association of caloric restriction with low inflammation suggests a role of energy accumulation in the origin of the chronic inflammation. This point is enforced by recent advances in obesity research. Abundant literature on obesity suggests that chronic inflammation is a consequence of energy accumulation in the body. The emerging evidence strongly supports that the inflammatory response induces energy expenditure in a feedback manner to fight against energy surplus in obesity. If this feedback system is deficient (Inflammation Resistance), energy expenditure will be reduced and energy accumulation will lead to obesity. In this perspective, we propose that an increase in inflammation in obesity promotes energy expenditure with a goal to get rid of energy surplus. A decrease in inflammation under caloric restriction contributes to energy saving. Inflammation is a mechanism for energy balance in the body. Inflammation resistance will lead to obesity. We will review the recent literature in support of the viewpoints.

Figure 1.. Energy accumulation induces inflammation.

Energy accumulation leads to elevation in glucose and fatty acids. These substrates lead to production of diaglycerids (DAG), Ceramide, reactive oxygen species (ROS) and activation of toll-like receptor 4 (TLR4) in cells including macrophages and endothelial cells. All of these events may activate the inflammatory signaling pathways, such as IKK/NF-kB and JNK/AP-1. As a consequence, expression of inflammatory cytokines and adhesion molecules may increase for chronic local inflammation. When inflammatory cytokines are elevated in the circulation, the energy accumulation causes systemic chronic inflammation, which is observed in obesity. This kind of chronic inflammation is limited or prevented by calorie restriction

Figure 2.. Inflammation in obesity.

Rapid growth of adipose tissue leads to quick expansion of adipose tissue. When angiogenesis or vessel dilation can not meet the demand for blood supply, there will be an adipose tissue hypoxia (ATH) from lack of blood supply. ATH will induce angiogenesis and trigger inflammation. Inflammation will promote angiogenesis and vasodilation locally in the tissue for extracellular remodeling. When inflammatory cytokines and fatty acids are elevated in the circulation, they will promote energy expenditure systemically. The inflammatory response may also induce hyperglycemia and energy disposal through glucose excretion in urine. In this way, inflammation acts through insulin resistance and hyperglycemia.