Neuroinflammation and neurodegeneration in overnutrition-induced diseases

Abstract

Overnutrition-induced diseases such as obesity and type 2 diabetes (T2D) involve neural dysregulation of metabolic physiology. Recently, interdisciplinary research in neuroscience and immunology has linked overnutrition to a non-classical onset of inflammation in the brain, particularly in the hypothalamus. This neuroinflammation impairs central regulatory pathways of energy balance and nutrient metabolism, and leads to obesity, diabetes, and cardiovascular complications. This review describes recent findings on the roles of overnutrition-induced hypothalamic inflammation in neurodegeneration and defective adult neurogenesis, as well as in impaired neural stem cell regeneration, and their relevance to obesity and related diseases. In addition, commonalities in terms of neuroinflammation between neurodegenerative diseases and overnutrition-induced metabolic diseases are discussed. Targeting neuroinflammation and neurodegeneration will provide promising approaches for treating obesity and other overnutrition-related diseases.

Figure 1. Inflammation-mediated neurodegeneration in overnutrition-related diseases

A. While majority of neurons in adult mammalian brain are terminally stable, a pool of neural cells including neurons undergoes slow-speed turnover in normal physiology, and this process requires neurogenesis induced by adult neural stem cells (NSCs) including hypothalamic NSCs, a small number of multipotent cells residing in several brain regions including the mediobasal hypothalamus. Although this NSCs-directed neurogenesis in physiological conditions is rather slow and also region-specific, recent research suggests that it may have important roles in maintaining the brain’s controls during life-long physiological homeostasis. B. Under pathophysiological conditions such as long-term overnutrition and probably aging, the resulting neuroinflammation affects the turnover pool of neural cells in adult brain. This process involves the inhibitory action of neuroinflammation on survival and differentiation of NSCs, mediated by NF-κB-directed apoptosis and Notch signaling. The neurodegenerative change under these conditions is slow and modest; however, when it affects certain neuronal types which by nature have small populations but critical functions, it can have severe disease outcomes. For example, the impairment of NSCs in the mediobasal hypothalamus can lead to a factional reduction of hypothalamic POMC neurons over a long period and mediate a late-onset development of obesity and pre-diabetes.

Figure 2. Role of neuroinflammation in overnutrition-induced diseases

Under conditions of chronic overnutrition, the mediobasal hypothalamus (MBH) is affected by chronic overnutrition, a prolonged and persistent nutritional changes in the body which primarily arises from environmental and social-behavioral factors such as Western diet, sedentary lifestyle and disrupted diurnal order of life. These lead to IKKβ/NF-κB-directed inflammatory response and several intracellular organelle stresses in the MBH. Many of these cellular and molecular components promote each other, resulting in overnutrition-related neuroinflammation. Such neuroinflammation impairs intracellular hormonal signaling of regulatory neurons and disrupts neurogenesis through depletion of NSCs. The progression of overnutrition-related diseases such as obesity and diabetes, characterized by hyperlipidemia and hyperglycemia, secondarily leads to pathophysiological overnutrition in the body’s internal environment and exacerbates this mechanism. In summary, neuroinflammation employs multiple pathways including hormonal signaling dysfunction and neurodegeration to link overnutrition to overnutrition-related diseases such as obesity, diabetes and related complications. Abbreviations: TLRs: toll-like receptors; NSCs: neural stem cells.