Friday, May 9, 2025
5/9/2025
ANT2 in metaflammation and insulin resistance - PROJECT SUMMARY/ABSTRACT The prevalence of Type 2 diabetes mellitus (T2DM) is rising dramatically on a global basis and has now reached epidemic proportions. Current anti-diabetic therapeutics are available, but are inadequate to fully control T2DM in most patients, resulting in a great deal of morbidity and mortality. Insulin resistance is a major etiologic cause underlying T2DM. However, there are no clinical options to directly improve insulin sensitivity, except for thiazolidinediones, which are infrequently used due to unwanted side effects. Obesity is the most common cause of insulin resistance, and accumulating evidence indicates that obesity-induced inflammation (or metaflammation) is an important cause of insulin resistance and obesity- associated metabolic complications. Therefore, there are huge unmet medical needs for the prevention and treatment of metaflammation. However, it is not known how chronic metaflammation is initiated and propagates during the development of obesity, and why it is not resolved. Macrophages are the major immune cell type mediating metaflammation, and evidence suggest that changes in macrophage mitochondria activity can promote pro-inflammatory activation and M1-like polarization of macrophages. However, how mitochondrial activity is regulated during the course of M1- or M2-like macrophage polarization, especially in the obese/energy-excess adipose tissue microenvironment is not clearly understood. We will tackle the question of obesity-induced metaflammation from a new angle, focusing on mitochondrial biology with a novel target and hypothesis. Our preliminary suggest that ANT2 is a mitochondrial sensor of FFAs in macrophages to induces mitochondria remodeling favoring pro- inflammatory activation. Since the major source of increased plasma FFAs in obesity is adipocytes, FFA- induced ANT2 activation can provide an adipose tissue-specific pro-inflammatory macrophage activation mechanism in obesity. Interestingly, the effect of macrophage ANT2 KO includes the changes in mitochondrial number, mass, and capacity, whereas adipocyte or myocyte ANT2 KO does not cause these changes. This suggest that macrophage ANT2 mediates mitochondria remodeling through a cell type-specific mechanism that is distinct from ANT2 effects in adipocytes and myocytes. We will explore whether macrophage ANT2 mediates the initiation and/or maintenance of metaflammation in obese adipose tissue. We will then assess how ANT2 regulates mitochondrial capacity, dynamics, and metabolism to support the pro-inflammatory activation of macrophages, and how macrophage ANT2 activation induces insulin resistance. If successful, our studies will provide a novel mechanism for how obesity induces tissue-selective metaflammation and insulin resistance. Successful completion of the proposed study will identify ANT2 as a potential target for novel therapeutics to prevent metaflammation, insulin resistance, and glucose intolerance.
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