Contemporary inflammatory disorders and the evolutionary energy crisis: the pivotal role of AMPK

• Published in: Indian journal of clinical biochemistry 2016-12, Vol.31 (S1), p.S16
• Main Author: Unnikrishnan, M.K
• Format: Article
• Language: English
• Subjects: Health aspects; Inflammation; Physiological aspects
• ISSN: 0970-1915

Inflammation is a complex adaptive cellular response to infections and bodily injury that attempts to repair damage and restore tissue homeostasis. Inflammation is energy intensive because ATP is required for biosynthesis of inflammatory mediators and for maintaining membrane potential. Adaptive repair processes are selected to be brief and have evolved primarily to deal with acute injury. Therefore protracted maladaptive inflammatory responses are relatively recent in evolutionary time scale. Inflammation is high cost--high return process in an injury prone environment. The well-cushioned, energy-rich environment in contemporary urbanized societies constitute an evolutionary mismatch that drives low grade chronic inflammation, termed "para-inflammation". Most lifestyle diseases constitute a component of complex maladaptive inflammatory pathology involving multiple signaling pathways. Therefore the conventional wisdom of targeting a single pathway is not likely to succeed in treating chronic inflammation, exemplified by the ignominious exit of selective cycloxygenase (COX) inhibitors. Energy allocation and metabolic provisioning appear to be inextricably linked to inflammatory repair systems because nutritional challenge was a key driver of evolutionary fitness. Therefore, 5' AMP-activated protein kinase (AMPK) a serine/ threonine kinase operating at the helm of energy budgeting, immune regulation and metabolic provisioning, could be a key drug target for inflammatory pathologies linked to metabolic disorders. Rise in AMP/ATP ratio activates AMPK and stimulates catabolic processes that raise ATP levels and shut down anabolic processes. AMPK also activates mitochondrial biogenesis. Energy dysregulation being the common denominator in metabolic disorders, the over-nourished modern man probably suffers from chronic under activation of AMPK. Additionally, AMPK is an upstream regulator of Nrf2 (Nuclear factor erythroid-derived 2) a potent antioxidant activator and inducer of cytoprotective responses to oxidative stimulus. AMPK also downregulates NF-kB, (a key driver of inflammatory responses) and upregulates autophagy, which could be underplayed in over nourished sedentary individuals.