Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

Abstract

Strategies to prevent and treat obesity aim to decrease energy intake and/or increase energy expenditure. Regarding the increase of energy expenditure, two key intracellular targets may be considered (1) mitochondrial oxidative phosphorylation, the major site of ATP production, and (2) AMP-activated protein kinase (AMPK), the master regulator of cellular energy homeostasis. Experiments performed mainly in transgenic mice revealed a possibility to ameliorate obesity and associated disorders by mitochondrial uncoupling in metabolically relevant tissues, especially in white adipose tissue (WAT), skeletal muscle (SM), and liver. Thus, ectopic expression of brown fat-specific mitochondrial uncoupling protein 1 (UCP1) elicited major metabolic effects both at the cellular/tissue level and at the whole-body level. In addition to expected increases in energy expenditure, surprisingly complex phenotypic effects were detected. The consequences of mitochondrial uncoupling in WAT and SM are not identical, showing robust and stable obesity resistance accompanied by improvement of lipid metabolism in the case of ectopic UCP1 in WAT, while preservation of insulin sensitivity in the context of high-fat feeding represents the major outcome of muscle UCP1 expression. These complex responses could be largely explained by tissue-specific activation of AMPK, triggered by a depression of cellular energy charge. Experimental data support the idea that (1) while being always activated in response to mitochondrial uncoupling and compromised intracellular energy status in general, AMPK could augment energy expenditure and mediate local as well as whole-body effects; and (2) activation of AMPK alone does not lead to induction of energy expenditure and weight reduction.

AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases

“…AMPK is activated by the increase in AMP:ATP ratio associated with ATP consumption during exercise, muscle contraction, and hypoxia ( 123,141,142 ). During stress conditions in which ATP levels are reduced, AMPK increases catabolic processes, such as glycolysis and fatty acid oxidation, and represses anabolic processes, including glycogen, protein, and lipid synthesis ( 141,142 ).…”

Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis

“…Cold and energy stress also induce the stress-activated protein kinase AMP-activated protein kinase (AMPK), which enhances EE and thus is a major target in obesity and T2D (19)(20)(21)(22)(23)(24). β-ARmediated AMPK activation augments insulin sensitivity in a UCP1-dependent manner (22).…”

Human Brown Fat Inducible Thioesterase Variant 2 Cellular Localization and Catalytic Function

“…Notably, when queried with the BFIT2 amino acid sequence, the search engine SUMOplot (http://www.abgent.com/tools/sumoplot) did not detect a sumoylation site whereas the search engine NetPhos 2.0 (http://www.cbs.dtu.dk/services/NetPhos/) predicted the MLS Ser22 and Ser25 as kinase phosphorylation sites with the high score of 0.997. If the MLS Ser residues are in fact subject to protein kinase phosphorylation/phosphatase dephosphorylation, it follows that the location of hBFIT2 (cytoplasm vs mitochondrial matrix) is subject to regulation via phosphorylation (52). …”