ATP-consuming futile cycles as energy dissipating mechanisms to counteract obesity

Abstract

Obesity results from an imbalance in energy homeostasis, whereby excessive energy intake exceeds caloric expenditure. Energy can be dissipated out of an organism by producing heat (thermogenesis), explaining the long-standing interest in exploiting thermogenic processes to counteract obesity. Mitochondrial uncoupling is a process that expends energy by oxidizing nutrients to produce heat, instead of ATP synthesis. Energy can also be dissipated through mechanisms that do not involve mitochondrial uncoupling. Such mechanisms include futile cycles described as metabolic reactions that consume ATP to produce a product from a substrate but then converting the product back into the original substrate, releasing the energy as heat. Energy dissipation driven by cellular ATP demand can be regulated by adjusting the speed and number of futile cycles. Energy consuming futile cycles that are reviewed here are lipolysis/fatty acid re-esterification cycle, creatine/phosphocreatine cycle, and the SERCA-mediated calcium import and export cycle. Their reliance on ATP emphasizes that mitochondrial oxidative function coupled to ATP synthesis, and not just uncoupling, can play a role in thermogenic energy dissipation. Here, we review ATP consuming futile cycles, the evidence for their function in humans, and their potential employment as a strategy to dissipate energy and counteract obesity.

Mitochondrial Energy Metabolism in the Regulation of Thermogenic Brown Fats and Human Metabolic Diseases

“…FFAs and G3P derived from secreted glycerol and the glycolysis pathway are re-esterified to triglycerides. The futile cycle functions as an ATP metabolic sink because the synthesis of fatty acyl-coenzyme A (CoA) consumes ATP during partial and full re-esterification [ 137 ]. In total, seven ATP molecules are consumed for every complete cycle, which leads to the release of heat [ 138 ].…”

Depot-Dependent Impact of Time-Restricted Feeding on Adipose Tissue Metabolism in High Fat Diet-Induced Obese Male Mice

“…In addition to UCP1-dependent thermogenesis, several ATP-consuming futile cycles are known to play a role in energy dissipation, including mitochondrial ADP/ATP carrier (AAC)-mediated proton leak, SERCA2b-mediated calcium cycling, creatine-dependent ADP/ATP substrate cycling, and lipid cycling (lipogenesis/TAG synthesis and lipolysis) [ 41 ]. However, it is unknown whether the futile cycle mechanism is involved in the TRF regulation of weight loss.…”

“…These results indicate that TRF restores the HFD-induced changes, increasing them back towards the control level, for the expression of adipogenic and lipolytic genes in Epi-WAT. These results collectively imply lipid cycling (an ATP-dependent futile cycle consisting of an anabolic segment and catabolic segment), i.e., lipogenesis and lipolysis, is decreased by HFD, whereas TRF can restore the lipid cycling in epididymal adipose tissue [ 41 ].…”

Maternal exercise intergenerationally drives muscle-based thermogenesis via activation of apelin-AMPK signaling

“… 16 This futile energy consumption in the skeletal muscle improves the metabolic homeostasis of muscle and the whole body. 17 , 18 On the other hand, its thermogenic function is impaired due to diet-induced obesity. 12 , 19 In addition, uncoupling protein 3 (UCP3), a mitochondrial inner membrane protein is also associated with NST in skeletal muscle.…”