UCP1-independent thermogenesis

Abstract

Obesity results from energy imbalance, when energy intake exceeds energy expenditure. Brown adipose tissue (BAT) drives non-shivering thermogenesis which represents a powerful mechanism of enhancing the energy expenditure side of the energy balance equation. The best understood thermogenic system in BAT that evolved to protect the body from hypothermia is based on the uncoupling of protonmotive force from oxidative phosphorylation through the actions of uncoupling protein 1 (UCP1), a key regulator of cold-mediated thermogenesis. Similarly, energy expenditure is triggered in response to caloric excess, and animals with reduced thermogenic fat function can succumb to diet-induced obesity. Thus, it was surprising when inactivation of Ucp1 did not potentiate diet-induced obesity. In recent years, it has become clear that multiple thermogenic mechanisms exist, based on ATP sinks centered on creatine, lipid, or calcium cycling, along with Fatty acid-mediated UCP1-independent leak pathways driven by the ADP/ATP carrier (AAC). With a key difference between cold- and diet-induced thermogenesis being the dynamic changes in purine nucleotide (primarily ATP) levels, ATP-dependent thermogenic pathways may play a key role in diet-induced thermogenesis. Additionally, the ubiquitous expression of AAC may facilitate increased energy expenditure in many cell types, in the face of over feeding. Interest in UCP1-independent energy expenditure has begun to showcase the therapeutic potential that lies in refining our understanding of the diversity of biochemical pathways controlling thermogenic respiration.

A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting that Central Effects Can Be Avoided

“…RIM had similar, if not greater, increases in expression at both time points. While some UCP1-independent pathways are only active when Ucp1 is downregulated, no such dynamic has been shown for futile calcium cycling [32]. There are, in fact, a number of examples of alternative thermogenesis pathways that do not require the inactivation of UCP1 [33,34].…”

Cold Exposure Protects from Neuroinflammation Through Immunologic Reprogramming

“…Our study is in line with this scenario and shows that cold exposure dampens autoimmunity, thus providing evidence and a conceptual advance in our understanding of the energetic trade-off at the cost of autoimmunity. In support of these conclusions, cold exposure ameliorates EAE to a higher extend in absence of UCP1 and following acclimatization and activation of the UCP1independent thermogenic mechanisms, which function at a very high energetic cost (Ikeda et al, 2017;Reynes et al, 2019;Roesler and Kazak, 2020). The cold-induced immune changes seem to originate already in the bone marrow and can be partially provoked by beta adrenergic agonism, which may suggest contribution of the nervous system to the energy trade-off.…”

Thermogenic adipocytes: lineage, function and therapeutic potential

“…The existence of UCP1-independent NST mechanisms is well established, particularly in skeletal muscle [136][137][138] and, to a lesser extent, in BAT [107][108][109]139], and provides insight into the origins of endothermy in mammals. Importantly, similar mechanisms have been identified in specialised beige and white adipocytes [115][116][117], and promotion of these mechanisms leads to improved metabolic health, opening new avenues for the treatment of metabolic disease. Evolutionary evidence suggests that these mechanisms pre-date the emergence of UCP1, a defining feature of BAT, with many species entirely reliant on their existence to facilitate high core body temperatures [136,140].…”

“…These adaptations creatine kinase (mi-CK) to drive creatine phosphorylation to PCr. The reversal, driven by an as yet unidentified enzyme completes the futile cycle [115][116][117][118]. (d) Non-canonical thermogenesis by SERCA2b-driven Ca 2+ futile cycling on the ER [114,[119][120][121].…”