Loss of UCP1 function augments recruitment of futile lipid cycling for thermogenesis in murine brown fat

An insight into brown/beige adipose tissue whitening, a metabolic complication of obesity with the multifactorial origin

“…Recently, Oeckl et al. ( 69 ) identified the futile ATP-consuming triglyceride/fatty acid cycle as a central process that contributes to thermogenesis in BAT of UCP1-knockout mice. To date, UCP1 is the most investigated mitochondrial carrier protein, involved in the modulation of oxidative phosphorylation, with its isoforms like UCP2 also found in other tissues like the heart where they protect against oxidative stress ( 70 ).…”

Impairment of adrenergically-regulated thermogenesis in brown fat of obesity-resistant mice is compensated by non-shivering thermogenesis in skeletal muscle

“…Our results suggest that AJ mice represent a model for characterizing UCP1-independent mechanisms of NST [ 2 , [5] , [6] , [7] ] outside BAT and their physiological role. Reflecting the relatively low thermogenic activity of their BAT, these mice may provide a better model of the situation in humans compared with B6 and mixed genetic background mice, used in most of the previous studies in this field with the focus on the role of UCP1 [ 14 , 43 ], SERCA-sarcolipin [ 9 , 38 , 42 ] or other mechanisms [ 7 , 10 , 22 , 23 , 31 , 36 , 50 ] in NST. To get further insight into the mechanisms engaged in NST and the role of genetic background [ [15] , [100] ], several inbred strains of mice differing in susceptibility to dietary obesity [ 99 ] should be used in future studies.…”

“…The former approach worked even in humans, but cardiovascular side effects prevented its clinical use [ 21 ]. Therefore, UCP1-independent mechanisms of NST and their potential to counteract obesity and improve metabolic health [ 2 , [5] , [6] , [7] , 22 , 23 ] need to be explored.…”

The Role and Regulatory Mechanism of Brown Adipose Tissue Activation in Diet-Induced Thermogenesis in Health and Diseases

“…In addition, adaptive thermogenesis including shivering and non-shivering thermogenesis is crucial to maintaining mammal body temperature [ 22 , 23 ]. In non-shivering thermogenesis, brown and brite/beige fat dissipates chemical energy as heat by UCP1-dependent thermogenesis [ 24 ], as well as by other “futile” enzymatic cycles UCP1 independent thermogenesis [ 24 , 25 ].…”

“…On the other hand, it has been reported that the inactivation of UCP1 did not potentiate diet-induced obesity in mice. Recent studies have demonstrated that multiple UCP1 independent thermogenic mechanisms such as Ca 2+ futile cycling through the SERCA2b-RyR2 pathway in the endoplasmic reticulum, creatine cycling in the mitochondria, and lipolysis/re-esterification (to provide fuel for futile cycling based on ATP sinks centered on fatty acid-mediated leak pathways driven by the ADP/ATP carrier) [ 24 , 25 ]. UCP1-independent EE has begun to be therapeutic potential that lies in refining our understanding of the regulation of adaptive thermogenesis.…”