Regulation of energy expenditure by mitochondrial dynamics in brown adipose tissue from subcellular to whole body level
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Obesity is a disorder of energy imbalance in which energy intake exceeds energy expenditure (EEX). Brown adipose tissue (BAT) is unique in that it can increase whole body EEX when it is adrenergically activated. The thermogenic capacity of BAT is mediated by mitochondrial uncoupling through the activation of Uncoupling Protein 1 which uncouple respiration from ATP production. Mitochondria is a dynamic organelle that undergo continuous cycles of fusion and fission. Alteration in mitochondrial dynamics correlates with changes in energy efficiency in different cell types; however, its role in regulating EEX in BAT has not been investigated. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in EEX in BAT. Norepinephrine (NE) induces mitochondrial fragmentation in brown adipocytes (BA) though posttranslational modifications - phosphorylation and proteolytic cleavage -of mitochondrial dynamic proteins. NE-induced EEX is reduced in fission-deficient brown adipocytes while forced mitochondrial fragmentation increases the respiration in response to exogenous free fatty acids (FFAs) indicating increase in EEX. We further investigated whether forced mitochondrial fragmentation in BAT could be utilized as an approach to increase whole body EEX is response to FFA in vivo. We found that a mouse model with forced mitochondrial fragmentation in BAT (BAT-Mitofusin2-KO) gained less body weight and less fat mass and remained more glucose tolerant and insulin sensitive under high fat diet (HFD) compared to the wild type. Additionally, FFA oxidation was enhanced in BAT-Mitofusin2-KO mice indicated by lower respiratory exchange ratio. We also found that subcellular heterogeneity in dynamics leads to the generation of subpopulations of mitochondria with diverse bioenergetics characteristics within the same cell. We described that a subpopulation of mitochondria surrounding the lipid droplet in BA had higher ATP synthesis capacity, supported by higher ATP synthase protein expression and elongated morphology. We suggest that this subpopulation of mitochondria is responsible for addressing the ATP demand of the BA when it is not activated. In conclusion, changes to mitochondrial dynamics are required for BAT thermogenic activity and for the control of EEX efficiency from sub-cellular to the whole body level. Additionally, mitochondrial dynamics in BAT can regulate fatty acid oxidation.