Abstract
Animals undergoing calorie restriction (CR) often lower their body temperature to conserve energy. Brown adipose tissue (BAT) is stimulated through norepinephrine when rapid heat production is needed, as it is highly metabolically active due to the uncoupling of the electron transport chain from ATP synthesis. To better understand how BAT metabolism changes with CR, we used metabolomics to identify 883 metabolites that were significantly differentially expressed in the BAT of C57BL/6 mice, fed graded CR (10%, 20%, 30%, and 40% CR relative to their individual baseline intake), compared with mice fed ad libitum (AL) for 12 hours a day. Pathway analysis revealed that graded CR had an impact on the TCA cycle and fatty acid degradation. In addition, an increase in nucleic acids and catecholamine pathways was seen with graded CR in the BAT metabolome. We saw increases in antioxidants with CR, suggesting a beneficial effect of mitochondrial uncoupling. Importantly, the instigator of BAT activation, norepinephrine, was increased with CR, whereas its precursors l-tyrosine and dopamine were decreased, indicating a shift of metabolites through the activation pathway. Several of these key changes were correlated with food anticipatory activity and body temperature, indicating BAT activation may be driven by responses to hunger.
Highlights
Brown adipose tissue (BAT) is found in many mammals [1,2]
It was suggested that C57BL/6 mice on 40% calorie restriction (CR) had elevated “beigeing” in subcutaneous and visceral white adipose tissue (WAT), possibly through type 2 cytokine signaling and increased sirtuin 1 (SIRT1) in M2 macrophages in fat tissues [23]
Recent work has indicated that alternate macrophage activation does not induce adaptive thermogenesis through production of catecholamines [61], and the same mice used in this study did not show any increase in uncoupling protein 1 (UCP1) messenger RNA in epididymal WAT [62]
Summary
Brown adipose tissue (BAT) is found in many mammals [1,2]. The principal role of BAT is thermogenesis [3], which is activated when organisms require additional heat to raise body temperature, such as during arousal from torpor, or hibernation [4,5,6]. CR leads to browning of WAT into functional BAT-like beige fat in lean male C57BL/6 and BALB/c mice after only 1 week of restriction [23] This may contribute to metabolic improvements with CR, including improved insulin sensitivity and glucose tolerance. The relative weight and protein content of BAT did not change and DNA content in the BAT increased by 93% indicating acceleration of cell proliferation [24] It may be beneficial for mammals under CR to initiate browning, as during CR, rodents and primates decrease their core body temperature [25,26,27] and once body mass falls to a critically low level, they initiate periods of torpor, presumably in an effort to achieve energy balance [28]. To acutely increase body temperature for periods of high activity during feeding (food anticipatory activity [FAA] [29]), it might be necessary to activate BAT
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