Brown adipose tissue dynamics in wild-type and UCP1-knockout mice: in vivo insights with magnetic resonance

Abstract

This article is available online at http://www.jlr.org body temperature maintenance of small eutherian mammals and newborns during periods of cold exposure. BAT thermogenesis is activated by the release of noradrenaline (NA) from sympathetic innervation. Uncoupling protein 1 (UCP1) in the inner mitochondrial membrane of the brown adipocytes uncouples the respiratory chain from ATP synthesis and thus energy is dissipated as heat ( 1-3 ). Prolonged cold exposure or a short photoperiod induces the recruitment of BAT ( 4-6 ). Brown adipocytes of coldadapted mice, contain small and multilocular lipid vacuoles, which are rich in cytoplasm and have a high content of mitochondrial protein (7)(8)(9). This provides an enhanced thermogenic capacity during cold exposure, and BAT can be considered as the major site of adaptive nonshivering thermogenesis (NST) in rodents and other small mammals ( 4, 10-12 ).The breakdown of lipids via lipoprotein lipase plays an important role during UCP1-mediated heat production ( 13 ). Free fatty acids (FFAs) directly activate UCP1 and feed the respiratory chain, i.e., FFAs are the major substrate for NST ( 14,15 ). Therefore active BAT is considered as a main consumer of lipids and FFAs and its contribution to plasma clearance of administered triglycerides has been shown previously ( 16,17 ). On the other hand a release of fatty acids during thermogenesis from BAT has been assumed, indicating a substrate supply to other tissues ( 18,19 ). Sympathetic activation by cold exposure or injections of NA not only activate BAT but also stimulate sympathetic receptors in general, leading to an increase in heart rate, blood flow, and metabolic responses in other tissues. The contribution of these UCP1-independent processes to total NST remain unclear ( 20, 21 ).Abstract We used noninvasive magnetic resonance imaging (MRI) and magnetic resonance spectroscopy to compare interscapular brown adipose tissue (iBAT) of wild-type (WT) and uncoupling protein 1 (UCP1)-knockout mice lacking UCP1-mediated nonshivering thermogenesis (NST). Mice were sequentially acclimated to an ambient temperature of 30°C, 18°C, and 5°C. We detected a remodeling of iBAT and a decrease in its lipid content in all mice during cold exposure. Ratios of energy-rich phosphates (ATP/ADP, phosphocreatine/ATP) in iBAT were maintained stable during noradrenergic stimulation of thermogenesis in coldand warm-adapted mice and no difference between the genotypes was observed. As free fatty acids (FFAs) serve as fuel for thermogenesis and activate UCP1 for uncoupling of oxidative phosphorylation, brown adipose tissue is considered to be a main acceptor and consumer of FFAs. We measured a major loss of FFAs from iBAT during noradrenergic stimulation of thermogenesis. This mobilization of FFAs was observed in iBAT of WT mice as well as in mice lacking UCP1. The high turnover and the release of FFAs from iBAT suggests an enhancement of lipid metabolism, which in itself contributes to the sympathetically activated NST and which is independent fro...

A Creatine-Driven Substrate Cycle Enhances Energy Expenditure and Thermogenesis in Beige Fat

“…In contrast, while higher steady-state creatine levels were observed in BAT, cold exposure had no detectable effect (Figure S1I). There was no difference in PCr levels in either iWAT or BAT in response to cold (Figure S1J), although a modest trend towards lower PCr levels in BAT was observed; these observations are in line with a recent report (Grimpo et al, 2014). As a consequence of these measurements, it is clear that the PCr/creatine ratio in iWAT was reduced significantly in cold-exposed animals (Figure 1K), suggesting increased creatine metabolism in beige fat.…”

“…Furthermore, it has been shown with adrenergic stimulation and peptide factors that the thermogenic responses of Ucp1 +/+ and Ucp1 −/− mice are similar (Granneman et al, 2003; Grimpo et al, 2014; Veniant et al, 2015). These findings imply the presence of UCP1-independent thermogenic mechanisms.…”

“…These findings imply the presence of UCP1-independent thermogenic mechanisms. Glycerol-3-phosphate shuttle activation and lipid turnover (Flachs et al, 2011; Grimpo et al, 2014) have been posited to act independently of UCP1. Calcium cycling has been proposed to be an additional source of thermogenesis in BAT (Ukropec et al, 2006) and is a well-established thermogenic mechansim in the extraocular heater muscle cells of certain fish and in mammalian skeletal muscle (Bal et al, 2012; Block et al, 1994).…”

Brown adipose tissue: what have we learned since its recent identification in human adults

“…Validation studies of magnetic resonance have already been done in animals, with promising results and good capacity for detecting brown depots within white adipose tissue (103)(104)(105)(106). Pilot studies have also been performed in humans and suggest a good sensitivity with the additional advantage of detecting even non active tissue (although, logically, it must have at least been recruited) (106,107).…”

Magnetic Resonance Imaging of Adipose Tissue in Metabolic Dysfunction

“…could be detected by an increased conversion of pre-polarized (1 -13C) pyruvate into its downstream products 13C bicarbonate and (1 -13C) lactate [47]. Grimpo et al used 1H MRS to monitor the metabolic dynamics in murine BAT and detected a significant loss of free fatty acids from BAT after pharmacological stimulation [48]. Quantification of blood flow and perfusion of BAT is another method to collect information about BAT activation.…”