Nature's fat-burning machine: brown adipose tissue in a hibernating mammal

Abstract

Brown adipose tissue (BAT) is a unique thermogenic tissue in mammals that rapidly produces heat via nonshivering thermogenesis. Small mammalian hibernators have evolved the greatest capacity for BAT because they use it to rewarm from hypothermic torpor numerous times throughout the hibernation season. Although hibernator BAT physiology has been investigated for decades, recent efforts have been directed toward understanding the molecular underpinnings of BAT regulation and function using a variety of methods, from mitochondrial functional assays to 'omics' approaches. As a result, the inner-workings of hibernator BAT are now being illuminated. In this Review, we discuss recent research progress that has identified players and pathways involved in brown adipocyte differentiation and maturation, as well as those involved in metabolic regulation. The unique phenotype of hibernation, and its reliance on BAT to generate heat to arouse mammals from torpor, has uncovered new molecular mechanisms and potential strategies for biomedical applications.

Keywords: Brown adipose tissue; Gene expression; Hibernation; Mitochondria; Thermogenesis.

Fig. 1.

Graph showing body temperature tracings (solid line) between September and April of a thirteen-lined ground squirrel (Ictidomys tridecemlineatus) inside an environmental chamber. Body temperature (T_b) was measured using a surgically implanted transmitter. The dashed blue line represents ambient (environmental) temperature, which is lowered to 5°C on 1 November and raised back to 23°C in March or April depending on the experiment. Periodic interbout arousals (IBAs) are seen as regular spikes in body temperature despite a constant ambient temperature of 5°C. Photographs of animals at four different points during the year are indicated and shown above the graph. Characteristic measurements of T_b, oxygen consumption (V_O2) and heart rate (f_H) during torpor and IBA are shown above the respective photographs. The figure is duplicated from Hampton et al., 2013 (with permission).

Fig. 2.

Examples of torpor bouts and interbout arousal (IBA) cycles in the thirteen-lined ground squirrel (Ictidomys tridecemlineatus). (A) Passive whole-body cooling that occurs during ‘entry into torpor’ is almost as abrupt as the warming during ‘arousal’. Body temperature shows that this abrupt heating and cooling occurs at regular intervals as measured by surgically implanted transmitters. This regular heating and cooling is a regulated process. (B) The highest rate of brown adipose tissue activity occurs during IBAs, where heat production occurs very quickly. The animal's body temperature rises 20°C in less than 1 h and is able to rise to normothermia within 3 h (adapted from Schwartz et al., 2015b).

Fig. 3.

Circannual cycle of brown adipose tissue (BAT) in hibernators. Colored lines are hypothetically drawn from data simplified from literature (MacCannell et al., 2017; Heim et al., 2017; Ballinger et al., 2016; Hampton et al., 2013; as reviewed by Florant and Healy, 2012). BAT metabolism (purple) is highest during the hibernation season and overall is suppressed during the active season when body temperature (T_b; red gradient) is at a normothermic 37°C. BAT mass (blue) peaks during the autumn preparation phase and at the beginning of the hibernation season when body mass (black) is also highest. Model was adapted from Florant and Healy (2012).

Fig. 4.

Model highlighting differentially expressed genes involved in fuel utilization and heat generation in brown adipose tissue (BAT) during hibernation. The role of gene products in various metabolic processes in a brown adipocyte is shown. Genes with abbreviations in red meet the criteria for differential expression, showing highest messenger ribonucleic acid (mRNA) levels during the hibernation phases of torpor or interbout arousal (IBA). Abbreviations of genes that are not differentially expressed but their mRNAs are highly abundant and/or encoded by tissue-specific genes in BAT, are shown in black. Molecules that serve as a source of fuel are labeled in green. Data were taken from a transcriptomic study using RNA sequencing (Hampton et al., 2013). Ad, adenosine; ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; NA, noradrenaline; NEFA, non-esterified fatty acid; TAG, triacylglycerol; UCP1, uncoupling protein 1. Figure is duplicated from Hampton et al., 2013 (with permission).

Fig. 5.

Seasonal messenger ribonucleic acid (mRNA) expression patterns of EPHX1 and EPHX2 across seven tissues in the thirteen-lined ground squirrel (Ictidomys tridecemlineatus). (A) EPHX1 and (B) EPHX2 mRNA levels were determined in previous studies of BAT and WAT (Hampton et al., 2013), cortex and hypothalamus regions of the brain (Schwartz et al., 2013), bone marrow (Cooper et al., 2016), and heart and skeletal muscle (Vermillion et al., 2015a). Measurements shown on the y-axis are means±s.e.m. of the upper-quartile normalized counts of reads from the four collection points (April, October, torpor and IBA). BAT, brown adipose tissue; BM, bone marrow; Cor, brain cortex; EPHX1, epoxide hydrolase 1; EPHX2, epoxide hydrolase 2; Hypo, hypothalamus; IBA, interbout arousal; Oct, October; Skel, skeletal muscle; Tor, torpor; SUM, summer; WAT, white adipose tissue.

Fig. 6.

Model highlighting differentially and highly expressed proteins involved in mitochondrial metabolism and heat generation in brown adipose tissue (BAT) during hibernation. Proteins with abbreviations in red meet the criteria for differential expression, with highest protein levels during the hibernation phases of torpor or interbout arousal. Abbreviations of proteins that are not differentially expressed but are highly expressed, and/or tissue-specific proteins in BAT, are shown in black. Data were taken from recent proteomic (Hindle and Martin, 2014) and mitoproteomic (Ballinger et al., 2016) studies, where similar states were sampled across the year in BAT from thirteen-lined ground squirrels. Cy c, cytochrome c; FADH, reduced flavin adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; TCA, tricarboxylic acid cycle; UCP1, uncoupling protein 1.