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Brown Fat – Hotting up Again

For a decade or so from the late 1970s brown adipose tissue was a key focus of obesity research. The concept that adaptive changes in energy expenditure are important in the regulation of energy balance, with reductions in thermogenesis as a major factor in the development of obesity, had taken centre stage. This was based on some pivotal observations from studies on experimental animals. Brown adipose tissue provided the missing locus for thermogenesis, with the molecular mechanism by which heat is produced being elucidated. Evidence in support of the idea that brown adipose tissue thermogenesis is a major component of adaptive energy expenditure in laboratory rodents accumulated rapidly in the 1980s from a range of studies. However, there was considerable scepticism on the relevance to human energetics (beyond the newborn) and to the aetiology of obesity in particular. Alexander Pope’s aphorism ‘The Proper Study of Mankind is Man’ resonated strongly. But the situation has changed dramatically over the past couple of years, with a surge of interest in brown fat in humans and its potential role in adult energy metabolism. Brown adipose tissue (or brown fat), which has been proposed to be part of a single ‘adipose organ’ [1], was first described in 1551 by the Swiss naturalist Conrad Gessner and subsequently termed the ‘hibernating gland’. However, it was not until some three centuries later through the work of Robert Emrie Smith in the 1960s that brown fat was clearly recognised as a thermogenic tissue [2]. This was in the context of thermoregulation – as ‘non-shivering thermogenesis’. The quantitative importance of brown adipose tissue to total heat production was considered to be modest until blood flow measurements with radioactively labelled microspheres by Foster and Frydman [3, 4] showed that more than half of the heat generated by non-shivering thermogenesis in rats acclimated to the cold is due to brown fat. These critical observations came at the time when the controlled uncoupling of mitochondria through a proton conductance pathway specific to brown adipose tissue was being demonstrated as the primary mechanism by which adaptive heat is produced [5, 6]. The groups exploring in experimental animals the thesis that adaptive changes in energy expenditure are central to the regulation of energy balance and underlie the development of obesity were considering several tissue locations and biochemical mechanisms by which this might occur. The tissues of primary interest were skeletal muscle and the liver, while processes such as substrate cycles (also known as futile cycles), protein turnover and Na transport across the plasma membrane were all considered as candidate mechanisms. None, however, were thought to be sufficiently important in terms of the amount of heat that they might produce. The demonstration of the quantitative importance of brown fat to non-shivering thermogenesis in rats suggested that this tissue could be the key site of adaptive thermogenesis beyond the demands of thermoregulation. In other words, it might be involved in other forms of adaptive heat production, such as diet-induced thermogenesis. Two pivotal observations made in 1978 and 1979 directly linked brown adipose tissue to obesity. In the first, HimmsHagen and Desautels [7] showed, using biochemical indices, that the thermogenic activity of brown fat mitochondria was reduced in obese (ob/ob) mice relative to their lean siblings [7]. They also demonstrated impaired brown fat activation in the obese mutants in response to cold. The second pivotal observation came from the work of Rothwell and Stock [8] and Brooks et al. [9], who showed in rats exhibiting substantial levels of diet-induced thermogenesis following the consumption of a ‘cafeteria diet’ that the activity and capacity of brown fat were increased. These studies led to a radical new perspective on brown adipose tissue function and of energy exchange in small mammals. They were followed by the demonstration that changes in brown adipose tissue activity occur in a wide range of situations and model systems, from different forms of obesity to lactation, fasting and other types of nutritional intervention [10, 11]. One of the further critical developments was the discovery that a specific protein, termed uncoupling protein (now known as uncoupling protein-1 (UCP1)), located in the inner mem-