Wherefore art thou brown fat?

Brown fat has once more reached the headlines, this time with the aid of molecular biology. Lowell et al. (1993) report in Nature their work using transgenic mice in which brown fat is ablated. Brown fat is a specialized tissue which in mice is involved in non-shivering thermogenesis. In this process heat is produced by a flow of protons across the inner mitochondria1 membrane without the generation of ATP, utilizing a specific pathway associated with a membrane protein referred to as an 'uncoupling protein'. Using a transgenic toxigene approach involving this uncoupling protein, the authors created two lines of transgenic mice but with variable deficiency of brown fat. In the diphtheria toxin A-chain (UCP-DTA) strain, brown fat was decreased by 68%, whereas in the second strain, an attenuated mutant (UCP-l76), reduction was 96%. Total body lipid was increased at 16 days of age by 31% in the former and 68% in the latter, correlating with their relative deficiency of brown fat. At this age neither strain was hyperphagic compared to their non-transgenic littermates, a feature also exhibited by other murine" models of obesity (e.g. ob/ob, db/db). As the UCP-DTA mice aged, they maintained their relative deficiency of brown fat but in the UCP-176 strain brown fat regenerated. In the UCP-DTA model this relative absence of brown fat resulted in the development of extreme obesity ( > 50% body fat) by 19 weeks, with the presence of insulin resistance, hyperinsulinaemia, hypertrigl yceridaemia and hypercholesterolaemia. Hyperphagia began in this strain at about 5 weeks of age and was uniformly present at 7 weeks. In the other strain in which brown fat regenerated, hyperphagia did not develop; the mouse having initially become fat, showed reversal of the obesity with total body fat returning to normal by 8 weeks. The hyperphagia was not thought to be due to a hypothalamic lesion, for the UCP-DTA strain was fertile and grew normally. They surmise that there may be a link between prolonged brown fat deficiency and the eventual development of hyperphagia. The delay in the development of hyperphagia also suggested that the deficiency of brown fat itself may not be the direct stimulus, but that this might be a secondary consequence of the metabolic sequelae, possibly the hyperinsulinaemia associated with insulin resistance. How does this work relate to obesity in man? Brown fat has widespread presence in infants but decreases considerably by adulthood, although still detectable at least up to the sixth decade (Lean, 1992; Cunningham et al., 1985; Jung, 1990). In adults the small amount of brown fat is functionally active but the difficulty has been to quantify this. Astrup et al. (1985) and our own group (Cunningham et al., 1985) have concluded that in adults it has only minimal energetic potential, possibly as little as 0.2% of the thermogenic response to infused noradrenaline. Nevertheless there is the possibility that it could be relevant in energy balance and even appetite imprinting during the foetal period and in early infancy. Studies suggest that fat babies do not necessarily become fat adults (Poskitt & Cole, 1977) but no one knows whether some of those babies who remain fat have a deficiency of brown fat, inherited or acquired. There are some clues. Roberts et al. (1988) using the double-labelled water method to measure total energy expenditure in babies concluded that those who became overweight at 1 year had an energy expenditure at 3 months of age some 20.7% lower than those who were of normal weight at 1 year. This and an earlier study (Griffiths & Payne, 1976) suggest that a reduced energy expenditure might play a part in subsequent weight gain. It has yet to be shown that this is associated with reduced brown fat, as is the situation in transgenic mice. Nonetheless, molecular biology may soon answer this question. So far some 22 genes have been implicated in the development of obesity suggesting a multifactorial aetiology, a possible deficiency of brown fat being one of many factors in the equation. One fact is certain, brown fat deactivates with age in man. Why and how are as yet unknown. Nevertheless with a better understanding of the gene controlling the uncoupling protein, there is the distinct possibility that a drug might be developed to reverse this aging effect in a controlled manner, literally burning off excess fat as was demonstrated in the UCP-176 transgenic mouse.