The aim of this presentation is to illustrate how discoveries in one area of physiology may impact on other, seemingly unrelated fields, and in turn depend on multidisciplinary approaches.

Many animals and humans maintain body weight and body energy content within fairly close limits over long periods of time, lending support to the proposal that energy balance is regulated. Disruption of this regulation, due to a sustained but modest imbalance between energy intake and energy expenditure, leads to the conditions of obesity (positive energy balance) or cachexia (wasting). My research with Mike Stock demonstrated that rodents can adjust energy expenditure in response to increases in food intake through activation of diet-induced thermogenesis (DIT). DIT is highly dependent on age, genetic background and environmental factors, and in rodents results from sympathetic activation of brown adipose tissue (BAT) where heat is generated through the presence of the mitochondrial uncoupling protein (UCP). This process is regulated primarily within the hypothalamus, which responds to neural and humoral afferent signals, is influenced by endocrine systems most notably the hypothalamic-pituitary-adrenal axis and insulin and regulates the activity of the sympathetic nervous system as well as appetite.

Defective DIT in rodents leads to obesity, while excessive activation of brown fat thermogenesis leads to body weight and energy loss. We demonstrated the importance of brown fat thermogenesis in several protocols of experimentally induced cachexia including infection, injury and inflammation and cancer.

The relevance of DIT and brown fat to the development of obesity in adult humans is questionable, but may be important in cachectic status since BAT is markedly activated in cachectic children and the metabolic rate induced by an inflammatory/ immune stimulation (typhoid vaccine) is prevented by β-adrenoceptor antagonists.

Pro-inflammatory cytokines such as interleukin-1 (IL-1) and TNFα tumour necrosis factor α (TNFα1) have been identified as important mediators of cachexia. They inhibit appetite and feeding, stimulate thermogenesis and lead to depletion of fat and protein stores. These cytokines have local actions on adipose tissue, but are also synthesised and act within the brain (particularly within the hypothalamus), and in animals cause fever and hypermetabolism via the neuropeptide CRF. More recently we demonstrated that the hormone leptin, an important mediator of energy balance regulation, inhibits food intake and stimulates energy expenditure partly through induction of IL-1 in the hypothalamus. Mice lacking IL-1 or IL-6 show modest, maturity onset obesity, suggesting a role for these cytokines in normal physiology. Indeed leptin, like IL-6 and CNTF signals through the gp130 receptor family, and on the basis of some of its actions may be considered a cytokine rather than a hormone.

Research Symposium – Human Energy MetabolismResearch Symposium – Human Energy MetabolismResearch Symposium – Human Energy Metabolism a role for these cytokines in normal physiology. Indeed leptin, like IL-6 and CNTF signals through the gp130 receptor family, and on the basis of some of its actions may be considered a cytokine rather than a hormone.