Obesity: mechanisms, models and management

J Harrold

University of Liverpool

Summer School 15-18 July 2003
University of Manchester, Hulme Hall, Manchester, UK

In recent years, knowledge has advanced rapidly about the signals which indicate the body’s energy requirements and the neuronal circuits that sense and respond appropriately to these signals, by effecting changes in food intake and energy expenditure.

Much interest has focused on the hormone leptin, which is predominantly expressed in white adipose tissue and circulates at levels broadly proportional to fat mass (the body’s major energy store). It readily enters the hypothalamus and other brain regions, where it targets specific neuronal populations with the overall effect of inhibiting feeding and increasing energy expenditure.

Mutations in key components of the leptin signalling pathway underlie some of the syndromes of genetic obesity in rodents. The phenotypes of these models are predictable from the known actions of leptin. The ob/ob mouse is characterised by hyperphagia and decreased energy expenditure, leading to obesity (with over 50% adipose tissue and body weight three times that of normal mice). Two distinct mutations of the ob gene have been identified that essentially result in the failure to produce leptin mRNA. ob/ob mice are sensitive to exogenous leptin and respond with decreased food intake and obesity. The leptin receptor gene maps to chromosomal regions containing the db and fa mutations. These leptin receptor mutations render leptin unable to activate signalling pathways and result in the animals being insensitive to the biological effects of leptin. Consequently, mutant db/db mice and fa/fa rats are phenotypically similar to ob/ob mice but – in contrast to the latter – administration of leptin does not reduce food intake or body weight.

Such mutations are responsible for only a small minority of human obesity – which is mostly due to adverse lifestyle with increased intake of readily available palatable food and reduced physical activity. However, various abnormalities of leptin and hypothalamic peptides have been identified in dietary-induced obesity in rodents, which is more closely analagous to ‘common’ human obesity. Potential contributors include orexigenic neuropeptide Y neurones in the arcuate nucleus (ARC), which are inhibited by leptin, and ARC pro-opiomelanocortin neurones, which are stimulated by leptin and contribute to its central hypophagic effects. Orexin neurones in the lateral hypothalamic area also stimulate feeding, but only under specific conditions of hypoglycaemia in conjunction with the absence of food from the gut. Cannabinoids also act to increase food intake. However, the functionally significant cannabinoid pathways lie outside the hypothalamus and do not appear to be regulated by leptin.

These examples illustrate the variety of signalling peptides and their functional diversity and thus demonstrate the complexity of the processes required to maintain energy homeostasis. The relevance of many of these players to human energy homeostasis remains uncertain, but some promising novel anti-obesity drugs are likely to emerge in the near future.

The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society

Revised: 04-Sep-2003