A sideway glance: a new role for endoplasmic reticulum chemical chaperones as leptin sensitizers

Abstract

The epidemic surge in the prevalence of obesity is one of the most serious public health problem confronting the western societies. Among the adult population in the USA, 65% is overweight and more than 30% is obese and the picture in Europe is becoming very similar. There has also been an increase in the obese pediatric population with one out of three Americans born in the year 2000 expected to suffer from the complications of obesity like hypertension, type-2 diabetes and arteriosclerosis later in life [1]. However, the mechanisms behind obesity are still controversial. Obesity is usually considered as merely lifestyle disease caused by overeating and/or decreased physical activity. Although these factors have obviously great influence on weight gain, results of many investigations strongly indicate that hereditary factors could be of equal importance for the development of obesity and of its complications. Studies conducted on twins and on adoptive children show that most familial aggregation of obesity is due to genetic influence rather than to family environment. Interestingly, even in obese subjects, the weight gain throughout life is very small compared to the amount of energy ingested; and a weight gain of about 15 kg, compared to about 50 million cal (18 tons of food) ingested in lifetime which means that the regulation of the fat depots would be off by only 0.02%. This regulation must be extremely precise and the refined control mechanism is at least in part under genetic control. It has been proposed that secondary to overeating, the storage of additional fat will send signals to the brain informing that the body is overweight, inducing the subject to eat less and to burn more calories [2]. A major player in regulating energy intake and energy expenditure is leptin. This hormone protein was discovered as the product of the ob gene. Mice ob/ob were obese and had type-2 diabetes, due to the segregation of a single genetic locus containing the mutation. The gene is expressed only in fat cells, white and brown, and encodes a 167 amino acid-long protein, leptin. Leptin is secreted after its synthesis and functions as part of a lipostatic signaling pathway that modulates energy balance by central and peripheric effects. When fat cells increase in number and size, greater amounts of leptin are secreted into the circulation in order to maintain body weight and energy depots in equilibrium. Hypothalamus, with its central role in the regulation of hunger and satiety, is most probably the major target for leptin [3]. Treatment with recombinant leptin has resulted in a marked weight reduction in obese animals with ob gene mutations as well as in normal mice. According to its function it was found also that mutations in the Ob receptor gene resulted in marked obesity in rodents.