The growing problem of obesity
by David Bradley
The number of people worldwide who are overweight now rivals the number who are underweight, according to the World Health Organisation - obesity is a growing problem. In the UK, 15% of men and 18% of women are clinically obese, while the figures in the US are closer to 25%. The search for anti-obesity drugs and ways of controlling body metabolism is more than simply helping people to slim, it could be a lifesaver as there are some serious health risks associated with being overweight.
Research is now gathering pace with the announcement in July of a genetically engineered mouse that seemingly never puts on weight irrespective of how much it eats. John Clapham and his colleagues at SmithKline Beecham in Harlow, Essex, working with biochemists and nutritionists at the MRC-Dunn Human Nutrition Unit at Cambridge have designed a mouse that over expresses the human version of UCP-3, uncoupling protein 3.
UCP-3 is a member of the mitochondrial transporter super family involved in
skeletal muscle metabolism and its cousin UCP-1, a critical factor in heat
production and lipid turnover, is found in infant brown adipose tissue. The
conversion of food to energy occurs in the mitochondria the excess is
converted to fat and stored but UCP-3, which is found in muscle tissue,
decouples this process so that excess chemical energy is burned off.
Clapham and his colleagues found that mice with the gene for UCP-3 ate between 15 and 54% more food than wild-type controls but showed a 44 and 57% decrease in the ratio of adipose tissue volume to total animal volume for males and females, respectively. Moreover, serum cholesterol levels in the transgenic mice were 37% lower. Blood glucose too was lower in fasting mice and plasma insulin levels lower, indicating a greater sensitivity to insulin. This hints at the possibility that UCP-3 research might eventually lead to a novel treatment for Type 2, adult-onset, diabetes. Almost half of Type 2 diabetics are obese, in the US.
Previous results with UCP-3 have been inconclusive with some demonstrating a role in energy expenditure regulation while others showed no association between the protein and metabolism. Clapham and his colleagues have proved that despite an increase in energy intake, overexpression of UCP-3 elicits a marked reduction in body weight, better insulin sensitivity and a reduction in adipose fat. Clapham cautions that his results do not imply that UCP-3 is the culprit in the development of obesity but rather that enhancing its activity might provide a promising approach to treating it.
A new chapter on the causes of obesity may also have been opened recently. In some instances, obesity may be caused by a viral infection, according to Nikhil Dhurandhar and his team at the University of Wisconsin, Madison. They found that inoculating chickens with human adenovirus (Ad-36) resulted in fat chickens. Interestingly, animals cross-infected by receiving transfused blood from the inoculated chickens also become severely obese although their serum triglyceride and cholesterol levels fall.
The virus does not lead to increased food intake, in vitro studies revealed that it increases fat cell size and number, although the exact mode of action is not yet known. Dhurandhar suggests that should infectious obesity turn out to be a real disease then a vaccine against it would certainly be a possibility. It might, however, emerge that obesity simply increases susceptibility to the virus and not vice versa.
Meanwhile, a second protein called Wnt-10b has been found to act as a fat switch, quieting two molecules known to initiate gene expression for fat formation or adipogenesis. Wnt proteins are secretory proteins regulating various developmental processes through signal transduction and so gene expression.
Within the cell nucleus, two adipogenic transcription factors transform pre-adipocytes, into fat cells, or adipocytes. According to Ormond MacDougald of the University of Michigan, Wnt signaling seems to inhibit these factors - CCAAT/enhancer binding protein (C/EBP) and peroxisome proliferator- activated receptor-gamma (PPAR-gamma) - so that pre-adipocytes do not differentiate. When this cellular signal is switch off, however, the transcription factors are activated and adipocytes develop.
MacDougald, Sarah Ross and their colleagues have found that pre-fat cells injected under the skin of mice, led to the formation of pads of fat, but only from cells lacking Wnt proteins or in cells in which Wnt is blocked. When mice were injected with pre-adipocytes expressing high levels of Wnt proteins, only non-fatty pads of fibroblast-like cells formed.
'Although this work will likely be important for our understanding of how obesity develops, the best drug targets remain, at this point, the specific nuclei in the hypothalamus that control appetite and whole body energy metabolism,' MacDougald told us. Finding out exactly what flips the switch would win half the battle although a drug would have to target adipose tissue very specifically to avoid severe side-effects.
1 Clapham, Nature, 2000, 406, 415-418
2 MacDougald, Science, 2000, 289, 950-953
3 Dhurandhar Int. J. Obesity, 2000, 8, 989-996.