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.
References
1 Clapham, Nature, 2000, 406, 415-418
2 MacDougald, Science, 2000, 289, 950-953
3 Dhurandhar Int. J. Obesity, 2000, 8, 989-996.