OB GENE PRODUCT: WEIGHT LOSS WONDER?
By Sean Henahan, Access Excellence
A protein product of the recently identified obesity gene
(ob) appears to cause weight loss in experimental animals,
reported researchers in a series of news studies.
The reports come only months after researchers reported the
identification, cloning and sequencing of the ob gene, the
culmination of eight years of work. The initial research showed
that mice with mutations in the ob gene do not make the ob gene
product, now called leptin (from the Greek leptos, meaning
thin), believed essential for weight maintenance.
Three separate teams reported that injections of leptin
caused mice to lose weight and keep the weight off. The mice
were a special breed of genetically obese animal known as ob/ob
mice because they have two mutant copies of the ob gene. The
leptin was expressed in E. Coli from a PET 15b plasmid and was
then purified and renatured.
The obese mice dropped 40% of their body weight after on
month of treatment with the protein. The leptin injections also
appeared to improve symptoms of diabetes in the mice. Non-obese
mice also lost weight when given the protein.
"I'm really impressed. The level at which body weight is
defended is reduced by this stuff," obesity researcher Richard
Atkinson, University of Wisconsin, told Science magazine.
Another gene identified in a different strain of obese mice
called db (for diabetes) has also been identified. Leptin
injections had no effect on this kind of mice. This supports a
previous hypothesis that db mice had an impaired receptor for
Earlier research suggested that ob gene regulates energy
balance in the mouse. The gene appears to play a role in the
signaling pathway from adipose tissue that in turn regulates the
amount of stored body fat. The ob gene encodes a protein
secreted by fat cell and associated with satiety, the signal to
stop eating. Mutations of this gene prevent translation and
expression of the gene product. Lacking this satiety factor, the
mice become obese.
The current research suggest the gene product both reduces
the mouse's appetite and increases its metabolism. "The new
findings indicate that when ob is defective, leptin is not made
and does not transmit the signal to stop eating," said Jeffrey
Halaas, a research fellow at Rockefellar University and lead
author of one of the studies.
It remains to be seen whether the compound causes similar
effects on human metabolism. A human homologue of the gene has
also been cloned. The human homologue matches 84% of the murine
nucleotide sequence. Indeed, obese mice injected with human
leptin also lost weight. 'The fact that human leptin
reduces weight in the mice raises the possibility that giving
leptin to people might have similar effects. However, we must
proceed cautiously to prove that the protein treatment is safe
in animals. Studies of humans cannot begin until the protein has
been confirmed to be without unwanted side effects,' said
Jeffrey Friedman, M.D., Ph.D., of Rockefellar university.
If similar effects are seen in humans, the protein could
form the basis for a whole new way of treating obesity. A
biotech company has already paid $20 million for rights to
develop potential drugs from the ob gene product.
"While diet and exercise are presently the cornerstone of
weight control, this new molecular approach to understanding the
regulation of body weight is one of the best examples of real
progress in biomedical research," noted Philip Gorden, M.D.,
director of the National Institute of Diabetes, Digestive and
These current findings contribute much to the study of
the physiological mechanisms of appetite and satiety. In
particular, the discovery of the ob gene has added support to
the theory of lipostasis wherein the amount of body fat is
regulated by the central nervous system via a product of fat
metabolism in plasma.
The identification of the ob gene suggested a possible
source for generation of a blood borne regulatory factor. It is
possible that the level of expression of this gene determines
the size of the body's fat stores. Researchers now hypothesize
that an increase in the level of the ob signal following a
session of overeating may act directly or indirectly on the
central nervous system to maintain body fat at the post-binge
The next stage will be to identify the location of the
leptin receptor. Preliminary research suggests the receptor may
be found in the brain.
The three latest studies on the ob gene appeared in
Science, 7/28/95, Vol. 269, in articles by Halaas et al., pp
543-546; Campfield et al., 546-548; and Pelleymounter et al,
540-543. The original report on the ob gene localization
appeared in Nature, 12/1/94, v.372, Freidman et al.