Obesity and overweight conditions continue to be difficult to treat in the 21st century.
People who try to lose weight through diet and exercise usually fail in the long run.
The body counteracts weight loss by increasing hunger, lowering metabolic rate and burning
fewer calories. Bariatric surgery, such as Roux-en-Y gastric
bypass, is very effective in treating obesity. It can also restore insulin sensitivity and
cure type II diabetes, BUT it is also very costly, making it out of reach for most people
in the world, and like all surgical operations, is not without risk.
Medicines to help people lose weight have been hard to come by. Drugs that work in the
brain to reduce appetite have often failed in the clinic. Eating and enjoying a healthy
diet is critical to our well-being. Drugs that inhibit food intake often disrupt the
reward pathways in the brain that make us feel happy and contented with life. Calorie
restriction can also lead to rebound weight gain, undoing all the hard work that was done
before. But, what if we could find a drug that stimulated
our basal metabolic rate and burned calories without disrupting our appetite?
Researchers at the University of Virginia, the University of New South Wales, and Virginia
Tech with collaborators at other sites in Australia have recently discovered a compound
with these properties…at least in preclinical models. Their investigational compound, BAM15,
is a mitochondrial uncoupling agent that triggers fat burning and leads to weight loss in overweight
mice without changing food intake. So, what are mitochondrial uncoupling agents and how
do they work? Ordinarily, in the mitochondria of every cell,
the breakdown of food creates a source of energy in the form of NADH and FADH2. NADH
and FADH2 are used to drive the electron transport chain resulting in the transport of protons
across the inner mitochondrial membrane. This creates an electrochemical gradient with high
concentration of protons (shown as H+) on one side and low concentration on the other.
This electrochemical gradient is used to drive the production of ATP. The downhill flow of
protons through ATP synthase converts ADP to ATP, the universal currency of energy in
the cell. Uncoupling agents, like BAM-15, disrupt the proton gradient. They transport
the protons back across the membrane. The net result is that the breakdown of food is
uncoupled from the creation of ATP. In effect, uncoupling agents decrease the efficiency
of the engine and trigger the consumption of fuel. In other words, uncoupling agents
lead to wasted calorie burning. The concept behind uncoupling agents is not
new, in fact it is pretty old. 2,4-dinitrophenol, or simply DNP is a mitochondrial uncoupler
with well-documented weight loss effects. Munitions factory workers in world war I who
were handling DNP were observed to lose weight. Tragically, at higher exposure levels, many
workers got sick and died. Later, in the 1930’s doctors at Stanford university investigated
DNP and found that patients lost 2-3 lbs per week without any changes in food intake or
alterations in appetite. It was estimated that over 100,000 people used DNP in diet
pills in the 1930’s. The problem was that DNP had off target effects and a narrow therapeutic
window. That is, the dose range between positive therapeutic effects and toxic effects was
very slim. It was all too easy to overdose on the medicine, leading to toxicity and even
death. In 1938, the drug was banned by the US Food and drug Administration. Even today,
there continue to be illegal sales of the drug, and, sadly, fatal poisonings from its
use. Nevertheless, the concept of uncoupling agents
lived on. There were several important learnings since the 1930’s. One is that there are
endogenous, or naturally occurring proteins that are mitochondrial uncouplers, called
uncoupling proteins (UCP’s). These allow the flow of protons through the membrane,
decreasing the proton gradient and leading to fuel burning and heat production. Infants
and other small mammals depend on this mechanism to generate heat in cold conditions. So, there
is nothing inherently toxic about the uncoupling process. Approximately 25% of basal metabolism
results from the spontaneous flow of protons across the membrane leading to wasted calorie
burning.
Now, back to mitochondrial uncoupler BAM15. The research team investigated BAM15’s effects
in C57 black 6 mice. Mice fed normal chow will add fat mass as they grow normally over
a period of weeks. In contrast, mice fed a high-fat and sugar diet (a so-called “western”
diet) gained fat rapidly. At the four-week mark, the western diet group was divided into
two with some of them receiving BAM15 in addition to the western diet. These animals lost fat
mass over the next five weeks, while those mice not receiving BAM15 continued to put
on fat. The team discovered that BAM15 works primarily
in the liver to increase fat oxidation. They also observed that the compound was selective
for fat. There was no change in lean mass in the mice treated with BAM15.
Significantly, the weight loss occurred without any change in food consumption.
The team also saw antidiabetic effects. BAM15 restored insulin sensitivity in mice fed the
high fat western diet. BAM15 is not a medicine yet. Nevertheless,
it represents an important investigational compound and hopefully it will lead to a safe
and effective treatment for obesity and overweight conditions.
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