Why is it so Hard to Maintain a Reduced Body Weight?

Why is it so Hard to Maintain a Reduced Body Weight?

Posted: 18 May 2011 06:00 AM PDT

Yesterday, I had the pleasure of attending a lecture by Rudy Leibel from
Columbia University, who is perhaps best known for his considerable
contributions to our current understanding of energy metabolism.

The talk was hosted by William Colmers as part of the University of Alberta
Merck Translational Lecture Series.

In his presentation, Leibel addressed the issue of why it is so hard to keep
weight off - in fact, even in people who undergo bariatric surgery, weight
always comes back when surgery is reversed.

One of the key underlying problems is that when people lose weight, their energy
expenditure does not simply fall to that of the energy expenditure of a person
`naturally' at that lower weight - it drops to levels far greater than expected.

Thus, a formerly-obese person burns 20% less calories than a never-obese person
of that lower weight - or in other words a 200 lb person, who loses 40 lbs burns
about 20% fewer calories than someone who is 160 lbs, but has never been obese.
On top of this, the formerly-obese person experiences hunger, cold intolerance,
and other behavioural and metabolic changes that make sustaining this lower body
weight difficult.

From an evolutionary sense, this makes a lot of sense, as maintaining or
`defending' fat stores in the past has always been vital for human survival and
therefore complex biological systems have evolved to readily take up and store
excess calories when available and reduce caloric expenditure when times are
tough.

In a large series of carefully conducted energy balance studies in humans,
Leibel examined the impact of weight loss on energy expenditure, energy intake,
neuroendocrine function, autonomic physiology, metabolism and brain imaging.

Whereas a short-term increase in body weight by 10 % results in a transient
increase in energy expenditure, this returns to baseline, when the weight is
lost. This means that weight-loss per se does not reduce energy expenditure.

On the other hand, a 10% drop in body weight immediately reduces energy
expenditure by as much as 20%.

Interestingly, this fall in energy expenditure is not simply due to a fall in
metabolic rate, but largely due to a decline in activity expenditure. This means
that the body 'saves' energy not simply by turning down the furnace, but by
becoming substantially more `fuel efficient' during activity. In other words,
someone who loses weight, will burn substantially fewer calories for a given
amount of exercise than for the same amount of exercise performed before weight
loss.

Much of this increase in `muscle efficiency' can be attributed to the remarkable
fall in the fat tissue-derived hormone leptin that occurs with weight loss.

Obese individuals apparently need a higher level of leptin to sustain energy
balance. When they lose weight, thereby lowering their leptin levels, the system
will aim to increase body fat levels to once again produce enough leptin to
suppress the orexogenic response. Thus, weight reduction looks like `leptin
deficiency' to the brain, which it seeks to correct, by promoting weight gain.

The importance of leptin in this `defense' response is clearly evident from both
animal and human studies, in which leptin levels were maintained at or restored
to pre-weight loss levels despite weight loss, by injecting leptin at levels
just high enough to `mimic' baseline levels.

In all of these experiments, using exogenous leptin to restore leptin levels to
baseline, abolished the `defense' mechanisms including the decline in total
non-resting energy expenditure, thus making it easier to keep the weight off.

This `relative leptin-deficiency' dependent improvement in muscle efficiency
with weight loss can be clearly and consistently demostrated at the functional
(exercise), imaging (MRI) and biological (biopsy) level.

Apart from reversing the improvements in muscle efficiency, Leibel also showed
how the increased activation of hunger and appetite centres in the brain with
weight loss can be reversed by leptin replacement. Thus, administration of
leptin to individuals post-weight loss, reverses the decreased/delayed satiation
and decreased perception of caloric density that would act to restore body
weight to baseline.

Increases in the weight set-point occur with chronic weight gain, neuronal loss
of aging, puberty and pregnancy. Unfortunately, lowering this threshold is far
less likely, requiring such drastic measures as hypothalamic lesions or
cachexia.

Thus, from an energy regulatory perspective, weight loss induces a
`non-physiological' state that can be restored to a `physiological' state by
leptin administration at levels high enough to mimic baseline levels.

So why is leptin not being sold to maintain weight loss? Because there is
currently no regulatory pathway to license drugs that prevent weight regain.
Regulators like the FDA and the EMEA simply lack a sound understanding of the
complex physiology of weight regulation because after all, in weight management,
the problem is never how to lose weight - the problem is always how to keep it
off.

Unfortunately, based on the current guidelines for obesity drugs, there is no
way for a pharma company to even apply to have a drug licensed that does not
help reduce body weight (which leptin does not) but merely helps people keep
weight off (which leptin does).

This is a shame, because in the end replacing leptin may well be the safest way
to restore the `physiological' state of being obese by correcting the
`unphysiological' state of having lost weight, which essentially drives weight
regain.

AMS
Edmonton, Alberta