- Date: June 23, 2017
- Source: Harvard Medical School
- Summary:
- Decades after the discovery of anti-obesity hormone, scant evidence that leptin keeps lean people lean, scientists caution.
-
FULL STORY
Discovered more than two decades ago,
the hormone leptin has been widely hailed as the key regulator of
leanness. Yet, the pivotal experiments that probe the function of this
protein and unravel the precise mechanism of its action as a guardian
against obesity are largely missing.
These are the conclusions in a commentary published June 22 in Cell Metabolism by Harvard Medical School metabolism experts Jeffrey Flier and Eleftheria Maratos-Flier.
Flier, the HMS George Higginson Professor of Physiology and Medicine,
and Maratos-Flier, HMS professor of medicine at Beth Israel Deaconess
Medical Center, have made significant contributions to the understanding
of the metabolism of obesity and starvation in general, and of leptin
in particular.
The commentary highlights what the authors say is a startling lack of
experimental evidence detailing the biologic roles of leptin in
metabolism, and calls for a renewed effort to characterize the action of
the hormone.
"It's been assumed -- but never shown -- that leptin helps keep lean
people lean, staving off weight gain," Flier said. Science demands
nothing less than a rigorous study and demonstration of this hormone's
mechanism of action, he added.
"Without doing the experiments, we can't determine whether the emperor of energy balance is wearing any clothes."
Twenty-two years ago, researchers discovered the identity of a mouse
obesity gene and found that it encodes a previously unknown hormone made
by fat cells, which they named leptin, a term derived from the Greek
word for leptos for "slim." In a rare genetic deficiency,
people born with two defective copies of the gene are extremely obese,
and their obesity can be reversed by restoring their leptin levels with
daily injections.
In mice and in people without the mutation, studies have shown that
leptin plays an important role in regulating metabolism -- just not the
one it's most famous for -- obesity prevention. Studies from the Flier
lab first showed that falling leptin levels signal the body that it may
be in danger of starvation. The role for leptin as a starvation signal
is now well established.
Early on, researchers speculated that this protein might also play a
key role in helping healthy lean people remain thin, perhaps by serving
as a signal that orchestrates resistance to obesity. Paradoxically,
obese mice and people who don't have the defective obesity gene almost
always have high levels of leptin. Flier first hypothesized that this
may be due to some kind of leptin resistance, analogous to the insulin
resistance seen in type 2 diabetes, a condition in which the body
produces more than normal amounts of the sugar-regulating hormone
insulin, but cannot use it to normally metabolize sugar.
While some leptin is clearly necessary to prevent obesity, the
authors write, the physiologic role of leptin in most individuals may be
limited to signaling the response to hunger or starvation, and then
reversing that signal as energy stores are restored, as they first
hypothesized more than 20 years ago, they say. If that is true,
according to the authors, the biology of leptin has little to do with
leanness or obesity, apart from a few rare cases of primary deficiency
with severe obesity.
Nevertheless, Flier and Maratos-Flier say, an anti-obesity role for
leptin persists as a dogma in the field of metabolism and obesity and
remains the most common description of what leptin does in textbooks and
literature reviews. Yet, Flier and Maratos-Flier caution, this role for
leptin has never been demonstrated experimentally in humans.
"Before we write the next chapter on leptin physiology and obesity,"
Flier said, "we should commit to seeing that these important questions
are finally answered."
Obesity is becoming a catastrophic health problem, both nationally
and globally -- one that fuels a range of chronic diseases, including
diabetes, high blood pressure, liver disease, kidney damage, arthritis
and cardiovascular disease, among others. More than $140 billion is
spent each year in the United States to treat obesity-related diseases,
according to the CDC. Worldwide obesity rates have doubled since 1980,
and most people now live in countries where more deaths are caused by
overweight and obesity than by malnourishment, according to the World
Health Organization.
"What we find most surprising is the extent to which scientists in
the field of metabolism and energy balance seem minimally concerned that
key experiments to define the actions of leptin have yet to be
reported," Maratos-Flier said. "The widely accepted 'anti-obesity limb'
of leptin physiology has never been clearly demonstrated to be present
in human biology."
The authors note that it's possible, even likely, that as-yet
undiscovered molecules, not leptin, mediate the regulation of body
weight and its dysregulation in obesity.
Treatment with leptin was approved in the United States in 2014 for
use in congenital leptin deficiency as well as in an unusual syndrome of
lipodystrophy, but the protein has not been readily available for
clinical experiments. There has also been limited interest in funding
the types of experiments necessary to rigorously test the
still-hypothetical benefits of leptin for preventing or reversing
obesity, apart from obesity due to rare genetic mutations in the leptin
gene, the authors write.
As one example, the authors propose a clinical study measuring how
lean people respond to increased leptin levels. If leptin is an
anti-obesity hormone, it might suppress hunger or increase energy
expenditure in trial participants compared to those who get a placebo.
"We continue to believe that healthy and lean individuals exist who
resist obesity at least in part through their leptin levels, and that
some individuals develop obesity because they have insufficiently
elevated leptin levels or cellular resistance to leptin," Flier said.
"But in science, belief and knowledge are two different things, and as
much as we may lean toward this belief, we ought to develop evidence for
this hypothesis or abandon it in favor of new potential mechanisms for
the regulation of body weight."
Gain muscle mass. It's a good idea to continue to exercise while you attempt to gain weight the healthy way. However, it's probably best to lay off the cardio (which burns those hard-earned calories) and focus on strength training instead (which builds muscle mass and helps you to gain weight).
Quit smoking. Smoking is a bad idea for those who are trying to gain weight as it suppresses the appetite.
Keep a food journal. Keeping a food journal will allow you to keep track of your weight gain and enable you to see which methods are working and which or not.
Stay committed. Gaining weight is not an easy process - in fact, gaining weight can be much harder than losing it. However, it is important that you stay committed and keep your eyes on the prize.
Stay healthy. The most important thing through the entire weight gain process is to stay healthy - eating a balanced diet and continuing to exercise throughout.
