Dr Mel Siff Blog

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Here are some extracts from a highly informative article on leptin, a hormone
secreted by fat cells that influences energy expenditure and food intake in
mammals. At one stage it was popular to administer leptin to obese people in
attempts to make them eat less and stimulate weight loss, but its lack of
success in these applications led to it falling into disfavour. This article
discusses ongoing research into leptin.

<http://134.174.17.116/publications/Focus/2002/Feb8_2002/endocrinology.html>

Hormone Leptin Tied to Fat Breakdown in Muscle

Findings Connect Diabetes and Obesity, Suggest New Look at Obesity Treatment

Metabolic disorders like diabetes and obesity are entangled in a complex
relationship whose ins and outs are often murky. Both stem from malfunctions
in the body’s fuel engines– a vast machinery of metabolic processes that
turn glucose and fatty acids into energy. One of the most important but least
understood parts of this engine is leptin, a hormone secreted by fat cells
that has been shown to exert influence over energy expenditure and food
intake in several neuroendocrine pathways.

In a study in the Jan 17 Nature, a team led by Barbara Kahn, HMS professor of
medicine and chief of the Division of Endocrinology, Diabetes and Metabolism
at Beth Israel Deaconess Medical Center, and Yasuhiko Minokoshi, visiting
associate professor of medicine, establishes a new connection in the
metabolic machinery, tying leptin to a crucial pathway in fat metabolism in
muscle. This pathway suggests a role for leptin in clearing fat out of cells
and sheds light on the connection between diabetes and obesity……

The Stop Signal

Leptin first came to prominence as a satiety signal, a hormone that seemed to
signal to the brain how much fat was being stored and to regulate food
intake. With this discovery came the lure that administering leptin to obese
people could cause them to eat less and trigger weight loss. But in human
clinical trials, the weight loss was unspectacular, and the hormone’s flurry
of fame as a potential wonder drug petered out. Continued research has shown
that leptin is an important hormone with a hand in many metabolic processes
and undoubtedly has widespread effects that may influence diabetes as well as
obesity.

For one, leptin seems to regulate more than food intake; it has a role in how
fat is metabolized once it is in the body. Obesity is associated with insulin
resistance, and weight loss can often improve insulin’s abilities to clear
glucose from the blood. Several studies in animals suggest that excess lipid
is to blame for the insulin resistance–not the kind stored in fat cells but
lipids that accumulate in other tissues like skeletal muscle, liver, and
pancreatic beta cells. When leptin is given to mice, it helps reduce fat
tissue but also reduces intracellular lipids in these other tissues and
boosts insulin sensitivity. But why this glut of lipids impedes insulin
action is uncertain, as is leptin’s mechanism to clear it……..

Leptin’s known effects occur largely through the sympathetic nervous system.
Although direct effects have been shown in some tissues, it has been debated
whether the hormone directly affects muscle and fat. The relatively rapid
doubling of AMPK–which happens too quickly to be mediated by the central
nervous system–suggests a direct connection. When nerves in the hind legs of
the mice were severed, the muscle there still exhibited this sudden rise, but
the effects of the injection in the hypothalamus were blocked, suggesting
that leptin has two paths of action in fatty acid metabolism, a direct one on
muscle and an indirect one through the nervous system.

Both of these actions converge on the AMPK pathway, through which leptin
increases the oxidation of fatty acids in muscle tissue and keeps fat from
setting up residence in cells. “This is now giving us the molecular pathway
by which leptin may regulate fatty acid oxidation rather than fat
accumulation,” Kahn said.

Although the mechanism of leptin’s action on AMPK in the nervous system is
still unclear, her team further narrowed it down by determining that leptin
works through the system’s alpha-adrenergic arm, another revelation given
there has never been a recognized link between AMPK and this system. The
researchers found that for both routes of action, leptin activates AMPK
through phosphorylation of its alpha subunit. Only one isoform of the alpha
subunit was activated, a specificity that could be useful in drug
development.

Take Two on Obesity Treatment

In light of new knowledge about leptin’s role in fuel metabolism, it makes
sense to revisit the idea of targeting leptin’s actions to treat obesity.
Obese people develop resistance to leptin, so the ability to target a
downstream pathway and bypass leptin resistance may be more beneficial than
treating with leptin itself.

This direct path of leptin action also establishes an important link to
insulin resistance and diabetes. It is well established that the accrual of
lipid in muscle is associated with insulin resistance, and obesity is a risk
factor for type 2 diabetes. “This effect of leptin on the AMPK pathway could
be an important avenue by which it increases insulin sensitivity,” said Kahn.
If so, leptin resistance may help explain why obesity is a risk factor for
diabetes. “If we could reproduce this pathway in leptin-resistant people,
perhaps we could lower their risk of diabetes.”

Dr Mel Siff
Denver, USA
http://groups.yahoo.com/group/Supertraining/

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