Listening to Leptin: Understanding the Basic Components of Leptin Research
Mice model for obesity
Mice
provide an ideal model system to study diseases that mimic human diseases.
Rodents have the same enzymes and metabolic pathways that humans do,
which makes it possible to use these animals to mimic the same conditions
for humans. For more information on the link between human and mouse
genetics, please visit http://www.informatics.jax.org/.
To
observe the effects of diet-induced obesity and the leptinergic blockade
one group was fed a low fat diet, while the other was fed a high fat
diet. As the mice grew, changes in their weight and adipocyte diameter
were measured to study the development of obesity.
Fat storage in adipocytes
Observing
diet-induced obesity means examining changes in adipose tissue. Throughout
life, adipose tissue, comprised of adipocytes (fat cells), maintains
the same number of fat cells which increase or decrease in size. When
the amount of fat stored in the cell changes, it causes a corresponding
increase in adipocyte size. Fatty acids are stored in adipocytes as
triacylglycerols.
When dietary fat is ingested, triacylglycerol molecules from food
are cleaved by intestinal lipases to form fatty acids and glycerol
molecules that are then carried from the intestine to the rest of
the body by lipoprotein complexes called chylomicrons. Chylomicrons
are delivered to muscle cells for immediate oxidation to fuel or to
adipose tissue where they are reformed into triacylglycerols and stored
in a lipid droplet. During a state of overnutrition, adipocytes excrete
the hormone leptin as one way to regulate appetite. This is the body's
way of saying, "It's time to stop eating."
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Figure 5: Structural model of leptin |
In
addition to
storing fat, adipocytes are involved in paracrine signaling (the signaling
which occurs between neighboring cells). Adipocytes release the hormone
leptin when they have a high level of energy and are storing excess
energy as fat. Leptin acts at the hypothalamus to cause the secretion
of other hormones that decrease appetite and thus reduce energy intake
(Siegrist-Kaiser 1997).
Leptin was first discovered in mice and is the product of a gene named
OB. Homozygous mice with two defective copies of the OB
gene showed greatly increased appetite, elevated serum cortisol levels,
abnormal growth, lack of reproduction, and inability to stay warm, which
would probably be caused by reduced fatty acid oxidation. These physiological
conditions suggest a state of constant starvation and caused the mice
to be extremely obese (Nelson & Cox p.
911). Researchers were able to show that leptin plays a role in
the regulation of appetite. When the obese mutant mice were given leptin,
their appetites and food consumption decreased, resulting in weight
loss.
Leptin also acts in paracrine signaling to other adipocytes that leads
to changes in the levels of glucose used by cells when stimulated by
insulin and also increasing the basal levels of triacylglycerol oxidation
(Siegrist-Kaiser 1997).
Increase in weight causes hyperleptinemia
Hyperleptinemia, a state in which an excess of leptin is present in the blood, can occur naturally as leptin levels increase with increasing weight (Young 2001). In the laboratory, injecting mice with an expressible leptin cDNA (AdCMV-leptin) can cause an experimentally induced state of hyperleptinemia, which will cause a decrease in body fat in lean mice (Orci 2004).
 Figure
7: Pathway of leptin activity |
Leptinergic
blockade in obesity
Despite the correlation of hyperleptinemia with obesity, leptin's weight regulating effects are not seen in obese mice due to a leptinergic blockade (Wang 2005). A leptinergic blockade prevents a response to high levels of leptin that would stimulate the fat reducing response seen with hyperleptinemia induced in lean mice. This research was aimed at discovering whether the leptinergic blockade acted at a receptor or a post-receptor level.
Lepr-b: the leptin receptor
In paracrine signaling, leptin binds to a receptor, Lepr-b, which is a phosphotyrosine receptor dimer. Phosphorylation of the two monomers of the receptor by a Janus kinase activates STAT-3 (signal transducer and activator of transcription-3 shown in Figure 9), which then dimerizes (Vaisse 1996). The dimer is transported to the nucleus where it influences transcription of genes regulating energy use and metabolism (Nelson & Cox p. 913).
Action of the leptin receptor can be blocked by the phosphorylation of IRS-2 (insulin receptor substrate-2 shown in Figure 8) on a serine residue to block the phosphorylation of a tyrosine residue by the leptin phosphotyrosine receptor by a change in conformation. Additionally, suppressors of cytokine signaling (SOCS) can block the activity of leptin (a cytokine) by ubiquinating IRS-2 to cause desensitization (Nelson p. 914).
Leptin signaling and metabolic pathways
The response to leptin originates in the hypothalamus where a release of norepinephrine is transported to the adipocytes and stimulates production of cAMP by adenylyl cyclase. cAMP then activates protein kinase A, causing both the increased expression of the gene encoding uncoupling protein and activating a hormone sensitive lipase to cleave fatty acids from the lipid droplet (Nelson & Cox p. 911). This leads to an increased oxidation of fatty acids but the oxidation is uncoupled and the energy is dissipated as heat.
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Webpage
designed by Sara Warzecka
Biochemistry 462B: Dr. Don Bourque
Department
of Biochemistry
University of Arizona
Last Updated May 11, 2006