Leptin pathway to control body weight through food intake and metabolism
Leptin is an anorexigenic-signaling molecule. Its ability to
inhibit appetite and enhance sympathetic activity to reduce body weight is
mediated by neuropeptide y containing neurons and pro-opiomelanocortin (POMC)
containing neurons in the arcuate nucleus of the hypothalamus (Sitaramayya,
2010). These sites have peuropeptide
modulators, melanocortins and neuropeptide Y responsive for the opposing
effects on metabolism and feeding (Cowley et al., 2001).
Figure 1. Leptin receptor pathway within the arcuate nucleus. (From Cowley et al., 2001)
Figure 2. Leptin receptor pathway to signal decrease food intake and increase metabolic rate (From Volkoff, 2012)
Leptin is secreted from the adipose tissues, travels to the brain where they binds to leptin receptor within the hypothalamus (acuate nucleus). POMC neurons are depolarized directly by binding of leptin and indirectly through
the inhibition (hyperpolarization) of NPY/GABA neurons (Cowley et al., 2001).
This decreases the release of GABA from the NPY/GABA terminals. GABA inhibits
POMC neurons, so the decrease in GABA released increases the expression/activation
of the POMC neurons to increase frequency of action potentials. POMC then
stimulates production of melanocyte-stimulating hormone (alpha MSH) with acts
on second order neurons via melanocortin receptor (MC) (Volkoff, 2012). This
then signals a decrease in food intake and increase in metabolic rate. NPY is
an orexigenic signaling molecule that has the opposite effect, increase food
intake.
Hyperleptinemia
Characterized by high
serum levels of leptin
Loss of leptin signaling causes sever obesity in humans. Although
a leptin deficiency will cause obesity this has not been found in many
individuals with excess body fat. Levels of leptin are higher in majority of obese
people, indicating problems with leptin receptors are the cause of the
interference in signaling pathway in the brain. Without pathway functioning
properly, brain cannot signal to the body to decrease food intake and increase
metabolic rate.
Hypoleptinemia
Characterized by low serum levels of leptin
Studies have showed that decreased levels of leptin have
delayed pubery and growth in individuals, both males and females. This has been
seen in elite gymnasts that have very low body fat mass (Weimann et al., 1999).
Individuals suffering from the disorder anorexia nervosa also have low
circulating leptin levels. Leptin has been shown to have a role in controlling
gonadotropin secretion (Kimura, 1997).
Low levels of leptin would therefore decrease fertility and sexual
maturation. Learning this allowed researches to discover an association between
hypoleptinemia and hypothalamic amenorrhea. This disorder has a
dysfunction of the hypothalamic pituitary peripheral endocrine axes (Chou et
al, 2011). This is caused by chronic energy deficiency due from stenuous
exercise and/or decrease in food intake. This leads in infertility (as
menstruation stops) and bone loss. Studies have showed that leptin replacement
resulted with recovery of menstrual cycle and correction of abnormities in
gonadal, thyroid, growth hormone and adrenal axes (Chou et al., 2011). It
however showed no changes in bone mineral density over the duration of the
study.
References:
Chou, S., Chamberland, J., Liu, X., Matarese, G., Gao, C.,
Stefanakis, R., Brinkoetter, M., Gong, H., Arampatzi, K., Mantzoros, C. (2011).
Proceedings of the National Academy of Sciences of the United States of
America. 108:16. 6585-6590.
Cowley, M., Smart, J., Rubinstein, M., Diano, S., Horvath,
T., Cone, R., Low, M. (2001). Leptin activates anorexigenic POMC neurons
through a neural network in the arcuate nucleus. Nature. 411. 480-484.
Kimura, W., Walczewska, A., Karanth, S., McCann, S. (1997).
Role of leptin in hypothalamic-pituitary function. Proceedings of the National
Academy of Sciences of the United States of America. 94:3.1023-1028.
Sitaramayya, Ari. (2010). Signal Transduction: Pathways,
Mechanisms, and Disease. Springer. Heidelberg, Germany. Page 143-144.
Volkoff, Helen. (2012). Biology 4550: Endocrinology.
Gastrointestinal hormones and energy homeostasis. Memorial University of
Newfoundland. Class Notes.
Weimann, E., Blum, W., Witzel, C, Schwidergall, S., Bohles,
H. (1999). Hypoleptinemia in female and male elite gymnasts. European Journal
of Clinical Investigation. 29:10. 853-860
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