Leptin Signalling And Metabolic Control Of Energy Biology Essay


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Neuroendocrine control of metabolism by the hypothalamus consists of two pathways able to stimulate the use of energy in the body Knutson, K.L. et al., 2007. The pathway involving leptin suppresses appetite as well as exerts control over energy consumption by stimulating other pathways (Knutson, K.L. et al., 2007). The second pathway utilizes Ghrelin, which is secreted from the stomach and imposes the actions of leptin by increasing hunger to increase adipose in the body (Knutson, K.L. et al., 2007). Changes to the regulation of the signalling pathways of leptin and ghrelin can results in altering the regulation of energy expenditure such metabolic changes have been observed due to sleep deprivation (Knutson, K.L. et al., 2007).

Leptin is released from the adipose tissue, in amounts proportional to the amount of adipose tissue present (Jequier, E., 2002). The mechanistic release of leptin depends on signals in adipose cells that respond to increases in fat by increasing leptin translation (Jequier, E., 2002). The regulation of leptin production is established in mice were it is seen to be dependent on adipose reception of fat storage, hypothalamic response to leptin levels and stimulation of pathways that either increase energy expenditure or increase energy storage (Jequier, E., 2002). However, in human's leptin release doesn't coincide with energy intake, instead follows a regular cycle were leptin levels peak during the night, and are lowest in the middle of the day (Jequier, E., 2002). Leptin release in humans is proportionals to adipose levels, but also responds to other hormones (Jequier, E., 2002) When released from the adipose, leptin is transported to the brain, where it is transported across the blood brain barrier via an isoform of the leptin receptor (LepRa) (Tartalglia, R.A., 1997).

Once in the brain, leptin binds to the long form leptin receptor isoform (LepRb) which contains an intracellular domain that allows for binding (Tartalglia, R.A., 1997). Binding of leptin to LepRb causes a conformational change and forms a homodimer of LepRb (Banks, A.S. et al., 2000). This conformational change allows Janus Kinase 2 (Jak2) to phosporylate exposed tyrosine residues on LepRb, which are located within the box 2 motif (Kloek, C. et al., 2002). The box 2 motif contains three tyrosine residues, however only tyrosine 985 and tyrosine 1138 are able to be phosphorylated by Jak2 due to their hydrophilic surroundings (Banks, A.S. et al., 2000). Phosphorylation of tyrosine 985 and tyrosine 1138 recruits other proteins that influence metabolic signalling (Kloek, C. et al., 2002).

Phosphorylation of tyrosine 1138 recruits STAT3 (signal transducer and activator of transcription 3) which is phosphorylated and then binds to STAT3 responsive elements on the POMC (proopiomelanocortin) promoter (Munzberg, H. et al., 2003). Posttranslational modifications to POMC cause cleavage into α-MSH (melanocyte stimulating hormone) (Zhang, Y. et al., 2009). α-MSH binds to the MSH receptor MC4R which increases cyclic-AMP intracellular levels (Zhang, Y. et al., 2009; Harris, M. et al., 2000). This recruits CRB (CREB binding protein) which initiates transcription of TRH (thyroid releasing hormone) leading to stimulatation of the thyroid to increase metabolism (Harris, M. et al., 2000). STAT3 activation also activates SOCS3 (suppressor of cytosine signalling 3 protein) and PI3 (phosphoinositide 3 kinase) (Villanueva, E.C. & Myers Jr., M.G., 2008). The activation of SOCS3 and PI3 also occurs in phosphorylation of tyrosine 985 which recruits SHP-2 (SH2 domain containing phosphatase) and through a series of phosphorylations activates ERK (extracellular signal regulated kinases) (Bjorbaek, C. et al., 2000; Banks, A.S. et al., 2000). SOCS3 activation creates a feedback mechanism which binds to Jak2 and prevents leptin signalling (Banks, A.S. et al., 2000). PI3 activation allows leptin to inhibit the antagonist actions of AgRP (agouti-like receptor protien) and NPY (neuropeptide Y) which prevent metabolic control by leptin and act to increase appetite (Villanueva, E.C. & Myers Jr., M.G., 2008; Morrison, C.D. et al., 2005).

Sleep deprivation causes alteration to the metabolic pathway mentioned above, in which lower leptin levels are observed during SD-REM sleep (sleep deprived rapid eye movement sleep) (Taheri, S. et al., 2004; Koban, M. et al., 2006). The lower levels of leptin are observed to alter the pathway by decreasing the expression of POMC which diminishes the stimulation of THR and down-regulates metabolism (Martins, P.J.F. et al., 2009; Koban, M. et al., 2006). As well, increased expression of NPY and AgRP is observed which increases appetite (Martins, P.J.F. et al., 2009). These changes to the metabolic pathway are potentially due to increased expression of glucagon from sleep deprivation, which is presented in order to provide energy to the brain, needed due to increased wakefulness (Schmid, S.D. et al., 2007). The increased time spent awake due to sleep deprivation also potentially influences increased calorie intake, which also is influenced by increased appetite due to decreased leptin as well as increased hunger by increased levels of ghrelin also consequential of sleep deprivation (Everson, C.A. & Crowley, W.R., 2004).

Together the influence of sleep deprivation on decreased levels of leptin is seen to decrease metabolism and increase appetite (Everson, C.A. & Crowley, W.R., 2004). These consequences, together with the increased expression of glucagon and ghrelin provide reasoning for observed increase in BMI and potentially a cause for obesity associated with sleep deprivation (Taheri, S. et al., 2004). Several studies find a correlation between weight gain and sleep deprivation, generally under 6 hours of sleep (Taheri, S. et al., 2004). The association between sleep deprivation provide a means to identify potential causes of obesity and understanding the mechanistic implications of altered metabolic signalling due to sleep deprivation is useful in identifying potential options to manage sleep deprived weight gain. Potentially a focus on hormone therapy with exposure to leptin to aid in increasing leptin levels back to their regular state, in order to induce regular metabolic function. However, this approach wouldn't induce weight loss likely needed in the case of obesity, but would aid in regulating the metabolic functions of leptin. Most importantly would be focus on meeting sleep requirements as to not disrupt the metabolic pathway of leptin to begin with, especially due to the interconnectedness of the pathways, in which disruption of one corresponds to changes in the others.

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