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Title: Studies on the expression and secretion of the neurotrophin nerve growth factor in white adipose tissue
Author: Peeraully, Muhammad Riyad
ISNI:       0000 0001 3482 2262
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2005
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White adipose tissue (WAT) is now recognised to be a complex endocrine organ which plays a key role in energy balance through the secretion of hormones and other protein factors (adipokines). The sympathetic nervous system (SNS) plays a central role in lipolysis and leptin production in WAT. The work in this thesis examined whether WAT, and specifically white adipocytes, are a source of the neurotrophin nerve growth factor (NGF), a key signal in the development and survival of the SNS, and an immune and inflammatory mediator. NGF gene expression was detected in each of the major white adipose tissue depots of mice, rats and humans, with mature adipocytes themselves found to express the NGF gene. Obesity was not found to have a clear link with NGF gene expression in WAT, as investigations using three different models of rodent obesity (diet-induced obese mice and rats, and fa/fa rats) failed to establish a consistent relationship between the two. However, comparisons of ob/ob mice versus their lean counterparts indicate that NGF gene expression is higher in the depots of the obese, as did a comparison using a small number of human subjects. Circulating NGF levels were found to be elevated in ob/ob mice. Sympathetic activity does not appear to be a major regulator of NGF gene expression in WAT in vivo, as cold acclimation and fasting had little effect on NGF mRNA levels in the tissue. White adipocytes in vitro were found to synthesise and release NGF, which can therefore be termed an adipokine. Sympathetic neurotransmitters do not appear to be major regulators of NGF synthesis by 3T3-L1 adipocytes, in concordance with the findings of the in vivo cold acclimation and fasting studies. The pro-inflammatory cytokine TNFα, however, strongly stimulates NGF production in these cells, suggesting that NGF may be associated with the inflammatory response of adipocytes. This is supported by the substantial inhibitory effects on NGF synthesis of dexamethasone and rosiglitazone, agents with recognised anti-inflammatory effects. Although it was not possible to identify the precise mechanism by which TNFα up-regulates NGF production, it would not appear to be through induction of NFκB activity, and does not seem to be mediated by interleukins or prostaglandins. Small inhibitory effects on NGF expression and secretion were induced by IL-1β, IL-10, IL-18 and PGI₂, with adiponectin, IL-6 and PGF₂α reducing NGF synthesis by a greater extent. A substantial stimulation of NGF production occurred in response to PGD₂ and the J-series prostaglandins PGJ₂ and Δ¹²-PGJ₂, although an inhibitory effect was seen with 15d-PGJ₂ which may well relate to its properties as a PPARγ agonist. Expression of the two PGD₂ receptors, DP and CRTH2, was demonstrated at the mRNA level in 3T3-L1 cells, with DP appearing to mediate the stimulatory effect of PGD₂ on NGF production. Both NGF receptors appear to be expressed in mouse WAT, as the mRNA was detected for p75 and trkA. Evidence was also found that the receptor proteins may be present within adipose tissue. In conclusion, these studies indicate that the neurotrophin NGF is expressed in WAT and that white adipocytes secrete NGF, synthesis of this adipokine being influenced by several factors, with the pro-inflammatory agents TNFα, PGD₂, PGJ₂ and Δ¹²-PGJ₂ having major stimulatory effects. They also suggest that in WAT, the SNS does not play a major role in the regulation of NGF expression. Strong evidence has been provided that NGF is a key adipokine which may be linked to the inflammatory responses of WAT.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral