Ab Aziz, Muhamad Faris
(2018)
Effects of metabolic modifiers on lipogenic and lipolytic gene expressions in sheep.
PhD thesis, University of Nottingham.
Abstract
The metabolic modifiers, which include growth hormone, beta-adrenergic agonists, and anabolic steroids, modify animal metabolism and affect the mechanism of nutrient absorption. This experiment aimed to investigate the effect of a beta-adrenergic agonist (BA) and growth hormone (GH) in sheep on processes involved in regulating lipid metabolism, in the tissues principally responsible for nutrient energy metabolism; adipose tissue (subcutaneous adipose tissue), skeletal muscles (longissimus dorsi (LD) and supraspinatus (SS)) and liver. In addition, the study sought to determine whether a transdifferentiated-myogenic cell culture system demonstrating myogenic and adipogenic characteristics would respond to these agents in a similar manner as in vivo.
Male lambs (120 days old) given ad-libitum feed were exposed for 6 days to bovine GH (bGH, 3.75mg/kg body weight, POSILAC, Monsanto) (n=10), the BA cimaterol (at 10mg/kg in the feed) (n=10) or a control C group (n=11). BA treatment significantly induced muscle hypertrophy, whilst GH increased liver weight without any significant effect on muscle weights. The increase in plasma IGF-1 in GH-treated lambs suggested that the GH effect was mediated by the IGF-1. There was no effect of both treatments on fatty acid profile in the SS muscle, whilst in subcutaneous adipose tissue, BA tended to increase the unsaturated fatty acids proportion (P = 0.058). The metabolomics analysis suggested the strong effect of GH on significantly elevating plasma NEFAs and glycerol concentrations (P<0.05). This was associated with significantly higher plasma concentration of the ketone body 3-hydroxybutyrate (P<0.05) and glucose (P<0.001). These changes were accompanied by reduced plasma glucogenic non-essential amino acid concentrations. Given the lack of increase in muscle mass, these have might contribute to the increase in plasma glucose level, in GH-treated lambs, in addition to the lipolytic effect of GH. This would suggest GH induced an insulin resistance. Similar effects were not observed in BA-treated sheep. In addition, in GH- and BA-treated lambs the reduction of muscle fatty acid synthase (FAS) mRNA (P<0.01) indicated a lowered lipogenic potential implicating the effect of both agents in developing leaner muscle. Although, this effect was more pronounced in GH treated muscles with both acetyl CoA carboxylase (ACC) and FAS mRNA being reduced in subcutaneous adipose tissue.
The cell culture experiment was carried out using transdifferentiated-myogenic C2C12 cell lines. Expression of genes with associated with myogenesis and adipogenesis were induced, and fat droplets were observed. This suggested the presence of both myotubes and adipocytes in co-culture and thereby the establishment of a cell culture system analogous in vivo where the muscle has an intramuscular fat deposition. Upon the treatment with dibutyryl cyclic adenosine monophosphate (dbcAMP) and Des (1-3) insulin-like growth factor-1 (Des (1-3) IGF-1, there was a strong stimulatory effect of dbcAMP in regulating genes associated with myogenesis (P<0.05), which might contribute to the hypertrophic effect, whilst lipogenic gene expression was reduced (P<0.05). This indicated that this cell culture system exhibited the similar characteristics as had been observed in vivo in the sheep trial. Des (1-3) IGF-1 appeared to induce adipogenesis, while not affecting lipogenesis or lipolysis, suggesting different pathways of IGF-1 induction between in vivo or in vitro.
In conclusion, the BA strongly affects the muscle development and hypertrophy, whilst GH affects the lipid mobilisation and deposition. However, both agents were demonstrated to potentially affect metabolism which would impact of the production of lean muscle.
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