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N Hoggard, D V Rayner, S L Johnston, and J R Speakman

The melanocortin system coordinates the maintenance of energy balance via the regulation of both food intake and energy expenditure. Leptin, a key adipogenic hormone involved in the regulation of energy balance is thought to act by stimulating production, in the hypothalamic arcuate nucleus, of α-melanocyte stimulating hormone (αMSH), a potent agonist of MC3/4 melanocortin receptors located in the paraventricular nucleus of the hypothalamus. Additionally leptin inhibits release of agouti-related protein (AgRP), an MC4R antagonist. During periods of caloric restriction, weight loss is not sustained because compensatory mechanisms, such as reduced resting metabolic rate (RMR) are brought into play. Understanding how these compensatory systems operate may provide valuable targets for pharmaceutical therapies to support traditional dieting approaches. As circulating leptin is reduced during caloric restriction, it may mediate some of the observed compensatory responses.

In addition to decreases in circulating leptin levels, circulating AgRP is increased during fasting in rodents while αMSH is decreased. As central administration of AgRP depresses metabolism, we hypothesised that the peripheral rise in AgRP might be involved in signalling the depression of RMR during food restriction. We hypothesised that changes in plasma AgRP and αMSH may coordinate the regulation of changes in energy expenditure acting through central MC4 melanocortin receptors via the sympathetic nervous system.

We show here that acute peripherally administered AgRP at supra-physiological concentrations in both lean (C57BL/6) and obese leptin-deficient (ob/ob) mice does not depress RMR, possibly because it crosses the blood–brain barrier very slowly compared with other metabolites. However, in vitro AgRP can decrease leptin secretion, by approximately 40%, from adipocytes into culture medium and may via this axis have an effect on energy metabolism during prolonged caloric restriction. In contrast, peripheral [Nle4,d-Phe7]-α MSH produced a large and sustained increase in resting energy expenditure (0.15 ml O2/min; P <0.05) with a similar response in leptin-deficient ob/ob mice (0.27 ml O2/min) indicating that this effect is independent of the status of leptin production in the periphery. In both cases respiratory exchange ratio and the levels of energy expended on spontaneous physical activity were unaffected by the administration of peripheral [Nle4,d-Phe7]-α MSH. In conclusion, αMSH analogues that cross the blood–brain barrier may significantly augment dietary restriction strategies by sustaining elevated RMR.

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A A I Daffada, S R D Johnston, J Nicholls, and M Dowsett


Using reverse transcription (RT)/PCR we have shown that four breast cancer cell lines expressed oestrogen receptor (ER) mRNA, irrespective of whether they were assessed as ER-positive (MCF-7 and BT-474) or ER-negative (MDA-MB-231 and BT-20) by enzyme immunoassay (EIA). In addition to the wild type (WT) form, they were all found to express the exon 5-deleted variant (V) form of ER mRNA by RT/PCR; this is thought to code for a truncated constitutively active protein. By Northern blot analysis only the ER-positive cell lines (MCF-7 and BT-474) were found to express detectable levels of ER mRNA. Oestradiol-induced growth was found only in the ER-positive (by EIA) cell lines. These results confirm that the differences between ER-positive and ER-negative cell lines are quantitative rather than qualitative. As low levels of ER mRNA could be detected by RT/PCR, this may reflect the greater sensitivity of this approach. The presence of exon 5-deleted V form ER mRNA in addition to the WT form in all four breast cancer cell lines may allow these lines to be used to assess differential regulation of transcription and the impact of this on their oestrogen dependence.