e11534 Background: Weight gain in women receiving chemotherapy following breast cancer diagnosis has negative implications on quality of life and those who gain weight during treatment appear to be at higher risk of disease recurrence. The mechanism(s) implicated in chemotherapy associated weight gain are poorly understood. Methods: To investigate this further, we assessed the metabolic, cytokine and appetite related peptide alterations before and during adjuvant FEC chemotherapy for early breast cancer in post-menopausal women, and correlated these with body mass measurements. Specifically, we performed global metabolic profiling (metabonomics/ metabolomics) using 1H nuclear magnetic resonance spectroscopy of sequential sera, examined ghrelin immunoreactivity, performed radioimmunoassays for glucagon like peptide-1 (GLP-1) and peptide YY (PYY) and electro-chemiluminescent cytokine analyses (tumor necrosis factor-α and interleukin-6; TNF-α, IL-6) on the sequential samples. Results: In those who gained ≥ 1.5kg (on average ∼5% of initial body weight), several metabolite levels were positively associated with weight change, in particular lactate which was 55% greater in patients with increased body weight during chemotherapy compared to those with stable weight during chemotherapy (p<0.01; the pre-specified primary end-point). A significant inverse relationship was also observed between levels of TNF-α and weight change group (ρ 0.476, p<0.05). Baseline lactate, alanine and body fat were all prognostic for weight gain (ROC AUC >0.77, p<0.05). No significant associations were observed between any other parameter and weight gain, nor any parameter and tumor burden, including cytokine and appetite peptide alterations. Conclusions: Metabonomics identifies pathways perturbed during early chemotherapy for breast cancer, and establishes a positive association between serum lactate, body fat, TNF-α and substantive weight changes during chemotherapy. Interventions that target these processes may be clinically useful in breast cancer. No significant financial relationships to disclose.

The balance between energy (food) intake and energy expenditure is closely regulated to keep body weight stable over time. Increasingly, however, the homeostatic mechanisms responsible are failing to keep pace with societal changes in eating behaviour and activity levels. The prevalence of obesity in many parts of the world has now reached epidemic proportions. It is estimated that it causes 30,000 deaths per year in the UK, and in the USA it is set to overtake smoking as the leading cause of preventable illness and premature death [1, 2]. Current strategies for the non-surgical treatment of the morbidly obese have met with limited success [3–5] and without the development of more effective treatments, the socioeconomic and public health implications of an unchecked rise in obesity are grave.

The worsening global obesity epidemic, particularly the increase in childhood obesity, has prompted research into the mechanisms of appetite regulation. Complex pathways modulate energy balance, involving appetite centres in the hypothalamus and brain stem, and hormonal signals of energy status released by the gut and by the periphery. Better understanding of appetite regulation improves understanding of the aetiology of obesity. Manipulation of this homoeostatic system offers potentially useful treatments for obesity.

This study was designed to see if endogenous opioids suppressed luteinising hormone (LH) secretion in the absence of ovarian steroids and if they mediated negative feedback suppression of LH secretion by progesterone in the ewe. Twelve ovariectomised ewes received each of four treatments at 1 day intervals: (1) intravenous saline infusion, (2) naloxone infusion (0.5 mg kg−1 h−1), (3) progesterone infusion (42 μg kg−1 h−1), (4) naloxone and progesterone infusion for 12 h. Progesterone (5.07±0.27 ng ml−1) decreased LH pulse frequency and mean and basal serum concentration of LH. Naloxone increased mean and basal serum concentrations of LH. The administration of progesterone and naloxone together resulted in LH pulse frequency (1.62±0.07 pulses h−1) and mean (1.89±0.13 ng ml−1) and basal serum concentrations (1.33±0.11 ng ml−1) of LH that were similar to the control ewes (1.80±0.06 pulses h−1, 2.26±0.28 ng ml−1, 1.67±0.20 ng ml−1, respectively) but lower than in ewes receiving naloxone alone (1.94±0.04 pulses h−1, 3.00±0.37 ng ml−1, 2.09±0.22 ng ml−1, respectively). The combined treatment also resulted in LH pulse frequency (1.62±0.07 pulses h−1) that was greater than in ewes only receiving progesterone (1.39±0.09 pulses h−1). We concluded that there are steroid-independent effects of opioids on LH secretion in long-term ovariectomised ewes, that opioids probably do not entirely mediate the negative feedback effects of progesterone on LH secretion and that opioids largely affect LH secretion at the hypothalamus but pituitary effects cannot be ruled out.