Leptin and oestrogen are both involved in the regulation of adipose tissue deposition and feeding behaviour. We investigated whether 5 years of hormone replacement therapy (HRT) affected serum leptin and body composition differently in 89 postmenopausal women treated with HRT compared with 178 controls. At baseline, leptin was significantly correlated with oestradiol (r=0.13, P<0.05) and in multiple backward regression analysis including oestradiol and any estimate of body fat, oestradiol remained a significant determinant of leptin levels. In the control group, all estimates of body fat determined by dual energy X-ray absorptiometry (DEXA) or anthropometry were increased (3.6-16.9%) and leptin increased 31.3% (16.03+/-1.02 to 20.84+/-1.2 ng/ml (s.e.m.), P<0.001). In the HRT group all estimates of body composition also increased during the 5-year observation but to a lesser extent than observed in the control group (1.0-8.5%). Leptin was raised by 19.7% (17.81+/-1.32 to 20.57+/-1.65 ng/ml, P<0.001). However, the DEXA scans revealed that the control group gained 2.4-fold more fat during the 5-year observation (1.9+/-0.3 vs 0.8+/-0.4 kg, P<0.05), and especially the trunk fat increased (1.4+/-0.2 vs 0.7+/-0.3 kg, P<0.05). This was reflected in the increase in leptin levels, which were increased by 7.4% in the control group compared with the HRT group (4.81+/-0.60 vs 2.76+/-0.87 ng/ml, P<0.05). Adjusting for the difference in adipose tissue revealed that HRT had no independent effect on leptin levels. Comparisons between obese (body mass index>25 kg/m(2)) and non-obese (<25 kg/m(2)) subjects by stratifying for HRT treatment using multiple linear regression revealed that the change in fat mass was significantly less among treated subjects (P=0.038) and especially in the non-obese subjects (P=0.001). The change in trunk fat was similarly correlated with treatment status (P=0.029) and with the degree of obesity (P=0.006). In conclusion, 5 years of HRT treatment significantly reduced fat mass accumulation, especially in the trunk region. This effect of HRT was more pronounced in non-obese as compared with obese subjects. The HRT-induced reduction in fat mass seems not to be mediated by leptin.

A number of neuropeptide Y (NPY) receptor subtypes, including the recently cloned Y5 receptor, have been implicated in the stimulation of food intake. In the present study, Y5 receptor antisense oligodeoxynucleotides (ODNs) were used to assess the potential involvement of the Y5 receptor in the regulation of spontaneous as well as NPY-induced food intake. Repeated central administration of Y5 antisense ODN significantly decreased spontaneous food intake and subsequently resulted in a significant weight loss. Furthermore, Y5 antisense ODN pre-treatment significantly inhibited the robust feeding response elicited by central administration of NPY (5.3+/-0. 8 vs 1.08+/-0.28 g, vehicle+/-s.e.m. vs Y5 ODN+/-s.e.m.). The present results provide evidence that central Y5 receptors are involved in both spontaneous as well as NPY-induced food intake, which may prove to be a new therapeutic route in the treatment of obesity and other disorders of appetite.

During the transition from pregnancy to lactation, dairy cows experience a 70% reduction in plasma IGF-I. This reduction has been attributed to decreased hepatic IGF-I production. IGF-I circulates predominantly in multi-protein complexes consisting of one molecule each of IGF-I, IGF binding protein-3 and the acid labile subunit (ALS). Recent studies in the mouse have shown that absence of ALS results in accelerated turnover and severely depressed concentration of plasma IGF-I. These observations suggest that reduced plasma ALS could be a second factor contributing to the fall of plasma IGF-I in peri-parturient cows. This possibility has not been studied due to the lack of bovine ALS reagents. To address this, we isolated the bovine ALS cDNA and used its sequence to develop a ribonuclease protection assay (RPA) and a bovine ALS antiserum. Using the RPA, ALS mRNA abundance was approximately fivefold higher in liver than in lung, small intestine, adipose tissue, kidney and heart, but was absent in muscle and brain. The antiserum detected the highest ALS levels in plasma followed by ovarian follicular fluid, lymph and colostrum. A portion of colostrum and follicular fluid ALS appears to be synthesized locally as ALS mRNA was found in mammary epithelial cells and ovarian follicular cells. Finally, we measured plasma ALS in dairy cows during the peri-parturient period (days −35 and +56 relative to parturition on day 0). Plasma ALS dropped by 50% between late pregnancy and the first day of lactation and returned to prepartum levels by day +56. To determine whether this reflected a change in hepatic expression, ALS mRNA was measured in liver biopsies collected on days −35, +3 and +56. ALS mRNA expression was significantly lower on day +3 than on day −35, but recovered completely by day +56. Finally, we examined the ability of GH to increase plasma ALS abundance at selected times before and after parturition (weeks −5, −2, +1 and +5). GH increased plasma ALS at weeks −5, −2 and +5, but not at week +1. Identical effects of GH were seen when the response considered was plasma IGF-I. We conclude that the decline in plasma ALS after parturition is a consequence of hepatic GH resistance and contributes to the associated reduction of plasma IGF-I.