Oleoyl-estrone treatment affects the ponderostat setting differently in lean and obese Zucker rats

Abstract

OBJECTIVE: To determine whether the slimming effects of treatment with oleoyl-estrone (OE) in liposomes of normal and obese rats are permanent, or disappear as soon as the treatment with the drug ceased. This study was devised to gain further knowledge on the postulated role of OE as a ponderostat signal, evaluating whether (in addition) it can lower the ponderostat setting of the rat. DESIGN: The rats were infused for 14 d (using osmotic minipumps) with oleoyl-estrone in liposomes at a dose of 3.5 m mmolakg Á Á d, and were studied up to one month after the treatment ceased. SUBJECTS: Young adult lean controls (CL) or treated (TL) and obese controls (CO) or treated (TO) Zucker rats. MEASUREMENTS: Energy balance, blood glucose, liver glycogen, plasma insulin, leptin corticosterone, ACTH and estrone (free and total) concentrations, and expression of the OB gene in white adipose tissue (WAT). RESULTS: The loss of body weight caused by OE was recovered quickly in the TO, which gained weight at the same rate as the CO. TL rats, however remained at the low weight attained for one month after the treatment ceased. However, no differences were observed in calculated energy expenditure (EE) between the TL and TC rats once treatment had stopped. In TL and TO rats, liver glycogen concentrations decreased to normal shortly after treatment ceased, and leptin expression and concentrations remained normal and unchanged after the end of OE treatment. In TO rats, plasma glucose, insulin and leptin were lower than in the CO. Total estrone concentrations decreased rapidly in TL rats and more slowly in the TO, and free estrone followed a similar pattern. CONCLUSION: Continuous infusion of liposomes loaded with OE resulted in a decreased energy intake (EI), maintenance of EE and the utilization of body fat reserves in lean and obese rats alike. This process ended in obese rats as soon as the infusion ceased, so that even when the levels of free and total estrone in plasma remained high, there was a marked (and relatively fast) shift toward the basal situation, which translated into an increase in EI, maintenance of estimated EE and a marked buildup of energy stores. In lean rats, the effects of OE on leptin concentrations and OB gene expression persisted after infusion ended.

Effect of oral oleoyl-estrone treatment on plasma lipoproteins and tissue lipase activities of Zucker lean and obese female rats

“…However, oleoyl-estrone decreases circulating plasma lipids, 16 especially cholesterol and phospholipids, also inducing small decreases in triacylglycerols and slight change in free fatty acids and ketone bodies. 6,16 On the other hand, the overall loss of fat and decreased energy intake clearly indicates that oleoyl-estrone-treated rats oxidize significant amounts of fat from their WAT stores; respiratory quotient measurements agree with this interpretation. 5,17 However, neither the site of this oxidation nor the mechanism of lipid transport are known.…”

“…19 Since their plasma levels are unaltered, we can assume that the liver takes them up at sustained high rates, and either oxidizes them or converts them to ketone bodies, or incorporates them into VLDL triacylglycerols. The lack of increase in circulating ketone bodies, together with maintained glycaemia, liver glycogen and liver lipids under oleoyl-estrone treatment 6,16 further suggest that most of the WAT-derived fatty acids find their way into VLDLs. This prompted us to analyse the proportions and chemical composition of circulating lipoproteins.…”

“…2 -4 Oleoyl-estrone has been postulated as a lipostat signal 5,6 since its levels are highly correlated with body fat stores in normal-weight humans 7 and its administration to experimental animals modifies the body weight reference setting. 6 Oleoyl-estrone elicits a loss of fat, while body protein is preserved. 8 This is accomplished by decreasing appetite but maintaining energy expenditure.…”

Short-term oral oleoyl-estrone treatment increases plasma cholesterol turnover in the rat

“…This modulation of insulin sensitivity, which resulted in maintained glycaemia and decreased insulinaemia, was thus an early effect attributable to oral OE treatment. It is well known that OE decreases insulin resistance, 5,6 but no short-term effects on this parameter were described previously.…”

“…4 Chronic oleoyl-estrone treatment also induces a decrease in insulin levels and insulin resistance, with maintenance of plasma glucose and liver glycogen. 5,6 The imbalance between maintained energy expenditure and decreased energy intake induced by oleoyl-estrone treatment is maintained at the expense of lipid stores; 2 the massive mobilisation of adipose tissue lipid, and its oxidation, 1,7 spares glucose and protein, 4 increasing the transport of lipids by the blood.…”