Oleoyl‐Estrone

Abstract

Oleoyl-estrone (OE) is a powerful slimming agent that is also present in plasma and adipose tissue, where it is synthesized. It acts through the formation of a derivative W. OE effects (and W levels) are proportional to the dose. OE reduces food intake but maintains energy expenditure (thermogenesis). The energy gap is fulfilled with adipose tissue fat, sparing body protein and maintaining glycemia (and glycogen) with lower insulin and leptin levels. OE (in fact W) acts through specific receptors, different from those of estrogen. OE increases cholesterol catabolism, reducing hypercholesterolemia in obese rats. The main metabolic effect on adipose tissue is lowering of lipid synthesis, maintaining unchanged the intracellular lipolytic processes; the imbalance favors the progressive loss of fat, which is largely used by the muscle. OE administration induces additive effects with other antiobesity agents, such as β(3)-adrenergic agonists, forcing a massive loss of lipid. Corticosteroids markedly limit OE action by altering the liver control of lipogenesis. OE also inhibits the action of 17β-hydroxysteroid dehydrogenase, decreasing the synthesis of β-estradiol and testosterone. Discontinuous treatment allows for maximal efficacy both in rats and humans. OE has the advantage that the loss of fat is maintained and does not require additional dietary limitations.

Dietary Energy Partition: The Central Role of Glucose

“…Testosterone pairs with insulin as a main anabolic hormone [ 240 ], but glucocorticoids tend to limit testosterone production and availability [ 241 ], also affecting the availability of estrogen [ 242 ], which plays a critical function favoring the oxidation of 2C (i.e., saving 3C) in females [ 243 ] via direct intervention in mitochondrial function [ 244 , 245 ], and also preventing liver steatosis [ 246 ]. An estrogen-derivative has been found to down-modulate the adjustment of the ponderostat, i.e., the oxidation/mobilization of lipids from adipose tissue [ 247 , 248 ], by decreasing food intake and maintaining thermogenesis [ 249 ]. Unfortunately, there is insufficient mechanistic information on the effect of estrogen derivatives because only recently these hormones are considered important metabolic regulators [ 250 , 251 ] and act not only in the sex-related way indicated by its etymology.…”

Estrogens and the regulation of glucose metabolism

“…The oral pharmacological administration of oleoyl-E1 to normal weight and obese rats[ 166 , 167 ], induces a marked decrease in fat depots[ 168 ], not dependent on the degree of obesity and diet[ 167 , 169 ]. The loss of fat runs parallel to the normalization of glycemia, blood lipids and other metabolic syndrome (MS) markers[ 170 ], without apparent effects of estrogenization, and irrespective of energy intake manipulation[ 171 ]. AE1 has been proposed as a ponderostat signal[ 170 ], since the excess fat is shed without accompanying metabolic disorders[ 170 , 172 ].…”

“…The loss of fat runs parallel to the normalization of glycemia, blood lipids and other metabolic syndrome (MS) markers[ 170 ], without apparent effects of estrogenization, and irrespective of energy intake manipulation[ 171 ]. AE1 has been proposed as a ponderostat signal[ 170 ], since the excess fat is shed without accompanying metabolic disorders[ 170 , 172 ]. Its negative effects on humans are negligible (clinical studies, phase I, unpublished data), and the positive ( i.e.…”

“…There are sufficient elements to sustain the implication of AE1 in the regulation of body weight[ 170 ], but the lack of further complete studies on its mechanism of action has prevented both its clarification and its eventual therapeutic application. No other explanation has been put forward to justify the limited estrogenic potency of E1, despite its massive synthesis in the ovary and the brain[ 186 ], and, especially (in quantitative terms) in WAT[ 187 ], with a direct relationship of its total body content and circulating levels with WAT, lowered by obesity in rodents and humans[ 47 ].…”

“…Obviously there are problems to solve, but it seems that this line of study has not been sufficiently developed for reasons not based on contrasted arguments. In the case of AE1, a line of research developed by only one research group, obtained better results than those of any previous anti-obesity drug[ 170 , 179 ], but the development was discontinued largely for fear of “possible” future negative findings[ 179 ].…”