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- Holmberg, Ellinor, 1975-
(författare)
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Allopregnanolone effects on food intake and weight gain
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Obesity is currently one of the major causes of ill health and it is clear that overeatingis the cause of obesity. However, the actions of many endogenous factors that contribute to overeating are still not well understood. Gamma-aminobutyric acid (GABA)-ergic transmission has been shown to be of great importance for food intake regulation. The progesterone metabolite allopregnanolone is a potent positive GABAA receptor modulating steroid (GAMS) and in humans, elevated allopregnanolone levels have been suggested to be involved in increased food intake, and also with overweight and obesity. GABAA receptors that express the α2 and α3 subunits are proposed to be the main subtypes involved in food intake regulation. Therefore, the aims of the work in this thesis were to further investigate the effect of allopregnanolone on food intake, feeding behaviour, possible effects on weight gain and also to characterize a possible antagonist at α2β3γ2and α3β3γ2 GABAA receptors.Methods Allopregnanolone effects on food intake of different food items were recorded in male Wistar rats. Feeding patterns were analyzed. Food preference tests were also conducted and rats were repeatedly exposed to allopregnanolone under different feeding conditions to elucidate possible effects on body weight gain. To deeper investigate GABAA receptor subtypes suggested to be involved in food intake regulation, electrophysiological whole-cell patch-clamp recordings were performed to identify the specificity of the GAMS antagonist UC1020, at human α2β3γ2 and α3β3γ2 GABAA receptors expressed in HEK293-cells.Results Allopregnanolone increased the intake of standard chow, cookies and a high fat diet in male Wistar rats. Preferentially, allopregnanolone increased the rats´intake of the more calorie dense food type. Allopregnanolone reduced feeding latency and prolonged feeding duration. The increased chow intake induced by allopregnanolone was more pronounced at the beginning of the rats´ active period compared to the inactive. Repeated allopregnanolone administration during 5 consecutive days led to an increased body weight gain, more evident in schedule fed rats on a high fat diet. Both obesity prone and obesity resistant rats gained significantly more weight with repeated allopregnanolone exposure and the increased body weight gain correlated with increased food intake. The compound UC1020 was a potent antagonist of GAMS-enhanced GABA evoked currents at human α3β3γ2 GABAA receptors, whereas it had no effect at α2β3γ2 GABAA receptors.Conclusions Our findings indicate that allopregnanolone induced hyperphagia may be one of the endogenous factors involved in weight gain, especially when the diet is energy-rich. The compound UC1020 may prove useful for investigating the involvement of the α2 and α3 GABAA receptor subtypes in GAMS-induced hyperphagia.
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| 2. |
- Holmberg, Ellinor, 1975-, et al.
(författare)
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Repeated allopregnanolone exposure induces weight gain in schedule fed rats on high fat diet
- 2015
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Ingår i: Physiology and Behavior. - : Elsevier. - 0031-9384 .- 1873-507X. ; 140, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- Ingestion of energy rich high fat diets is one of the determining factors associated with the obesity epidemic. Therefore, much can be learned from studies of obesity-related substances given to animals fed a high fat diet.The progesterone metabolite allopregnanolone is a potent positive modulator of the gamma-aminobutyric acid(GABA)A-receptor, and both allopregnanolone and GABA have been implicated in evoking hyperphagia. In this study, food intake and body weight gain were investigated during repeated allopregnanolone exposure. Male Wistar rats were studied when fed chow ad libitum, with chow access for 4h per day or with 45% high fat pellets for 4 h per day. Rats on the high fat diet were separated into obesity prone and obesity resistant individuals.Subcutaneous injections of allopregnanolone were given once daily overfive consecutive days. Repeated exposure to allopregnanolone lead to increased weight gain, significantly so in schedule fed rats on a high fat diet. The increased weight gain was correlated to an increased energy intake. Both obesity resistant and obesityprone rats responded to allopregnanolone with increased weight gain. Obesity resistant rats treated with allopregnanolone increased their energy intake and ate as much as vehicle treated obesity prone rats. Their weight gain was also increased to the level of obesity prone rats injected with just the vehicle carrier oil. Thus, it appears that allopregnanolone may be one of the endogenous factors involved in weight gain, especiallywhen the diet is rich in fat.
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