Abstract

Obesity is strongly associated with ill health and obesity is mainly influenced by energy intake and energy expenditure via mechanisms based on needs of energy and reward. The hypothalamus plays a major role in feeding control, particularly the arcuate nucleus (ARC) and paraventricular nucleus, (PVN). It is known that appetite stimulation depends on activity in the gamma-butyric acid (GABA) system e.g. the GABA projection is required for ghrelin to stimulate food-take. We know that GABA activation enhances hunger and decreases satiation.
Several positive allosteric GABA modulators stimulate food intake by activating GABAA receptors (primarily with α3 and α2 subunits) in the hypothalamic ARC and PVN. Endogenous positive GABA-A-receptor modulating sex and stress steroids like the progesterone metabolite allopregnanolone (Allo) induce hyperphagia. In animal models, Allo increases food intake, preferences for energy-rich food, and weight increase. In obese humans Allo levels are high and in women with polycystic ovarian disease high levels are linked to uncontrolled eating and weight increases. Allo concentration increases during pregnancy and the degree of concentration increase correlates to the excess weight increase. Treatment with a GABA-A receptor modulating steroid antagonist (GAMSA) with alpha 3 receptor subtype antagonism reduces dose-dependently Allo-induced appetite increase in animal models. Women with premenstrual dysphoric disorder show increased appetite during the luteal phase when Allo is high. A double-blind randomized clinical trial shows significant appetite reduction with GAMSA treatment compared to placebo. However, regulating food intake also occurs through mechanisms involving rewarding, emotional, and cognitive drivers rather than hunger alone. The GABA-ergic system is involved in the reward system influencing the activity of dopamine neurons. Thus, Allo indirectly influences dopamine-induced food intake.
Take home message:

Food intake, weight gain, and allopregnanolone status are related in humans.
GABA and GABAA receptors are involved in the regulation of food intake.
Endogenous positive GABAA receptor-modulating steroids stimulate food intake.
Allopregnanolone induces weight gain by increasing food intake and preference for energy-rich food.