Allopregnanolone involvement in feeding regulation, overeating and obesity

Abstract

Obesity is strongly associated with ill health, primarily caused by consumption of excessive calories, and promoted (inter alia) by gamma-amino-butyric-acid (GABA) stimulating food intake by activating GABA receptors (primarily with α3 and α2 subunits) in the hypothalamic arcuate nucleus and paraventricular nucleus. Allopregnanolone is a potent positive GABA receptor modulating steroid (GAMS). As reviewed here, elevated allopregnanolone levels are associated with increases in food intake, preferences for energy-rich food, and obesity in humans and other mammals. In women with polycystic ovarian disease, high serum allopregnanolone concentrations are linked to uncontrolled eating, and perturbed sensitivity to allopregnanolone. Increases in weight during pregnancy also correlate with increases in allopregnanolone levels. Moreover, Prader-Willis syndrome is associated with massive overeating, absence of a GABA receptor (with compensatory >12-, >5- and >1.5-fold increases in α4, γ2, and α1, α3 subunits), and increases in the α4, βx, δ receptor subtype, which is highly sensitive to allopregnanolone. GABA and positive GABA-A receptor modulating steroids like allopregnanolone stimulates food intake and weight gain.

Astrocytes, emerging stars of energy homeostasis

“…Levels of allopregnanolone have been associated with changes in food intake and eating disorders in humans 82 96 . In rats, administration of allopregnanolone increased the feeding latency, as well as the meal duration and the preference for fat 97 98 . Although the specific mechanisms underlying the changes in feeding behavior have not been elucidated, neurosteroid’s best characterized molecular function is the modulation of GABA signaling at GABA A receptors 99 .…”

Activation of GABA(A) receptors inhibits T cell proliferation

“…To further explore the role of the GABA(A)R in T cell activation leading to proliferation we studied the effects of the neurosteroid allopregnanolone on human and murine T cells. Neurosteroids are implicated in various processes in the CNS [28][29][30]. It has been shown that allopregnanolone potentiates the actions of αβ-containing GABA(A)Rs at nanomolar concentrations and ρ-containing receptors at micromolar concentrations [31,32].…”

Neurosteroid Metabolites of Gonadal Steroid Hormones in Neuroprotection: Implications for Sex Differences in Neurodegenerative Disease

“…Because of their ability to modulate multiple signaling pathways, 3α-hydroxy, 5α-reduced neurosteroids have been shown to play important roles in physiological and pathophysiological regulation of stress, mood and feeding behavior (reviewed in Gunn et al, 2011 ; Mody and Maguire, 2012 ; Bäckström et al, 2014 ; Holmberg et al, 2018 ). In addition, and of particular interest for the focus of this review, 3α-hydroxy, 5α-reduced neurosteroids have been shown to have therapeutic potential for use in treatment of neurodegenerative and neurological diseases.…”