Alterations in neuronal control of body weight and anxiety behavior by glutathione peroxidase 4 deficiency

Abstract

Elevated levels of oxidative stress and neuronal inflammation in the hypothalamus or ventral midbrain, respectively, represent common denominators for obesity and Parkinson's Disease (PD). However, little is known about defense mechanisms that protect neurons in these regions from oxidative damage. Here, we aimed to assess whether murine Gpx4, a crucial antioxidant enzyme that protects neurons from membrane damage and ferroptosis, is critical for the protection from neuronal inflammation in two distinct pathophysiologic diseases, namely metabolic dysfunction in diet-induced obesity or PD. Gpx4 was deleted from either AgRP or POMC neurons in the hypothalamus, essential for metabolic homeostasis, or from dopaminergic neurons in the ventral midbrain, governing behaviors such as anxiety or voluntary movement. To induce a pro-inflammatory environment, AgRP and POMC neuron-specific Gpx4 knockout mice were subjected to high-fat high-sucrose (HFHS) diet. To exacerbate oxidative stress in dopaminergic neurons of the ventral midbrain, we systemically co-deleted the PD-related gene DJ-1. Gpx4 was dispensable for the maintenance of cellular health and function of POMC neurons, even in mice exposed to obesogenic conditions. In contrast, HFHS-fed mice with Gpx4 deletion from AgRP neurons displayed increased body adiposity. Gpx4 expression and activity were diminished in the hypothalamus of HFHS-fed mice compared to standard diet-fed controls. Gpx4 deletion from dopaminergic neurons induced anxiety behavior, and diminished spontaneous locomotor activity when DJ-1 was co-deleted. Overall, these data suggest a physiological role for Gpx4 in balancing metabolic control signals and inflammation in AgRP but not POMC neurons. Moreover, Gpx4 appears to constitute an important rheostat against neuronal dysfunction and PD-like symptoms in dopaminergic circuitry within the ventral midbrain.

Selenium and Selenoproteins in Adipose Tissue Physiology and Obesity

“…Another selenoprotein, GPX4, was also shown to be involved in hypothalamic energy metabolism control. Knockout of GPX4 in Agrp, but not POMC neurons resulted in increased weight gain and adipose tissue mass [248].…”

Regulation of lipid peroxidation and ferroptosis in diverse species

“…However, not all neuronal subpopulations are equally sensitive to Gpx4 loss. The selective disruption of Gpx4 in POMC (proopiomelanocortin) neurons or AgRP (agouti-related protein) neurons of the hypothalamus or dopaminergic neurons of the ventral midbrain did not impact the viability of these specialized neurons (Schriever et al 2017). This may be due to different redox systems compensating for GPX4 loss; different metabolic constraints, including vitamin E and ubiquinone utilization; different phospholipid metabolism; or different expression of lipid-modulating enzymes, such as ACSL4 or LPCAT3.…”

Ferroptosis and necroinflammation, a yet poorly explored link

“…GPX4 plays a crucial role in protecting neuronal populations in hippocampus, cortex, cerebellum and motor neurons [20,[35][36][37][38]. This protection appears to be neuronal subtype specific, as proopiomelanocortinergic and dopaminergic neurons are resistant to GPX4 depletion and ferroptosis induction [39]. Moreover, GPX4 has been shown to be essential for photoreceptor cells, endothelial cells, CD8 positive T-cells, kidney tubular cells and hepatocytes [15,[40][41][42][43].…”