Available online 26 March 2023, 101713

Under conditions of chronic or acute hypothalamic brain leptin signaling deficiency, such as in obese ob/ob mice or short-term food-deprived mice respectively, OX-A neurons become hyperactive and promote hyperarousal and food seeking also by upregulating hypothalamic endocannabinoid 2-AG biosynthesis.

OX-A-induced enhancement of 2-AG levels leads to the production of the 2-AG-derived 2-arachidonoyl-sn-glycerol-3-phosphate (2-AGP), a bioactive lysophosphatidic acid (LPA).

Overproduction of 2-AGP occurs in the hypothalamus of leptin signaling deficient mice and it promotes food intake by reducing α-MSH-expressing synaptic inputs to OX-A neurons via lysophosphatidic acid type-1 receptor (LPA1-R) activation, and pT231-Tau accumulation in α-MSH projections via the pTyr216-GSK3β pathway.

A strong correlation is found between OX-A and 2-AGP levels in the serum of human subjects and obese mice.

Orexin-A (OX-A) is a neuropeptide produced selectively by neurons of the lateral hypothalamus. It exerts powerful control over brain function and physiology by regulating energy homeostasis and complex behaviors linked to arousal. Under conditions of chronic or acute brain leptin signaling deficiency, such as in obesity or short-term food deprivation, respectively, OX-A neurons become hyperactive and promote hyperarousal and food seeking. However, this leptin-dependent mechanism is still mostly unexplored. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) is known to be implicated in food consumption by promoting hyperphagia and obesity, and we and others demonstrated that OX-A is a strong inducer of 2-AG biosynthesis. Here, we investigated the hypothesis that, under acute (6h fasting in wt mice) or chronic (in ob/ob mice) hypothalamic leptin signaling reduction, OX-A-induced enhancement of 2-AG levels leads to the production of the 2-AG-derived 2-arachidonoyl-sn-glycerol-3-phosphate (2-AGP), a bioactive lipid belonging to the class of lysophosphatidic acids (LPAs), which then regulates hypothalamic synaptic plasticity by disassembling α-MSH anorexigenic inputs via GSK-3β-mediated Tau phosphorylation, ultimately affecting food intake.

We combined cell-type-specific morphological (CLEM and confocal microscopy), biochemical, pharmacological, and electrophysiological techniques to dissect the leptin- and OX-A/2-AGP-mediated molecular pathways regulating GSK-3β-controlled pT231-Tau production at POMC neurons of obese ob/ob and wild-type (wt) lean littermate mice and in in vitro model of POMC neurons such as mHypoN41 neurons (N41).

2-AGP is overproduced in the hypothalamus of obese leptin-deficient, or lean 6h food-deprived mice and promotes food intake by reducing α-MSH-expressing synaptic inputs to OX-A neurons via lysophosphatidic acid type-1 receptor (LPA1-R) activation, and pT231-Tau accumulation in α-MSH projections. This effect is due to the activation of the Pyk2-mediated pTyr216-GSK3β pathway and contributes to further elevating OX-A release in obesity. Accordingly, we found a strong correlation between OX-A and 2-AGP levels in the serum of obese mice and of human subjects.

Hypothalamic feeding pathways are endowed with 2-AGP-mediated synaptic plasticity according to their inherent functional activities and the necessity to adapt to changes in the nutritional status. These findings reveal a new molecular pathway involved in energy homeostasis regulation, which could be targeted to treat obesity and related disturbances.

Leptin deficiency caused by obesity provokes an increment OX-A levels in arcuate nucleus with an enhancement of 2-AG levels and its interconversion in 2-AGP in POMC neurons. This novel endocannabinoid-derived lysophospatidic acid will increase the Tau phosphorylation cascade via its receptor LPA-1R. This effect is prevented by leptin or specific antagonist of both receptors implicated in this dysregulation.[Download : Download high-res image (166KB)Download : Download full-size image]

Hypothalamus

obesity

α-MSH

orexin/hypocretin

2-arachidonoyl-glycerol

2-AG

© 2023 Published by Elsevier GmbH.