1536-P: DEP-1 Is a Novel Modulator of Brain Energy Metabolism

Obesity's metabolic impact goes beyond peripheral insulin resistance, influencing the brain and thereby disrupting energy homeostasis by altering anabolic and catabolic reactions. Density-enhanced phosphatase-1 (DEP-1), a ubiquitously expressed receptor-like tyrosine phosphatase, has emerged as a novel regulator with a specific role in dephosphorylating the insulin receptor (IR). Strikingly, diet-induced obese mice exhibit elevated DEP-1 expression in metabolically sensitive tissues. In this study, we sought to elucidate the role of DEP-1 in brain insulin signaling and highlight its potential impact on the central regulation of metabolism in vitro and in vivo.

To explore DEP-1 deficiency in vitro, CRISPR/Cas9 was employed to create a DEP-1 knockout (KO) in mouse Neuro-2a cells. Given DEP-1’s high expression in the forebrain and the region's abundant IR expression, we examined the metabolic consequences of DEP-1 deficiency in the forebrain by deleting Dep-1 using CamKIIa Cre mice (DEFO KO).

DEP-1 KO cells exhibited an increase in IR phosphorylation and downstream signaling upon acute insulin stimulation, coupled with unexpected activation of AMP-activated protein kinase (AMPK) cascade. Similarly, male DEFO KO mice showed heightened insulin and AMPK signaling in the forebrain under random-fed conditions. A notable outcome manifested in the gonadal white adipose tissue of DEFO KO mice, where an ex vivo lipolysis assay revealed elevated basal lipolytic potential compared to control mice stimulated with isoproterenol, indicating enhanced sympathetic activation. Brown adipose tissue (BAT) of DEFO KO mice also demonstrated in a mitochondrial respiration assay, an upregulation of fatty acid oxidation, signifying increased BAT activity. Both tissues also revealed higher beta-adrenergic receptor gene expression, suggestive of sympathetic activity.

In conclusion, DEP-1 is a pivotal neuronal IR phosphatase, that prevents the establishment of futile cycles and emerges as a novel modulator of energy metabolism.