Dataset Information

DEP-1 is a novel brain insulin receptor phosphatase and disallows the development of futile cycles

ABSTRACT: A healthy metabolism relies on the precise regulation of anabolic and catabolic pathways. Insulin and AMPK serve as key regulators of anabolism and catabolism, respectively. While insulin deficiency markedly impairs anabolism, insulin resistance in obesity leads to metabolic dysfunction especially via altered brain insulin receptor activity. Density-enhanced phosphatase-1 (DEP-1), a ubiquitously expressed receptor-like tyrosine phosphatase, has been described as an insulin receptor phosphatase in peripheral tissues. Strikingly, diet-induced obese mice exhibit elevated DEP-1 expression in the brain. This study uncovers DEP-1's role in brain insulin signaling and its impact on ana- and catabolic pathways. Neurons lacking DEP-1 exhibit heightened insulin receptor phosphorylation and downstream signaling upon acute insulin stimulation. Surprisingly, this is accompanied by simultaneous activation of the AMPK cascade due to increased phospholipase C gamma 1 signaling. These opposing pathways in male DEP-1 forebrain/hippocampus-specific knockout mice result in heightened lipolysis in white adipose tissue, and enhanced fat oxidation in brown adipose tissue due to elevated sympathetic activation and enhanced beta-adrenergic receptor expression.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Luisa Marie Schmidt

LAB HEAD: André Kleinridders

PROVIDER: PXD051088 | Pride | 2024-11-27

REPOSITORIES: Pride

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DEP-1 is a brain insulin receptor phosphatase that prevents the simultaneous activation of counteracting metabolic pathways.

Chopra Simran S Kadiri Otsuware Linda-Josephine OL Ulke Jannis J Hauffe Robert R Jonas Wenke W Cheshmeh Sahar S Schmidt Luisa L Bishop Christopher A CA Yagoub Selma S Schell Mareike M Rath Michaela M Krüger Janine J Lippert Rachel N RN Krüger Marcus M Kappert Kai K Kleinridders André A

Cell reports 20241125 12

A healthy metabolism relies on precise regulation of anabolic and catabolic pathways. While insulin deficiency impairs anabolism, insulin resistance in obesity causes metabolic dysfunction, especially via altered brain insulin receptor (IR) activity. Density-enhanced phosphatase 1 (DEP-1) negatively modulates the IR in peripheral tissues. Our study shows that DEP-1 is an insulin-regulated gene, dysregulated in obesity, and uncovers its role in brain insulin signaling, impacting both anabolic and ...[more]

PMID: 39589923

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