DEsire - DEP-1 as potential modulator of cerebral insulin resistance and emotional behavior

• Applicants: Professor Dr. Kai Kappert; Professor Dr. André Kleinridders
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445157429

• Final Report Year: 2025

Final Report Abstract

Brain insulin signaling is crucial for metabolism and cognition, with impairments linked to obesity, diabetes, and depression. High-caloric diets can induce insulin resistance by elevating phosphatases like DEP-1/PTPRJ, which dephosphorylates the insulin receptor (IR). DEP-1 is upregulated in diet-induced obesity and inhibits insulin signaling. Further, DEP-1 N-glycosylation, contributing to ~50% of its molecular weight, is altered in obese mice with more highmannose and complex neutral, fucose-free glycans than lean controls. We investigated how altered DEP-1 expression impacts neuronal insulin signaling, metabolism, and behavior. In murine Neuro2a (N2A) cells, DEP-1 knockout (KO) markedly enhanced insulin sensitivity, shown by increased phosphorylation of insulin signaling proteins. A proximity ligation assay confirmed a direct DEP-1-IR interaction. RNA sequencing revealed upregulation of genes related to glucose metabolism, lipid synthesis, and neurotransmission. KO cells also displayed elevated glucose uptake and oxidation, increased endoplasmatic reticulum (ER) stress markers, and reduced protein synthesis. Functionally, DEP-1 KO impaired cell differentiation and neurite outgrowth, indicating a role in neuronal development. In N2A cells, DEP-1 loss also, unexpectedly, activated the AMPK pathway via increased Plcg1 activity. Forebrain/hippocampal DEP-1 deletion (DEFO KO mice) did not affect body weight, glucose tolerance, insulin sensitivity, or food intake, but females showed enhanced hippocampal insulin signaling and energy deprivation signs, including upregulated WAT lipolysis and liver ketogenesis. Males exhibited elevated cortical insulin and AMPK signaling, increased fatty acid oxidation in brown adipose tissue (BAT), and greater lipolysis in white adipose tissue (WAT). Both sexes had increased β-adrenergic receptor expression in BAT, WAT, and liver, along with elevated norepinephrine levels, indicating greater sympathetic activity. Behaviorally, DEFO KO mice were less anxious, consistent with improved brain insulin signaling in preliminary analyses. In summary, DEP-1 impacts insulin signaling and neurons on a functional level and suppresses concurrent insulin and AMPK signaling via Plcg1 modulation. Its deletion activates both anabolic and catabolic pathways, increasing fat mass in females and BAT activity in males. Moreover, in females anxiety-like behavior is reduced.

Publications

• Insulin modulates emotional behavior through a serotonin-dependent mechanism. Molecular Psychiatry, 29(6), 1610-1619.
  Martin, Hugo; Bullich, Sébastien; Martinat, Maud; Chataigner, Mathilde; Di Miceli, Mathieu; Simon, Vincent; Clark, Samantha; Butler, Jasmine; Schell, Mareike; Chopra, Simran; Chaouloff, Francis; Kleinridders, Andre; Cota, Daniela; De Deurwaerdere, Philippe; Pénicaud, Luc; Layé, Sophie; Guiard, Bruno P. & Fioramonti, Xavier
  
• Intuitive eating? Central regulation of food intake by nutrients and metabolic hormones. Ernahrungs Umschau 2022; 69(11): 176–86. (Review)
  Schell M. & A. Kleinridders A.
  
• Molecular Mechanisms of Brain Insulin Signaling1. Physiological Consequences of Brain Insulin Action, 1-20. CRC Press.
  Chopra, Simran; Hauffe, Robert & Kleinridders, André
  
• Physiological Consequences of Brain Insulin Action. CRC Press.
  Kleinridders, André
  
• Lactobacillus rhamnosus Sex-Specifically Attenuates Depressive-like Behavior and Mitigates Metabolic Consequences in Obesity. Biological Psychiatry Global Open Science, 3(4), 651-662.
  Schell, Mareike; Wardelmann, Kristina; Hauffe, Robert; Rath, Michaela; Chopra, Simran & Kleinridders, André
  
• DEP-1 is a brain insulin receptor phosphatase that prevents the simultaneous activation of counteracting metabolic pathways. Cell Reports, 43(12), 114984.
  Chopra, Simran; Kadiri, Otsuware Linda-Josephine; Ulke, Jannis; Hauffe, Robert; Jonas, Wenke; Cheshmeh, Sahar; Schmidt, Luisa; Bishop, Christopher A.; Yagoub, Selma; Schell, Mareike; Rath, Michaela; Krüger, Janine; Lippert, Rachel N.; Krüger, Marcus; Kappert, Kai & Kleinridders, André
  
• High-fat diet alters N-glycosylation of PTPRJ in murine liver. The Journal of Nutritional Biochemistry, 123, 109500.
  Ulke, Jannis; Schwedler, Christian; Krüger, Janine; Stein, Vanessa; Geserick, Peter; Kleinridders, André & Kappert, Kai
  
• PTPRJ is a negative regulator of insulin signaling in neuronal cells, impacting protein biosynthesis, and neurite outgrowth. Journal of Neuroendocrinology, 36(12).
  Ulke, Jannis; Chopra, Simran; Kadiri, Otsuware Linda‐Josephine; Geserick, Peter; Stein, Vanessa; Cheshmeh, Sahar; Kleinridders, André & Kappert, Kai
  
• HSP60 Reduction Causes an Abnormal Genotype and Sex Distribution and Impairs Mitochondrial Activity in Mouse Spermatozoa. Reproductive Medicine, 6(3), 16.
  Hauffe, Robert; Rath, Michaela; Chopra, Simran; Müller, Karin & Kleinridders, André
  
• Mitophagy Regulators as Novel Targets in Sepsis-Induced Myocardial Dysfunction. JACC: Basic to Translational Science, 10(8), 101290.
  Friedrich, Katharina & Kappert, Kai