Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Sophie Marie Steculorum, Katharina Timper, Linda Engström Ruud, Nadine Evers, Lars Paeger, Stephan Bremser, Peter Kloppenburg, Jens Claus Brüning
Uridine-diphosphate (UDP) and its receptor P2Y6 have recently been identified as regulators of AgRP neurons. UDP promotes feeding via activation of P2Y6 receptors on AgRP neurons, and hypothalamic UDP concentrations are increased in obesity. However, it remained unresolved whether inhibition of P2Y6 signaling pharmacologically, globally, or restricted to AgRP neurons can improve obesity-associated metabolic dysfunctions. Here, we demonstrate that central injection of UDP acutely promotes feeding in diet-induced obese mice and that acute pharmacological blocking of CNS P2Y6 receptors reduces food intake. Importantly, mice with AgRP-neuron-restricted inactivation of P2Y6 exhibit reduced food intake and fat mass as well as improved systemic insulin sensitivity with improved insulin action in liver. Our results reveal that P2Y6 signaling in AgRP neurons is involved in the onset of obesity-associated hyperphagia and systemic insulin resistance. Collectively, these experiments define P2Y6 as a potential target to pharmacologically restrict both feeding and systemic insulin resistance in obesity.

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Teaser

P2Y6 signaling was recently identified as regulator of AgRP neuron activity and food intake. Steculorum et al. now find that P2Y6 signaling in AgRP neurons remains functional in obese mice and that AgRP-neuron-restricted P2Y6 deficiency reduces food intake and fat mass, and improves systemic insulin sensitivity in obese mice. Their work thus defines P2Y6 as a target to regulate both hyperphagia and adiposity as well as systemic insulin resistance in obesity.


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