AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue

Abstract

Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis.

DOI: 10.1016/j.cell.2016.02.044

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@article{Steculorum2016AgRPNC, title={AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue}, author={Sophie Marie Steculorum and Johan T. Ruud and Ismene Karakasilioti and Heiko Backes and Linda Engstr{\"{o}m Ruud and Katharina Timper and Martin E. Hess and Eva Tsaousidou and Jan Mauer and Merly C. Vogt and Lars Paeger and Stephan Bremser and Andreas Klein and Donald A Morgan and Peter Frommolt and Paul Thomas Brinkkoetter and Philipp Hammerschmidt and Thomas Benzing and Kamal Rahmouni and F Thomas Wunderlich and Peter Kloppenburg and Jens C. Br{\"{u}ning}, journal={Cell}, year={2016}, volume={165}, pages={125-138} }