1. AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue
- Author
-
Katharina Timper, Heiko Backes, Philipp Hammerschmidt, Stephan Bremser, Thomas Benzing, Andreas Klein, Sophie M. Steculorum, Linda Engström Ruud, Peter Frommolt, Jens C. Brüning, Martin E. Hess, Johan Ruud, Jan Mauer, Donald A. Morgan, Paul Brinkkötter, Peter Kloppenburg, Ismene Karakasilioti, F. Thomas Wunderlich, Merly C. Vogt, Kamal Rahmouni, Eva Tsaousidou, and Lars Paeger
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Glucose uptake ,Adipose tissue ,Myostatin ,Carbohydrate metabolism ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Insulin resistance ,Adipose Tissue, Brown ,Internal medicine ,Brown adipose tissue ,medicine ,Glucose homeostasis ,Animals ,Agouti-Related Protein ,Neurons ,biology ,Appetite Regulation ,Biochemistry, Genetics and Molecular Biology(all) ,digestive, oral, and skin physiology ,Feeding Behavior ,medicine.disease ,Optogenetics ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Glucose ,nervous system ,biology.protein ,Neuron ,Insulin Resistance ,Transcriptome ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - 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.
- Published
- 2016
- Full Text
- View/download PDF