RT Journal Article
SR Electronic
T1 Focused Ultrasound Modulation of Hepatic Neural Plexus Restores Glucose Homeostasis in Diabetes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.16.440207
DO 10.1101/2021.04.16.440207
A1 Victoria Cotero
A1 Hiromi Miwa
A1 Zall Hirschstein
A1 Khaled Qanud
A1 Tomás S. Huerta
A1 Ningwen Tai
A1 Yuyan Ding
A1 Kevin Jimenez-Cowell
A1 Jacquelyn-Nicole Tomaio
A1 Weiguo Song
A1 Alex Devarajan
A1 Tea Tsaava
A1 John Graf
A1 Radhika Madhavan
A1 Kirk Wallace
A1 Evelina Loghin
A1 Christine Morton
A1 Ying Fan
A1 Tzu-Jen Kao
A1 Kainat Akhtar
A1 Meghana Damaraju
A1 Linda Barenboim
A1 Teresa Maietta
A1 Jeffrey Ashe
A1 Kevin J. Tracey
A1 Thomas R. Coleman
A1 Dino Di Carlo
A1 Damian Shin
A1 Stavros Zanos
A1 Sangeeta S. Chavan
A1 Raimund I. Herzog
A1 Chris Puleo
YR 2021
UL http://biorxiv.org/content/early/2021/04/18/2021.04.16.440207.abstract
AB While peripheral glucose sensors are known to relay signals of substrate availability to integrative nuclei in the brain, the importance of these pathways in maintaining energy homeostasis and their contribution to disease remain unknown. Herein, we demonstrate that selective activation of the hepatoportal neural plexus via transient peripheral focused ultrasound (pFUS) induces glucose homeostasis in models of well-established insulin resistant diabetes. pFUS modulates sensory projections to the hindbrain and alters hypothalamic concentrations of neurotransmitters that regulate metabolism, resulting in potentiation of hypothalamic insulin signaling, leptin-independent inhibition of the orexigenic neuropeptide Y system, and therapeutic alteration in autonomic output to peripheral effector organs. Multiomic profiling confirms pFUS-induced modifications of key metabolic functions in liver, pancreas, muscle, adipose, kidney, and intestines. Activation of the hepatic nutrient sensing pathway not only restores nervous system coordination of peripheral metabolism in three different species but does so across these organ systems; several of which are current targets of antidiabetic drug classes. These results demonstrate the potential of hepatic pFUS as a novel/non-pharmacologic therapeutic modality to restore glucose homeostasis in metabolic diseases, including type II diabetes.One Sentence Summary We utilize a non-invasive ultrasound technique to activate a liver-brain sensory pathway and demonstrate its potential to induce durable normalization of glucose homeostasis in models of well-established insulin resistant diabetes.Competing Interest StatementVC, JG, RM, KW, EL, CM, YF, TJK, JA, CP are employees of General Electric and declare that GE has filed US and international patent applications describing methods, devices, and systems for precision organ-based ultrasound neuromodulation. HM, ZH, KQ, TSH, NT, YD, KJC, JT, AD, TT, KA, MD, LB, TM, KJT, TRC, DDC, DS, SZ, SSC, RH have received research funding from GE to investigate the effects of ultrasound on metabolism