Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity

Kenichi Sakamoto; Mary A Butera; Chunxue Zhou; Giulia Maurizi; Bandy Chen; Li Ling; Adham Shawkat; Likhitha Patlolla; Kavira Thakker; Victor Calle; Donald A Morgan; Kamal Rahmouni; Gary J Schwartz; Azeddine Tahiri; Christoph Buettner

doi:10.1016/j.cmet.2024.09.012

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Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity

Journal article

Peer reviewed

Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity

Kenichi Sakamoto, Mary A Butera, Chunxue Zhou, Giulia Maurizi, Bandy Chen, Li Ling, Adham Shawkat, Likhitha Patlolla, Kavira Thakker, Victor Calle, …

Cell metabolism, Vol.37(1), pp.121-137.e6

01/2025

DOI: 10.1016/j.cmet.2024.09.012

PMCID: PMC11711004

PMID: 39437790

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https://pmc.ncbi.nlm.nih.gov/articles/PMC11711004/pdf/nihms-2029952.pdfView

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Abstract

The mechanisms underlying obesity-induced insulin resistance remain incompletely understood, as impaired cellular insulin signaling, traditionally considered the primary driver of insulin resistance, does not always accompany impaired insulin action. Overnutrition rapidly increases plasma norepinephrine (NE), suggesting overactivation of the sympathetic nervous system (SNS). However, the role of the SNS in obesity is controversial, as both increased and decreased SNS activity (SNA) have been reported. Here, we show that reducing catecholamine (CA) release from the SNS protects against overnutrition-induced insulin resistance as well as hyperglucagonemia, adipose tissue dysfunction, and fatty liver disease, as we demonstrate utilizing a mouse model of inducible and peripherally restricted deletion of tyrosine hydroxylase (th; THΔper). A key mechanism through which heightened SNA induces insulin resistance is by triggering adipose tissue lipolysis. Increased SNA emerges as a critical driver in the pathogenesis of overnutrition-induced insulin resistance and metabolic disease independent of cellular insulin signaling.

Diabetes

Obesity

adipose tissue lipolysis

norepinephrine

adipose tissue dysfunction

sympathetic nervous system

liver steatosis

metabolic disease

insulin resistance

metabolic inflammation

Details

Title: Subtitle: Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity
Creators: Kenichi Sakamoto - Icahn School of Medicine at Mount Sinai
Mary A Butera - Icahn School of Medicine at Mount Sinai
Chunxue Zhou - Icahn School of Medicine at Mount Sinai
Giulia Maurizi - Icahn School of Medicine at Mount Sinai
Bandy Chen - Icahn School of Medicine at Mount Sinai
Li Ling - Icahn School of Medicine at Mount Sinai
Adham Shawkat - Rutgers, The State University of New Jersey
Likhitha Patlolla - Rutgers, The State University of New Jersey
Kavira Thakker - Rutgers, The State University of New Jersey
Victor Calle - Rutgers, The State University of New Jersey
Donald A Morgan - University of Iowa
Kamal Rahmouni - University of Iowa
Gary J Schwartz - Albert Einstein College of Medicine
Azeddine Tahiri - Rutgers, The State University of New Jersey
Christoph Buettner - Icahn School of Medicine at Mount Sinai
Resource Type: Journal article
Publication Details: Cell metabolism, Vol.37(1), pp.121-137.e6
DOI: 10.1016/j.cmet.2024.09.012
PMID: 39437790
PMCID: PMC11711004
NLM abbreviation: Cell Metab
ISSN: 1550-4131
eISSN: 1932-7420
Publisher: CELL PRESS
Grant note: NIH: DK074873, DK083568, DK082724 Department of Defense: W81XWH-22-1-0200 Manpei Suzuki Diabetes FoundationNational Institutes of Health: R01 HL162773 Department of Veterans Affairs: BX004249, BX006040 University of Iowa Fraternal Order of Eagles Diabetes Research Center
We thank Dr. Richard Palmiter for the TH flox/flox mice; Dr. Henri H. Ruiz for the data regarding AAKO mice fed HFD; Dr. Xiaoyang Su and Dr. Maria Elena Diaz Rubio for lipidomics analysis; Ms. Patricia Greenberg for providing advice on statistical analysis; Dr. Susan K. Fried for advice on adipose tissue analysis; Mr. Licheng Wu and Dr. Haihong Zong for clamp study; Dr. Moshmi Bhatta-charya for providing advice on liver tissue analysis; Dr. Fredric E. Wondisford and members of the Wondisford lab for helpful discussions; and Ms. Sai Siri Dasari, Mr. Nicholas Dante, Ms. Min Sun Kim, Mr. David Menna, Mr. Nader Ahmed, and Ms. Aaheli Konar for technical assistance. AtglFlox mice (B6N.129S-Pnpla2tm1Eek/J; Stock No: 24278) were generated with Dr. Erin E. Kershaw with grant support from NIH R01 DK090166. The graphical abstract was created with biorender.com . This study was supported by the following grants: DK074873, DK083568, and DK082724 (C.B.) ; the Department of Defense (W81XWH-22-1-0200) and the Manpei Suzuki Diabetes Foundation (K.S.) ; and the National Institutes of Health (R01 HL162773) , the Department of Veterans Affairs (BX004249 and BX006040) , and the University of Iowa Fraternal Order of Eagles Diabetes Research Center (K.R.) .
Language: English
Electronic publication date: 10/15/2024
Date published: 01/2025
Academic Unit: Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984738439002771

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