Partial impairment of insulin receptor expression mimics fasting to prevent diet-induced fatty liver disease

Troy L. Merry (), Chris P. Hedges, Stewart W. Masson, Beate Laube, Doris Pöhlmann, Stephan Wueest, Michael E. Walsh, Myrtha Arnold, Wolfgang Langhans, Daniel Konrad, Kim Zarse and Michael Ristow ()
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Troy L. Merry: Swiss Federal Institute of Technology (ETH)
Chris P. Hedges: The University of Auckland
Stewart W. Masson: The University of Auckland
Beate Laube: Swiss Federal Institute of Technology (ETH)
Doris Pöhlmann: Swiss Federal Institute of Technology (ETH)
Stephan Wueest: University Children’s Hospital
Michael E. Walsh: Swiss Federal Institute of Technology (ETH)
Myrtha Arnold: Swiss Federal Institute of Technology (ETH)
Wolfgang Langhans: Swiss Federal Institute of Technology (ETH)
Daniel Konrad: University Children’s Hospital
Kim Zarse: Swiss Federal Institute of Technology (ETH)
Michael Ristow: Swiss Federal Institute of Technology (ETH)

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract Excessive insulin signaling through the insulin receptor (IR) may play a role in the pathogenesis of diet-induced metabolic disease, including obesity and type 2 diabetes. Here we investigate whether heterozygous impairment of insulin receptor (IR) expression limited to peripheral, i.e. non-CNS, tissues of adult mice impacts the development of high-fat diet-induced metabolic deterioration. While exhibiting some features of insulin resistance, PerIRKO+/− mice display a hepatic energy deficit accompanied by induction of energy-sensing AMPK, mitochondrial biogenesis, PPARα, unexpectedly leading to protection from, and reversal of hepatic lipid accumulation (steatosis hepatis, NAFLD). Consistently, and unlike in control mice, the PPARα activator fenofibrate fails to further affect hepatic lipid accumulation in PerIRKO+/− mice. Taken together, and opposing previously established diabetogenic features of insulin resistance, incomplete impairment of insulin signaling may mimic central aspects of calorie restriction to limit hepatic lipid accumulation during conditions of metabolic stress.

Date: 2020
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DOI: 10.1038/s41467-020-15623-z

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