Partial impairment of insulin receptor expression mimics fasting to prevent diet-induced fatty liver disease
Authors: Beate Laube
Stewart W Masson
Michael E Walsh
Chris P Hedges
Wolfgang Langhans
Troy L Merry
Michael Ristow
Myrtha Arnold
Doris Pöhlmann
Kim Zarse
Daniel Konrad
Stephan Wueest
Journal: Nature communications (2020)
Discipline: Multidisciplinary
Keywords: insulin signaling; insulin receptor; metabolic disease; obesity; type 2 diabetes
Affiliations: Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland. ., Discipline of Nutrition, School of Medical Sciences, The University of Auckland, Auckland, New Zealand. ., Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand. ., Discipline of Nutrition, School of Medical Sciences, The University of Auckland, Auckland, New Zealand., Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand., Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland., Division of Pediatric Endocrinology and Diabetology and Children's Research Centre, University Children's Hospital, Zurich, Switzerland., Physiology and Behavior Laboratory, Institute of Food and Nutrition, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland.

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. 

Retracted: No

PubPeer comments:
 Was reading this paper and noticed what it seems a duplication of a-tubulin panels in Fig 2i (twice the same blot for different conditions) and Supp. Fig 1 (cropped section of the blot presented in Fig 2i, but in this case is not +insulin condition). Maybe there was a mistake while preparing figures. In that case, authors should provide correct immunoblots to amend this mistake. ![file] , 
 Thank you for your interest in this publication. (i) The same blot membrane was probed for phosphoAkt and basal Akt (*Figure 2i*), and re-probed for the basal expression of the insulin receptor (*Suppl Figure 1a*). Therefore the same alpha-tubulin blot (loading control) is used in both figures. (ii) The mice depicted in *Suppl Figure 1a* (and hence also *Fig. 2i* Insulin right side) were injected with insulin i.p. 10 mins before sacrifice. (iii) The lower left alpha-tubulin panel (conditions: saline, skeletal muscle *M. gastrocnemius*) is wrong indeed; apologies, and thank you for bringing this to our attention. The correct alpha-tubulin blot (non-cropped whole membrane) is contained in the *Source Data* file which can be accessed through the *Nat Comm* website, and which was provided to the journal before acceptance. The corresponding authors have submitted a request for correction to the journal office as of today. , 
 Dear Dr. Ristow, Thank you for your swift reply and the clarification about the blots. ,