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Adipose tissue dysfunction and visceral fat are associated to hepatic insulin resistance and severity of NASH even in lean individuals

Chiara Saponaro, Silvia Sabatini, Melania Gaggini, Fabrizia Carli, Chiara Rosso, Vincenzo Positano, Angelo Armandi, Gian Paolo Caviglia, Riccardo Faletti, Elisabetta Bugianesi, Amalia Gastaldelli
doi: https://doi.org/10.1101/2022.01.19.476711
Chiara Saponaro
1Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy
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  • For correspondence: amalia@ifc.cnr.it chiara.saponaro@univ-lille.fr
Silvia Sabatini
1Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy
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Melania Gaggini
1Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy
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Fabrizia Carli
1Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy
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Chiara Rosso
2Division of Gastroenterology and Hepatology and Lab. of Diabetology, Dept. of Medical Sciences, University of Turin, Turin, Italy
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Vincenzo Positano
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Angelo Armandi
2Division of Gastroenterology and Hepatology and Lab. of Diabetology, Dept. of Medical Sciences, University of Turin, Turin, Italy
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Gian Paolo Caviglia
2Division of Gastroenterology and Hepatology and Lab. of Diabetology, Dept. of Medical Sciences, University of Turin, Turin, Italy
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Riccardo Faletti
2Division of Gastroenterology and Hepatology and Lab. of Diabetology, Dept. of Medical Sciences, University of Turin, Turin, Italy
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Elisabetta Bugianesi
2Division of Gastroenterology and Hepatology and Lab. of Diabetology, Dept. of Medical Sciences, University of Turin, Turin, Italy
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Amalia Gastaldelli
1Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy
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  • For correspondence: amalia@ifc.cnr.it chiara.saponaro@univ-lille.fr
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Abstract

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disorder, but the factors that determine this heterogeneity remain poorly understood. Adipose tissue (AT) dysfunction is causally linked to NAFLD since it causes intrahepatic triglyceride (IHTG) accumulation through increased hepatic lipid flow, due to insulin resistance (IR) and pro-inflammatory adipokines release. While many studies in NAFLD have looked at total adiposity (that is mainly subcutaneous fat, SC-AT), it is still unclear the impact of visceral fat (VF). Thus, we investigated how VF vs. SC-AT were related to NAFLD in lean, overweight, and obese individuals compared to lean controls.

Methods Thirty-four non-diabetic NAFLD with liver biopsy and eight lean control individuals (CT) were enrolled in this study. We measured fat distribution (VF, SC-AT and IHTG) by magnetic resonance imaging (MRI), adiponectin concentration, free fatty acids (FFAs) and triglyceride (TAG) concentration and composition by mass spectrometry (MS), lipolysis and IR by tracer infusion.

Results IHTG was positively associated with lipolysis, adipose tissue IR, TG concentrations, and increased ratio of saturated/unsaturated fatty acids. VF was higher in NAFLD (including lean individuals) compared to controls, was increased with fibrosis stage and was associated with IR in liver, muscle and adipose tissue, increased lipolysis, and decreased adiponectin levels. Collectively, our results suggest that VF accumulation, given its location close to the liver, is one of the major risk factors for NAFLD.

Conclusions These findings propose VF as an early indicator of NAFLD independently of BMI, which may allow for evidence-based prevention and intervention strategies.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflict of Interest statement/Financial Disclosure The authors declare no conflict of interest for this manuscript.

  • Abbreviations

    NAFLD
    Nonalcoholic fatty liver disease
    AT
    Adipose tissue
    IHTG
    Intrahepatic triglyceride
    IR
    Insulin resistance
    SC-AT
    Subcutaneous fat
    VF
    Visceral fat
    FFAs
    Free fatty acids
    TAG
    Triglyceride
    MS
    Mass spectrometry
    NASH
    Non-alcoholic steatohepatitis
    MRI
    Magnetic resonance imaging
    HDL
    High density lipoprotein
    LDL
    Low density lipoprotein
    LFTs
    Liver function tests
    APO-B
    Apolipoprotein B
    APO-A1
    Apolipoprotein A1
    NAS
    NAFLD activity score
    ROI
    Region of interest
    LFF
    Liver fat fraction
    EGP
    Endogenous glucose production
    Hep-IR
    Hepatic insulin-resistance
    Muscle-IR
    Muscle insulin-resistance
    Adipo-IR and Lipo-IR
    Adipose tissue insulin-resistance
    ALT
    Alanine aminotransferase
    AST
    Aspartate aminotransferase
    GGT
    Gamma-glutamyltransferase
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted January 21, 2022.
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    Adipose tissue dysfunction and visceral fat are associated to hepatic insulin resistance and severity of NASH even in lean individuals
    Chiara Saponaro, Silvia Sabatini, Melania Gaggini, Fabrizia Carli, Chiara Rosso, Vincenzo Positano, Angelo Armandi, Gian Paolo Caviglia, Riccardo Faletti, Elisabetta Bugianesi, Amalia Gastaldelli
    bioRxiv 2022.01.19.476711; doi: https://doi.org/10.1101/2022.01.19.476711
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    Adipose tissue dysfunction and visceral fat are associated to hepatic insulin resistance and severity of NASH even in lean individuals
    Chiara Saponaro, Silvia Sabatini, Melania Gaggini, Fabrizia Carli, Chiara Rosso, Vincenzo Positano, Angelo Armandi, Gian Paolo Caviglia, Riccardo Faletti, Elisabetta Bugianesi, Amalia Gastaldelli
    bioRxiv 2022.01.19.476711; doi: https://doi.org/10.1101/2022.01.19.476711

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