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Diet-Induced Nonalcoholic Fatty Liver Disease Is Associated with Sarcopenia and Decreased Serum Insulin-Like Growth Factor-1

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Abstract

Background

Decreased muscle mass or sarcopenia has been associated with nonalcoholic fatty liver disease (NAFLD). However, the functional consequences of this association and its pathogenesis remain ill-defined.

Aims

To evaluate muscle mass and function in a diet-induced NAFLD mouse model and explore its association with changes in serum insulin-like growth factor-1 (IGF-1).

Methods

Weight gain, visceral fat, serum biochemical parameters, liver histology, and hepatic triglyceride content (HTC) were assessed in C57/Bl6 mice fed a westernized diet during 16 weeks. In addition, we determined muscle fiber size and strength of limb skeletal muscle, myosin heavy chain (MHC) protein levels, and IGF-1 serum levels.

Results

Westernized diet feeding was associated with weight gain, increased visceral fat mass (epididymal pad weight: 0.76 g ± 0.13 vs. 0.33 ± 0.27 g; p = 0.0023), hepatic steatosis (HTC: 118.2 ± 6.88 mg/g liver vs. 43.26 ± 5.63 mg/g<, p < 0.05), and necroinflammation (histological scores: 1.29 ± 0.42 vs. 4.00 ± 0.53<, p < 0.05). Also, mice fed the experimental diet had an increased proportion of low-diameter muscle fibers (0–30 μm) and a decreased proportion of high-diameter muscle fibers (60–90 μm), which correlated with decreased MHC protein levels, consistent with significant muscle atrophy. Functional studies showed that mice fed a westernized diet had reduced muscle strength and lower serum levels of IGF-1 (284.2 ± 20.04 pg/ml) compared with chow-fed mice (366.0 ± 12.42 pg/ml, p < 0.05).

Conclusion

Experimental NAFLD is associated with sarcopenia, decreased muscle strength, and reduced IGF-1 serum levels. IGF-1 reduction may be involved in pathogenesis of NAFLD-associated sarcopenia.

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Abbreviations

NAFLD:

Nonalcoholic fatty liver disease

IGF-1:

Insulin-like growth factor 1

HTC:

Hepatic triglyceride content

MHC:

Myosin heavy chain

NASH:

Nonalcoholic steatohepatitis

KNHANES:

Korea National Health and Nutrition Examination Survey

ALIOS:

American lifestyle-induced obesity syndrome

NAS:

NAFLD activity score system

TA:

Tibialis anterior

Lo:

Optimum muscle length

Po:

Maximum isometric tetanic force

CSA:

Cross-sectional area

WGA:

Wheat germ agglutinin

ALT:

Alanine aminotransferase

IL1β:

Interleukin-1 beta

IL-6:

Interleukin-6

IL-8:

Interleukin-8

IL-10:

Interleukin-10

IL-12:

Interleukin-12

NAS:

NAFLD activity score

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Acknowledgments

This study was supported by research grants from the Fondo Nacional de Desarrollo Cientıfico y Tecnologico (FONDECYT 1150327 to M.A., 1161646 to C.C.V., 1150311 to F.B. and PD3140396 to D.C.) and the Comision Nacional de Investigacion Cientıfica y Tecnologica (Grant CONICYT PIA/Basal PFB12, Basal Centre for Excellence in Science and Technology to M.A.) both from the Government of Chile. Association-Francaise Contre Les Myopathies AFM 16670 (C.C.V.), Millennium Institute on Immunology and Immunotherapy, P09-016-F (C.C.V.), UNAB DI-741-15/N (C.C.V.).

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Author notes

    Authors and Affiliations

    1. Departamento de Gastroenterología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Marcoleta #367, 833-0024, Santiago, Chile

      Daniel Cabrera, Margarita Pizarro, Nancy Solis, Francisco Barrera & Marco Arrese

    2. Departamento de Ciencias Químicas y Biológicas, Facultad de salud, Universidad Bernardo O’Higgins, Santiago, Chile

      Daniel Cabrera & Lisbell Estrada

    3. Centro de Regeneración y Envejecimiento (CARE), Pontificia Universidad Católica de Chile, Santiago, Chile

      Daniel Cabrera, Enrique Brandan & Marco Arrese

    4. Instituto de Medicina, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile

      Alex Ruiz

    5. Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile

      Claudio Cabello-Verrugio

    6. Millennium Institute on Immunology and Immunotherapy, Santiago, Chile

      Claudio Cabello-Verrugio

    7. Laboratorio de Diferenciación Celular y Patología, Departamento de Biología Celular y Molecular, MIFAB, Pontificia Universidad Católica de Chile, Santiago, Chile

      Enrique Brandan

    8. Departamento de Patología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

      Javiera Torres

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    1. Daniel Cabrera
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    Daniel Cabrera and Alex Ruiz have contributed equally to this work.

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    Supplementary Figure 1

    Serum inflammatory cytokines profile in the American Lifestyle-Induced Obesity Syndrome [ALIOS]-diet mouse model of NAFLD. Serum was isolated from 16-weeks ALIOS diet-fed mice to evaluate the levels of IL-12, IL-10, IL-6, IL-1b, and IL-8 through a cytometric bead array (CBA) (JPEG 480 kb)

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    Cabrera, D., Ruiz, A., Cabello-Verrugio, C. et al. Diet-Induced Nonalcoholic Fatty Liver Disease Is Associated with Sarcopenia and Decreased Serum Insulin-Like Growth Factor-1. Dig Dis Sci 61, 3190–3198 (2016). https://doi.org/10.1007/s10620-016-4285-0

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