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Complementary role of peripheral and central autonomic nervous system on insulin-like growth factor-1 activation to prevent fatty liver disease

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A Correction to this article was published on 07 March 2024

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Abstract

Background

Insulin-like growth factor-1 (IGF-1) is involved in the pathology of non-alcoholic fatty liver disease (NAFLD) and ameliorates fatty infiltration in the liver. It is activated by growth hormone (GH); however, the role of GH–IGF-1 axis in NAFLD developmental phase has not been well identified. Therefore, in this study, we focused on the effect of IGF-1 in NAFLD pathology and GH excretion activation from the pituitary gland by peripheral autonomic neural pathways relaying liver–brain–gut pathway and by central neuropeptides.

Methods

GH and IGF-1 levels were assessed in wild-type and melanocortin-4 receptor knockout mice upon the development of diet-induced NAFLD. The contribution of the peripheral autonomic nervous system connecting the liver–brain–gut axis was assessed by its blockade using capsaicin and that of the central nervous system was assessed by the expression of hypothalamic brain-derived neurotrophic factor (BDNF) and corticotropin-releasing factor (CRH), which activates GH release from the pituitary gland.

Results

In the NAFLD mouse models, the levels of GH and IGF-1 increased (p < .05). Further, hepatic fatty infiltration was suppressed even under peripheral autonomic nervous system blockade (p < .001), which inhibited gastric ghrelin expression. In mice with peripheral autonomic nervous blockade, hypothalamic BDNF and CRH were inhibited (p < .05), resulting in GH and IGF-1 excretion, whereas other neuropeptides of somatostatin and cortistatin showed no changes. These complementary effects were canceled in melanocortin-4 receptor knockout mice, which diminished BDNF and CRH release control.

Conclusions

Our study demonstrates that the release of IGF-1 by the nervous system is a key factor in maintaining the pathological homeostasis of NAFLD, suggesting its therapeutic potential.

Graphical Abstract

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Data availability

The authors confirm that the data supporting the findings of this study are available in the article and/or its supplementary materials.

Change history

Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

SLD:

Steatotic liver disease

GH:

Growth hormone

IGF-1:

Insulin like growth factor-1

SCD:

Standard chow diet

CDAA:

Choline-deficient L-amino-acid-defined diet

HFD:

High fat diet

MC4RKO:

Melanocortin 4 receptor knock out

Cap:

Capsaicin

BDNF:

Brain derived neurotrophic factor

CRH:

Corticotropin-releasing factor

qRT-PCR:

Quantitative real-time polymerase chain reaction

ELISA:

Enzyme-linked immunosorbent assay

ANOVA:

Analysis of variance

H&E:

Hematoxylin and eosin

NS:

No statistical significance

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Acknowledgements

The authors would like to thank Takao Tsuchida in the Division of Gastroenterology and Hepatology at Niigata University for his excellent assistance in the histological analyses. The authors would also like to thank Nobuyoshi Fujisawa, Kanako Oda, Shuko Adachi, Toshikuni Sasaoka, and all staff members at the Division of Laboratory Animal Resources at Niigata University.

Funding

The authors declare that they have no conflict of interest. The research in the authors’ laboratories has been supported in part by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Sciences 18K19537 and 21K19478 to Terai S and Kamimura K, and by a grant from Taiju Life Social Welfare Foundation to Kamimura K.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1–757, Asahimachi–dori, Chuo–ku, Niigata, Niigata, 951-8510, Japan

    Itsuo Nagayama, Kenya Kamimura, Takashi Owaki, Masayoshi Ko, Takuro Nagoya, Yuto Tanaka, Marina Ohkoshi, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura & Shuji Terai

  2. Department of General Medicine, Niigata University School of Medicine, Niigata, Niigata, 951-8510, Japan

    Kenya Kamimura

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  1. Itsuo Nagayama
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Contributions

IN, KK, TO, MK, TN, and ST contributed to the study conception and design. Material preparation, data collection, and analysis were performed by IN, KK, TO, MK, TN, YT, MO, TS, AS, TY, HK, and ST. The first draft of the manuscript was written by IN, KK, and ST, and all authors read and approved the final manuscript.

Corresponding author

Correspondence to Kenya Kamimura.

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Conflict of interest

Itsuo Nagayama, Kenya Kamimura, Takashi Owaki, Masayoshi Ko, Takuro Nagoya, Yuto Tanaka, Marina Ohkoshi, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura and Shuji Terai have no competing interests.

Ethical approval

All animal experiments were approved by and conducted in full compliance with the Institutional Animal Care and Use Committee regulations at Niigata University, Niigata, Japan (SA00568, SA01077, and SA01212).

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Nagayama, I., Kamimura, K., Owaki, T. et al. Complementary role of peripheral and central autonomic nervous system on insulin-like growth factor-1 activation to prevent fatty liver disease. Hepatol Int 18, 155–167 (2024). https://doi.org/10.1007/s12072-023-10601-1

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