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  • Original Article
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Animal Models

IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia, obesity and diabetes by substituting for leptin

International Journal of Obesity volume 40, pages 425–433 (2016)Cite this article

Subjects

Abstract

Background:

Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity.

Aims:

The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lepob/ob mice.

Design:

Adeno-associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms.

Results:

In Lepob/ob mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT.

Conclusions:

These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.

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Acknowledgements

We thank Ms Seiko Ohkuma, Megumi Motoshima and Atumi Shinozaki for technical assistance. This work was supported by Grant-in-Aid for Challenging Exploratory Research (26670453) from Japan Society for the Promotion of Science (JSPS), Strategic Research Program for Brain Sciences (10036069) by the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), MEXT-Supported Programs for Strategic Research Foundation at Private Universities 2011-2015 and 2013-2017 and a grant from Salt Science Research Foundation (No. 1434) to TY. A part of this study was supported by Grant-in-Aid for Scientific Research (C) (24592277 and 15K09442) from JSPS and Japan Diabetes Foundation to MN.

Author contributions

MN designed the experiments. MN and SY performed in vivo experiments. TO and KO contributed to purification of AAV vector. MN and TY prepared the manuscript. HO provided Nestin-Cre STAT3flox/flox mice as a new obese model.

Author information

Author notes

  1. M Nakata and S Yamamoto: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Japan

    M Nakata, S Yamamoto, D Gantulga & T Yada

  2. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan

    T Okada & K Ozawa

  3. Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

    T Okada

  4. Department of Physiology, Keio University School of Medicine, Tokyo, Japan

    H Okano

  5. Department of Developmental Physiology, Division of Adaptation Development, National Institute for Physiological Sciences, Okazaki, Japan

    T Yada

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  1. M Nakata
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Corresponding author

Correspondence to T Yada.

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Competing interests

HO is a paid member of scientific advisory board for San Bio, Co. Ltd. The other authors declare no conflict of interest.

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Nakata, M., Yamamoto, S., Okada, T. et al. IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia, obesity and diabetes by substituting for leptin. Int J Obes 40, 425–433 (2016). https://doi.org/10.1038/ijo.2015.201

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