Obesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa–Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice.
Food intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in vitro.
ON-DP mice showed spontaneous overfeeding compared with ON-DR mice. Excessive body weight gain and fat accumulation in ON-DP mice were completely suppressed to the levels seen in ON-DR mice by pair-feeding with ON-DR mice. Deterioration of glucose tolerance in ON-DP mice was also ameliorated under the pair-feeding conditions. While no differences were seen in body weight and adipose tissue mass when comparing the two mouse lines at 5 weeks of age, the ON-DP mice had lower plasma leptin concentrations and adipose tissue leptin gene expression levels. In accordance with peripheral leptin status, ON-DP mice displayed lower anorexigenic leptin signalling in the hypothalamic arcuate nucleus when compared with ON-DR mice without apparent leptin resistance. Explant culture studies revealed that ON-DP mice had lower leptin production capacity in adipose tissue. ON-DP mice also displayed higher DNA methylation levels in the leptin gene promoter region of adipocytes when compared with ON-DR mice.
The results suggest that heritable lower leptin production capacity plays a critical role in overfeeding-induced obesity and subsequent deterioration of glucose tolerance in ON-DP mice. Leptin production capacity in adipocytes, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity caused by overeating and future onset of type 2 diabetes.
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The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.
Epididymal white adipose tissue
Signal transducer and activator of transcription 3
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The authors thank M. Kawahara (Department of Endocrinology, Diabetes and Metabolism, Nippon Medical School, Tokyo, Japan) for excellent technical assistance.
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The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
This study was supported by the Japan Society for the Promotion of Science (25860300, 15K08434, 17K08780), the Nippon Medical School Alumni Association and the Lotte Shigemitsu Prize.
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Asai, A., Nagao, M., Hayakawa, K. et al. Leptin production capacity determines food intake and susceptibility to obesity-induced diabetes in Oikawa–Nagao Diabetes-Prone and Diabetes-Resistant mice. Diabetologia (2020). https://doi.org/10.1007/s00125-020-05191-8
- DNA methylation
- Glucose intolerance
- Insulin resistance
- Oikawa–Nagao Diabetes-Prone/Resistant mouse