Objectives: The carbohydrate-insulin model (CIM) predicts that increases in fasting and post-prandial insulin in response to dietary carbohydrates stimulate energy intake and lower energy expenditures, leading to positive energy balance and weight gain. The objective of the present study was to directly test the CIM's predictions using C57BL/6 mice. Methods: Diets were designed by altering dietary carbohydrates with either fixed protein or fat content and were fed to C57BL/6 mice acutely or chronically for 12 weeks. The body weight, body composition, food intake, and energy expenditures of the mice were measured. Their fasting and post-prandial glucose and insulin levels were also measured. RNA-seq was performed on RNA from the hypothalamus and subcutaneous white adipose tissue. Pathway analysis was conducted using IPA. Results: Only the post-prandial insulin and fasting glucose levels followed the CIM's predictions. The lipolysis and leptin signaling pathways in the sWAT were inhibited in relation to the elevated fasting insulin, supporting the CIM's predicted impact of high insulin. However, because higher fasting insulin was unrelated to carbohydrate intake, the overall pattern did not support the model. Moreover, the hypothalamic hunger pathways were inhibited in relation to the increased fasting insulin, and the energy intake was not increased. The browning pathway in the sWAT was inhibited at higher insulin levels, but the daily energy expenditure was not altered. Conclusions: Two of the predictions were partially supported (and hence also partially not supported) and the other three predictions were not supported. We conclude that the CIM does not explain the impact of dietary macronutrients on adiposity in mice.
This study was funded by the Chinese Academy of Sciences Strategic Program (XDB13030100), the K.C. Wong Foundation, the 1000 Talents Program, and a Wolfson Merit Award to J.R.S. We thank those in the molecular energetics group in Beijing who contributed to handling the animals and the measurement of their food intake and body weight, including L. Li, B. Li, M. Li, G. Wang, X. Zhang, J. Li, C. Niu, E. Couper, A. Whittington-Davies, and M. Mazidi.
S.H. was involved in the initial experiment design, conducted experiment one, analyzed the data from experiments one and two, performed the IPA-related analysis, and co-wrote the manuscript. L.W. was involved in the sample collection for experiments one and two and conducted the RNA extractions and the RNA-seq. J.T. was involved in the sample and data collection for experiments one and two. D.Y. and Y.X. performed the initial data collection and glucose measurements for experiment two. Y.W. conducted the insulin measurements and was involved in the initial data collection for experiment two. A.D. was involved in the RNA-seq-related analysis. J.R.S. directed both projects, conceived and designed the experiments, contributed to the data analysis, and co-wrote the paper. All of the authors approved the final version prior to submission for publication.
- Carbohydrate-insulin model (CIM)
- Energy expenditure
- Energy intake
- FEMALE MICE
- HIGH-FAT DIETS
- KETOGENIC DIET
- RESPIRATORY EXCHANGE RATIO