The carbohydrate-insulin model does not explain the impact of varying dietary macronutrients on the body weight and adiposity of mice

Sumei Hu, Lu Wang, Jacques Togo, Dengbao Yang, Yanchao Xu, Yingga Wu, Alex Douglas, John R. Speakman

The carbohydrate-insulin model (CIM) suggests that high levels of dietary carbohydrates elevate insulin secretion, which suppresses fatty acid oxidation and the release of fatty acids from adipose tissue while promoting lipogenesis. This creates a state of cellular “internal starvation” that drives both increased food intake and decreased energy expenditure, leading to obesity. Hu et al. directly tested specific predictions of the CIM in a mouse model. They found that only the changes in the post-prandial insulin and fasting glucose followed the CIM’s predictions in relation to the dietary carbohydrate. Fasting insulin, energy intake, energy expenditure, and body fat mass did not follow the trends predicted by the CIM.

Objective: 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.