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. 2020 Feb:32:27-43.
doi: 10.1016/j.molmet.2019.11.010. Epub 2019 Nov 16.

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

Sumei Hu  1 , Lu Wang  2 , Jacques Togo  3 , Dengbao Yang  1 , Yanchao Xu  1 , Yingga Wu  2 , Alex Douglas  4 , John R Speakman  5
Affiliations

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

Sumei Hu et al. Mol Metab. 2020 Feb.

Abstract

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.

Keywords: Carbohydrate-insulin model (CIM); Energy expenditure; Energy intake; Insulin; Mice.

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Figures

Figure 1
Figure 1
The insulin and glucose levels of the mice in both post-prandial and fasting states. The values were the measured values of each individual. The post-prandial (A) insulin and (B) glucose levels of the mice 90–120 min after feeding. A total of 35 mice were used, with 5 mice per diet. The fasting (C) insulin and (D) glucose levels of the mice following 12 weeks on experimental diets. A total of 240 mice were used, with 10 mice per diet. See also Figure S1.
Figure 2
Figure 2
Diagram showing the correlation of the gene expression against the fasting insulin levels in the subcutaneous white adipose tissue of the C57BL/6 mice. (A) Lipolysis pathway-related genes. (B) Insulin signaling pathway-related genes. (C) Leptin signaling-pathway related genes. (D) Browning pathway-related genes. Red indicates the positive and blue indicates the negative correlations with the fasting insulin levels (p < 0.05). The color intensity is related to the absolute values of the correlation coefficients. Gray indicates no significance. A total of 24 pooled samples were used in the analysis across 24 diets, and each sample was pooled from 6 mice. See also Table S1.
Figure 2
Figure 2
Diagram showing the correlation of the gene expression against the fasting insulin levels in the subcutaneous white adipose tissue of the C57BL/6 mice. (A) Lipolysis pathway-related genes. (B) Insulin signaling pathway-related genes. (C) Leptin signaling-pathway related genes. (D) Browning pathway-related genes. Red indicates the positive and blue indicates the negative correlations with the fasting insulin levels (p < 0.05). The color intensity is related to the absolute values of the correlation coefficients. Gray indicates no significance. A total of 24 pooled samples were used in the analysis across 24 diets, and each sample was pooled from 6 mice. See also Table S1.
Figure 2
Figure 2
Diagram showing the correlation of the gene expression against the fasting insulin levels in the subcutaneous white adipose tissue of the C57BL/6 mice. (A) Lipolysis pathway-related genes. (B) Insulin signaling pathway-related genes. (C) Leptin signaling-pathway related genes. (D) Browning pathway-related genes. Red indicates the positive and blue indicates the negative correlations with the fasting insulin levels (p < 0.05). The color intensity is related to the absolute values of the correlation coefficients. Gray indicates no significance. A total of 24 pooled samples were used in the analysis across 24 diets, and each sample was pooled from 6 mice. See also Table S1.
Figure 2
Figure 2
Diagram showing the correlation of the gene expression against the fasting insulin levels in the subcutaneous white adipose tissue of the C57BL/6 mice. (A) Lipolysis pathway-related genes. (B) Insulin signaling pathway-related genes. (C) Leptin signaling-pathway related genes. (D) Browning pathway-related genes. Red indicates the positive and blue indicates the negative correlations with the fasting insulin levels (p < 0.05). The color intensity is related to the absolute values of the correlation coefficients. Gray indicates no significance. A total of 24 pooled samples were used in the analysis across 24 diets, and each sample was pooled from 6 mice. See also Table S1.
Figure 3
Figure 3
The respiratory exchange ratio (RER) of the mice following 10 weeks on experimental diets. The values were the measured values of each individual. The RER of the mice (A) when the dietary fat was fixed and (B) when the dietary protein was fixed. The discrepancy of the RER and FQ (C) when the dietary fat was fixed and (D) when the dietary protein was fixed. A total of 120 mice were used, with 4–7 mice per diet.
Figure 4
Figure 4
The energy/food intake of the mice following exposure to experimental diets. All of the values are presented as mean ± SD. (A) The energy/food intake of the mice fed diets with variable carbohydrate and fixed 60% fat. (B) The energy/food intake of the mice fed diets with variable carbohydrate and fixed 20% fat. (C) The energy/food intake of the mice fed diets with variable carbohydrate and fixed 10% protein. (D) The energy/food intake of the mice fed diets with variable carbohydrate and fixed 25% protein. a, b, c, and d represent p < 0.05. Groups with at least one same letter were not significantly different.
Figure 5
Figure 5
The energy expenditure of the mice following exposure to experimental diets. All of the values are presented as mean ± SD. The daily energy expenditure (DEE) of the mice fed diets with (A) fixed 60% or 20% fat and (B) fixed 10% or 25% protein. The REE of the mice fed diets with (C) fixed 60% or 20% fat and (D) fixed 10% or 25% protein. The physical activity of the mice fed diets with (E) fixed 60% or 20% fat and (F) fixed 10% or 25% protein. A total of 120 mice were used, with 4–7 mice per diet. The estimated energy expenditure of the mice fed diets with (G) fixed 60% or 20% fat and (H) fixed 10% or 25% protein throughout the experimental period. A total of 480 mice were used, with 20 mice per diet. a, b, c, and d represent p < 0.05. Groups with at least one same letter were not significantly different.
Figure 6
Figure 6
Hunger pathway diagram showing the correlation of the gene expression against the fasting insulin levels in the hypothalamus of the C57BL/6 mice. Red indicates the positive and blue indicates the negative correlations with the fasting insulin levels (p < 0.05). The color intensity is related to the absolute values of the correlation coefficients. Gray indicates no significance. A total of 48 pooled samples were used in the analysis across 24 diets, and each sample was pooled from 4 mice. See also Table S2.
Figure 7
Figure 7
The body weight, fat, and lean mass of the mice fed experimental diets. All of the values are presented as mean ± SD. (A) Fixed 60% fat. (B) Fixed 20% fat. (C) Fixed 10% protein. (D) Fixed 25% protein. A total of 480 mice were used, with 20 mice per diet. a, b, c, and d represent p < 0.05. Groups with at least one same letter were not significant.
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