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. 2023 Nov 10;22(1):191.
doi: 10.1186/s12944-023-01956-3.

Opposite effects of low-carbohydrate high-fat diet on metabolism in humans and mice

Lingli Cai #  1 , Xinyi Xia #  1 , Yunjie Gu #  1 , Lili Hu  1 , Cheng Li  1 , Xiaojing Ma  2 , Jun Yin  3   4
Affiliations

Opposite effects of low-carbohydrate high-fat diet on metabolism in humans and mice

Lingli Cai et al. Lipids Health Dis. .

Abstract

Background: Low-carbohydrate diet (LCD) is effective for weight loss and glycaemic control in humans. Here, the study aimed to explore the effects of LCD/high-fat diet (HFD) in both humans and mice.

Methods: Twenty-two overweight or obese participants received LCD for 3 weeks. Based on carbohydrate intake > 10% or ≤ 10% of calories, the participants were divided into moderate LCD (MLCD) and very LCD (VLCD) groups. The participants completed a 10-question food preference survey. Meanwhile, C57BL/6J mice were assigned to five groups: chow diet (CD, 10% fat), HFD with 60%, 70%, and 75% fat from cocoa butter (HFD-C), and HFD with 60% fat from lard (HFD-L) and fed for 24 weeks. Eight mice were acclimatised for the food-choice test.

Results: LCD decreased the total energy intake in humans. The VLCD group showed greater weight loss and better glycaemic control than the MLCD group. A food preference survey showed that 65% of participants tended to choose high-carbohydrate foods. In mice, HFD resulted in energy overconsumption, obesity, and metabolic disorders. When CD and HFD-L were administered simultaneously, mice rarely consumed CD. In the HFD-C groups, the energy intake and body weight increased with increasing dietary fat content. Compared with the HFD-C group, the HFD-L group consumed more energy and had poorer metabolism.

Conclusions: Lower carbohydrate intake contributed to lower energy intake and improved metabolism in humans. In mice, diets with a higher proportion of fat become more attractive and obesogenic by fixing the fat sources. Since the mice preferred lard to cocoa butter, lard induced excess energy intake and poorer metabolism. Different food preferences may be the underlying mechanism behind the opposite effects of the LCD/HFD in humans and mice.

Trial registration: The clinical trial was registered with the Chinese Clinical Trial Registry ( www.chictr.org.cn ). The registration number is ChiCTR1800016786. All participants provided written informed consent prior to enrolment.

Keywords: Appetite; Energy intake; Food preference; High-fat diet; Homeostatic mechanism; Ketogenic diet.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Body weight and blood glucose response to LCD in human study. (A) Body weight trend during the intervention. (B) Changes in body weight. Curves of (C) MSG, (D) SDSG, (E) CV, and (F) LAGE Notes: Data are expressed as mean ± SD (n = 9 for the MLCD group and n = 13 for the VLCD group). Independent-samples t test was used. * P < 0.05; ** P < 0.01; *** P < 0.001 Abbreviations: MLCD: moderately low-carbohydrate diet; VLCD: very low-carbohydrate diet; Before: 3 days before the intervention; During: during the intervention (21 days); After: 3 days after the intervention; MSG: mean sensor glucose; SDSG: standard deviations of sensor glucose; CV: coefficient of variation; LAGE: largest amplitude of glycemic excursion
Fig. 2
Fig. 2
Macronutrient compositions of diets and surveyed food preferences in subjects. (A) Macronutrient compositions of diets. (B) Total energy intake. (C) Total scores of the subjects Notes: Data are expressed as mean ± SD and the macronutrient content is expressed as a percentage of total energy intake (n = 9 for the MLCD group and n = 13 for the VLCD group). Independent-samples t test and paired t test were used. * P < 0.05; ** P < 0.01; *** P < 0.001. Figure 2C: Dots on the left side of the vertical axis indicate preference for high-fat foods. Dots on the right side of the vertical axis indicate preference for high-carbohydrate foods. Dots on the vertical axis indicate no preference for either Abbreviations: MLCD: moderately low-carbohydrate diet; VLCD: very low-carbohydrate diet; Before: 3 days before the intervention; During: during the intervention (21 days)
Fig. 3
Fig. 3
Effects of different diets on body weight and glucolipid metabolism in mice. Panels A-M respectively show values of body weight, liver weight, blood glucose, insulin, HOMA-IR, blood β-HB, fasting serum TC, LDL, HDL, TG, serum FFA, fasting serum ALT, and Oil red O staining of liver tissue Notes: Data are expressed as mean ± SD (n = 10 for A & C-F and n = 5 for B & G-L). Analysis of Variance and independent-samples t test were used. If the letters on the top of bars are different it means there is statistical difference between the two groups (P < 0.05); NS, no statistical difference Abbreviations: CD: chow diet; 60%HFD-C: HFD with 60% fat mainly from cocoa butter; 70%HFD-C: HFD with 70% fat mainly from cocoa butter; 75%HFD-C: HFD with 75% fat mainly from cocoa butter. 60%HFD-L: HFD with 60% fat mainly from lard; HOMA-IR: homeostatic model assessment for insulin resistance; TC: total cholesterol; LDL: low-density lipoprotein; HDL: high-density lipo-protein; TG: triglyceride; FFA: free fatty acid; β-HB: β-hydroxybutyric acid; ALT: Serum alanine transaminase
Fig. 4
Fig. 4
Tolerance tests in mice fed with different diets. Curves and AUCs for (A) IPGTT, (B) ITT, and (C) PTT Notes: Data are expressed as mean ± SD (n = 10). Analysis of Variance and independent-samples t test were used. If the letters on the top of or beside bars are different it means there is statistical difference between the two groups (P < 0.05) Abbreviations: CD: chow diet; 60%HFD-C: HFD with 60% fat mainly from cocoa butter; 70%HFD-C: HFD with 70% fat mainly from cocoa butter; 75%HFD-C: HFD with 75% fat mainly from cocoa butter. 60%HFD-L: HFD with 60% fat mainly from lard; AUC: area under the curve; IPGTT: intraperitoneal glucose tolerance test; ITT: insulin tolerance test; PTT: pyruvate tolerance test
Fig. 5
Fig. 5
Food intake, energy intake, and mRNA levels of hypothalamic hormones in mice. (A) Food intake. (B) Energy intake. (C) Food intake of mice provided with CD and HFD-L simultaneously. (D) The mRNA levels of Agrp, Npy, Pomc, and Cartpt in hypothalamus Notes: Data are expressed as mean ± SD (n = 10 for A& B, n = 8 for C and n = 5 for D). Analysis of Variance and independent-samples t test were used. If the letters on the top of bars are different mean there are statistical difference between the two groups (P < 0.05). * P < 0.05; ** P < 0.01; *** P < 0.001
Fig. 6
Fig. 6
Hepatic glycogen in mice. (A) PAS staining in liver tissue. (B) Glycogen level in liver tissue Notes: Data are expressed as mean ± SD (n = 5). Paired t test was used. * P < 0.05
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