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Randomized Controlled Trial
. 2014 Aug;60(2):545-53.
doi: 10.1002/hep.27149. Epub 2014 May 13.

Hypercaloric Diets With Increased Meal Frequency, but Not Meal Size, Increase Intrahepatic Triglycerides: A Randomized Controlled Trial

Free PMC article
Randomized Controlled Trial

Hypercaloric Diets With Increased Meal Frequency, but Not Meal Size, Increase Intrahepatic Triglycerides: A Randomized Controlled Trial

Karin E Koopman et al. Hepatology. .
Free PMC article


American children consume up to 27% of calories from high-fat and high-sugar snacks. Both sugar and fat consumption have been implicated as a cause of hepatic steatosis and obesity but the effect of meal pattern is largely understudied. We hypothesized that a high meal frequency, compared to consuming large meals, is detrimental in the accumulation of intrahepatic and abdominal fat. To test this hypothesis, we randomized 36 lean, healthy men to a 40% hypercaloric diet for 6 weeks or a eucaloric control diet and measured intrahepatic triglyceride content (IHTG) using proton magnetic resonance spectroscopy ((1) H-MRS), abdominal fat using magnetic resonance imaging (MRI), and insulin sensitivity using a hyperinsulinemic euglycemic clamp with a glucose isotope tracer before and after the diet intervention. The caloric surplus consisted of fat and sugar (high-fat-high-sugar; HFHS) or sugar only (high-sugar; HS) and was consumed together with, or between, the three main meals, thereby increasing meal size or meal frequency. All hypercaloric diets similarly increased body mass index (BMI). Increasing meal frequency significantly increased IHTG (HFHS mean relative increase of 45%; P = 0.016 and HS mean relative increase of 110%; P = 0.047), whereas increasing meal size did not (2-way analysis of variance [ANOVA] size versus frequency P = 0.03). Abdominal fat increased in the HFHS-frequency group (+63.3 ± 42.8 mL; P = 0.004) and tended to increase in the HS-frequency group (+46.5 ± 50.7 mL; P = 0.08). Hepatic insulin sensitivity tended to decrease in the HFHS-frequency group while peripheral insulin sensitivity was not affected.

Conclusion: A hypercaloric diet with high meal frequency increased IHTG and abdominal fat independent of caloric content and body weight gain, whereas increasing meal size did not. This study suggests that snacking, a common feature in the Western diet, independently contributes to hepatic steatosis and obesity. (

Trial registration:; nr.NCT01297738.)


Figure 1
Figure 1
Study design.
Figure 2
Figure 2
(A) Ad libitum caloric intake and surplus caloric intake during the diet interventions. Data are presented as mean and SEM, average of the 6-week diet period. (a) ANOVA of total caloric intake: P = 0.11, F = 2.24. (B) Baseline BMI and BMI gain after the hypercaloric diets. Data are presented as mean and SEM group averages. (b) ANOVA BMI gain: P = 0.42, F = 0.97; (c) ANOVA BMI after the diet: P = 0.81, F = 0.32.
Figure 3
Figure 3
Change in IHTG (%) by the different hypercaloric interventions *P < 0.05. Data are presented as mean and SEM.

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